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InternalMed_Harrison. Apoptosis Apoptosis is a form of programmed cell death that is a normal mechanism for the elimination of effete cells in organogenesis as well as in the cellular proliferation that occurs during a normal immune response (Chap. 372e). Apoptosis is largely dependent on cellular activation, and the aberrant cellular activation associated with HIV disease is correlated with a heightened state of apoptosis. HIV can trigger both Fas-dependent and Fas-independent pathways of apoptosis, the former of which is generally referred to as activation-induced cell death through an extrinsic pathway and involves the upregulation of the death receptor Fas and Fas ligand. Fas-independent pathways can be either extrinsic with different death receptors or intrinsic due to the downregulation of the antiapoptotic proteins such as Bcl-2. More recently, the phenomenon of pyroptosis, an inflammatory form of cell death involving the upregulation of the proinflammatory enzyme caspase-1 and release of the


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InternalMed_Harrison. proteins such as Bcl-2. More recently, the phenomenon of pyroptosis, an inflammatory form of cell death involving the upregulation of the proinflammatory enzyme caspase-1 and release of the proinflammatory cytokine IL-1 β, has been linked to a bystander effect of HIV replication on CD4+ T cells. Certain viral gene products have been associated with enhanced susceptibility to apoptosis; these include Env, Tat, and Vpr. In contrast, Nef has been shown to possess antiapoptotic properties. A number of studies, including those examining lymphoid tissue, have demonstrated that the rate of apoptosis is elevated in HIV infection and that apoptosis is seen in “bystander” cells such as CD8+ T cells and B cells as well as in uninfected CD4+ T cells. The intensity of apoptosis correlates with the general state of activation of the immune system and not with the stage of disease or with viral burden. It is likely that nonspecific apoptosis of immunocompetent cells related to immune activation


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InternalMed_Harrison. general state of activation of the immune system and not with the stage of disease or with viral burden. It is likely that nonspecific apoptosis of immunocompetent cells related to immune activation contributes to the immune abnormalities in HIV disease.


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InternalMed_Harrison. Autoimmune Phenomena The autoimmune phenomena that are common in HIV-infected individuals reflect, at least in part, chronic immune activation and the dysregulation of B and T cells. Although these phenomena usually occur in the absence of autoimmune disease, a wide spectrum of clinical manifestations that may be associated with autoimmunity have been described (see “Immunologic and Rheumatologic Diseases,” below). Autoimmune phenomena include antibodies against autoantigens expressed on intact lymphocytes and other cells, or against proteins released from dying cells. Antiplatelet antibodies have some clinical relevance in that they may contribute to the thrombocytopenia of HIV disease (see below). Antibodies to nuclear and cytoplasmic components of cells have been reported, as have antibodies to cardiolipin and phospholipids; CD4 molecules; CD43 molecules; C1q-A; variable regions of the T cell receptor α, β, and γ chains; Fas; denatured collagen; and IL-2. In addition,


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InternalMed_Harrison. as have antibodies to cardiolipin and phospholipids; CD4 molecules; CD43 molecules; C1q-A; variable regions of the T cell receptor α, β, and γ chains; Fas; denatured collagen; and IL-2. In addition, autoantibodies to a range of serum proteins, including albumin, immunoglobulin, and thyroglobulin, have been reported. Molecular mimicry, either from opportunistic pathogens or from HIV itself, is also a trigger or co-factor in autoimmunity. Antibodies against the HIV envelope proteins, especially gp41, often cross-react with host proteins; the best known examples are antibodies directed against the membrane-proximal external region of gp41 that also react with phospholipids and cardiolipin. The phenomenon of polyreactive HIV-specific antibodies may be beneficial to the host (see “Immune Response to HIV,” below).


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InternalMed_Harrison. The increased occurrence and/or exacerbation of certain autoimmune diseases have been reported in HIV infection; these diseases include psoriasis, idiopathic thrombocytopenic purpura, Graves’ disease, antiphospholipid syndrome, and primary biliary cirrhosis. The majority of these manifestations were described prior to the advent of cART and have decreased in frequency since its widespread use. However, with increasing availability of cART, an immune reconstitution inflammatory syndrome (IRIS) has become increasingly common in infected individuals, particularly those with low CD4+ T cell counts. IRIS is an autoimmune-like phenomenon characterized by a paradoxical deterioration of clinical condition, which is usually compartmentalized to a particular organ system, in individuals in whom cART has recently been initiated. It is associated with a decrease in viral load and at least partial recovery of immune competence, which is usually associated with increases in CD4+ T cell counts. The


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InternalMed_Harrison. has recently been initiated. It is associated with a decrease in viral load and at least partial recovery of immune competence, which is usually associated with increases in CD4+ T cell counts. The immunopathogenesis is felt to be related to an increase in immune response against the presence of residual antigens that are usually microbial and is commonly seen with underlying Mycobacterium tuberculosis and cryptococcosis. This syndrome is discussed in more detail below.


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InternalMed_Harrison. The immune system is homeostatically regulated by a complex network of immunoregulatory cytokines, which are pleiotropic and redundant and operate in an autocrine and paracrine manner. They are expressed continuously, even during periods of apparent quiescence of the immune system. On perturbation of the immune system by antigenic challenge, the expression of cytokines increases to varying degrees (Chap. 372e). Cytokines that are important components of this immunoregulatory network are thought to play major roles in HIV disease, during both the early and chronic phases of infection. A potent pro-inflammatory “cytokine storm” is induced during the acute phase of HIV infection, likely a response by inflammatory cells recruited to mucosal tissues where the virus initially replicates at very high levels. Cytokines that are induced during this early phase include IFN-α, IL-15, and the CXC chemokine IP-10 (CXCL10), followed by IL-6, IL-12, and TNF-α, and a delayed peak of the


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InternalMed_Harrison. at very high levels. Cytokines that are induced during this early phase include IFN-α, IL-15, and the CXC chemokine IP-10 (CXCL10), followed by IL-6, IL-12, and TNF-α, and a delayed peak of the anti-inflammatory cytokine IL-10. Soluble factors of innate immunity are also induced shortly after infection, including neopterin and β-microglobulin. Several of these early-expressed cytokines and factors are not down-regulated following the early phase of HIV infection, as seen in self-resolving viral infections, and persist during the chronic phase of infection and contribute to maintaining high levels of immune activation. Among the cytokines and factors associated with early innate immune responses, they are intended to contain viral replication, although most are potent inducers of HIV expression/replication because of their ability to induce immune activation that leads to enhanced viral production and an increase in readily available target cells for HIV (activated CD4+ T cells). The


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InternalMed_Harrison. because of their ability to induce immune activation that leads to enhanced viral production and an increase in readily available target cells for HIV (activated CD4+ T cells). The induction of IFN-α, one of the first cytokines induced during primary HIV infection, is thought to play a particularly important role in HIV pathogenesis by inducing a large number of IFN-associated genes that activate the immune system and alter the homeostasis of CD4+ T cells. Other cytokines that are elevated during the chronic phase of HIV infection and linked to immune activation include IFN-γ, the CC-chemokine RANTES (CCL5), macrophage inflammatory protein (MIP)-1β (CCL4), and IL-18.


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InternalMed_Harrison. Several specific cytokines and soluble factors have been associated with HIV pathogenesis at various stages of disease, in various tissues or organs, and in the regulation of HIV replication. Plasma levels of IP-10 are predictive of disease progression, whereas the proinflammatory cytokine IL-6, soluble CD14 (sCD14), and coagulation marker d-dimer are associated with increased risk of all-cause mortality in HIV-infected individuals. In particular, IL-6, sCD14, and d-dimer are associated with increased risk of cardiovascular disease and other causes of death, even in individuals receiving cART. IL-18 has also been shown to play a role in the development of the HIV-associated lipodystrophy syndrome, whereas increased levels of transforming growth factor (TGF)-β are associated with the induction of collagen deposition in lymph nodes (see above). Elevated levels of TNF-α and IL-6 have been demonstrated in plasma and cerebrospinal fluid (CSF), and increased expression of TNF-α, IL-1β,


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InternalMed_Harrison. of collagen deposition in lymph nodes (see above). Elevated levels of TNF-α and IL-6 have been demonstrated in plasma and cerebrospinal fluid (CSF), and increased expression of TNF-α, IL-1β, IFN-γ, and IL-6 has been demonstrated in the lymph nodes of HIV-infected individuals. RANTES, MIP-1α (CCL3), and MIP-1β (CCL4) (Chap. 372e) inhibit infection by and spread of R5 HIV-1 strains, while stromal cell–derived factor (SDF) 1 inhibits infection by and spread of X4 strains. The mechanisms whereby the CC-chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4) inhibit infection of R5 strains of HIV, or SDF-1 blocks X4 strains of HIV, involve blocking of the binding of the virus to its co-receptors, the CC-chemokine receptor CCR5 and the CXC-chemokine receptor CXCR4, respectively. Other soluble factors that have not yet been fully characterized have also been shown to suppress HIV replication, independent of co-receptor usage.


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InternalMed_Harrison. The immune systems of patients with HIV infection are characterized by a profound increase in lymphocyte turnover that is immediately reduced with effective cART. Studies utilizing in vivo or in vitro labeling of lymphocytes in the S-phase of the cell cycle have demonstrated a tight correlation between the degree of lymphocyte turnover and plasma levels of HIV RNA. This increase in turnover is seen in CD4+ and CD8+ T lymphocytes as well as B lymphocytes and can be observed in peripheral blood and lymphoid tissue. Mathematical models derived from these data suggest that one can view the lymphoid pool as consisting of dynamically distinct subpopulations of cells that are differentially affected by HIV infection. A major consequence of HIV infection appears to be a shift in cells from a more quiescent pool to a pool with a higher turnover rate. It is likely that a consequence of a higher rate of turnover is a higher rate of cell death. The role of the thymus in adult human T cell


InternalMed_Harrison

InternalMed_Harrison. a more quiescent pool to a pool with a higher turnover rate. It is likely that a consequence of a higher rate of turnover is a higher rate of cell death. The role of the thymus in adult human T cell homeostasis and HIV pathogenesis is an area of controversy. While some data point to an important role for the thymus in maintaining T cell numbers and suggest that impairment of thymic function may be responsible for the declines in CD4+ T cells seen in the setting of HIV infection, other studies have concluded that the thymus plays a minor role in HIV pathogenesis. More recently, it has been suggested that the more rapid decline in CD4+ compared to CD8+ T cells may be linked to alterations in inflammatory and homeostatic cytokines that caused increased activation-induced death of CD4+ but not CD8+ T cells (see Table 226-5 for additional mechanisms of depletion).


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InternalMed_Harrison. As mentioned above, HIV-1 utilizes two major co-receptors along with CD4 to bind to, fuse with, and enter target cells; these co-receptors are CCR5 and CXCR4, which are also receptors for certain endogenous Loss of plasma membrane integrity Aberrant intracellular signaling due to viral budding events Accumulation of unintegrated viral Autoimmunity DNA Activation of DNA-dependent protein kinase during viral integration into host genome Interference with cellular RNA Innocent bystander killing of viral processing antigen–coated cells Intracellular gp120-CD4 autofusion Apoptosis, pyroptosis (caspase-1 events associated inflammation), autophagy Syncytia formation Inhibition of lymphopoiesis from


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InternalMed_Harrison. Intracellular gp120-CD4 autofusion Apoptosis, pyroptosis (caspase-1 events associated inflammation), autophagy Syncytia formation Inhibition of lymphopoiesis from Elimination of HIV-infected cells by virus-specific immune responses chemokines. Strains of HIV that utilize CCR5 as a co-receptor are referred to as R5 viruses. Strains of HIV that utilize CXCR4 are referred to as X4 viruses. Many virus strains are dual tropic in that they utilize both CCR5 and CXCR4; these are referred to as R5X4 viruses. The natural chemokine ligands for the major HIV co-receptors can readily block entry of HIV. For example, the CC-chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4), which are the natural ligands for CCR5, block entry of R5 viruses, whereas SDF-1, the natural ligand for CXCR4, blocks entry of X4 viruses. The mechanism of inhibition of viral entry is a steric inhibition of binding that is not dependent on signal transduction (Fig. 226-25).


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InternalMed_Harrison. The transmitting virus is almost invariably an R5 virus that predominates during the early stages of HIV disease. In ~40% of HIV-infected individuals, there is a transition to a predominantly X4 virus that is associated with a relatively rapid progression of disease. However, at least 60% of infected individuals progress in their disease while maintaining predominance of an R5 virus. It should be pointed out that clade C viruses, unlike other subgroups, almost never switch from CCR5 tropism to CXCR4 tropism; the reason for this difference is unclear.


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InternalMed_Harrison. The basis for the tropism of different envelope glycoproteins for either CCR5 or CXCR4 relates to the ability of the HIV envelope, including the third variable region (V3 loop) of gp120, to interact with these co-receptors. In this regard, binding of gp120 to CD4 induces a conformational change in gp120 that increases its affinity for CCR5 (see above). Finally, R5 viruses are more efficient in infecting monocytes/macrophages and microglial cells of the brain (see “Neuropathogenesis in HIV Disease,” below).


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InternalMed_Harrison. tHe integrin α4β7 and mUcosal transmission of Hiv Several “accessory receptors” for HIV have been reported over the years, although only a few have withstood the test of time. These receptors are not necessary for virus binding and fusion to its target CD4+ T cell or for virus replication. However, the integrin α4β7 is an accessory receptor for HIV and it likely plays an important role in the transmission of HIV at mucosal surfaces such as the genital tract and gut. The integrin α4β7, which is the gut homing receptor for peripheral T cells, binds in its activated form to a specific tripeptide in the V2 loop of gp120, resulting in rapid activation of leukocyte function–associated antigen 1 (LFA-1), the central integrin in the establishment of virologic synapses, which facilitate efficient cell-to-cell spread of HIV. It has been demonstrated that α4β7high CD4+ T cells are more susceptible to productive infection than are α4β7low–neg CD4+ T cells because this cellular subset is enriched


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InternalMed_Harrison. cell-to-cell spread of HIV. It has been demonstrated that α4β7high CD4+ T cells are more susceptible to productive infection than are α4β7low–neg CD4+ T cells because this cellular subset is enriched with metabolically active CD4+ T cells that are CCR5high. These cells are present at the gut and genital tract mucosal surfaces. Importantly, it has been demonstrated that the virus that is transmitted during sexual exposure binds much more efficiently to α4β7 than does the virus that diversifies from the transmitting virus over time by mutation,


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders CC-Chemokine (RANTES, MIP-1˜, MIP-1°) ENV CD4 CXCR4 SDF-1 ENV CD4 CCR5 HIV HIV CD4+ Target Cell HIV HIV CD4+ Target Cell ABFIGuRE 226-25 Model for the role of co-receptors CXCR4 and CCR5 in the efficient binding and entry of X4 (A) and R5 (B) strains of HIV-1, respectively, into CD4+ target cells. Blocking of this initial event in the virus life cycle can be accomplished by inhibition of binding to the co-receptor by the normal ligand for the receptor in question. The ligand for CXCR4 is stromal cell–derived factor (SDF-1); the ligands for CCR5 are RANTES, MIP-1α, and MIP-1β. particularly involving the accumulation of glycosylation sites (see “Early Events in HIV Infection: Primary Infection and Initial Dissemination of Virus,” above).


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InternalMed_Harrison. particularly involving the accumulation of glycosylation sites (see “Early Events in HIV Infection: Primary Infection and Initial Dissemination of Virus,” above). Although the CD4+ T lymphocytes and to a lesser extent CD4+ cells of monocyte lineage are the principal targets of HIV, virtually any cell that expresses the CD4 molecule together with co-receptor molecules (see above and below) can potentially be infected with HIV. Circulating DCs have been reported to express low levels of CD4, and, depending on their stage of maturation, these cells can be infected with HIV. Epidermal Langerhans cells express CD4 and have been infected by HIV in vivo, although, as has been shown in vivo for DCs, FDCs, and B cells, these cells are more likely to bind and transfer virus to activated CD4+ T cells than to be productively infected themselves.


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InternalMed_Harrison. In vitro, HIV has been reported also to infect a wide range of cells and cell lines that express low levels of CD4, no detectable CD4, or only CD4 mRNA. However, since the only cells that have been shown unequivocally to be infected with HIV and to support replication of the virus are CD4+ T lymphocytes and cells of monocyte/macrophage lineage, the physiologic relevance of the in vitro infection of these other cell types is unclear.


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InternalMed_Harrison. Of potentially important clinical relevance is the demonstration that thymic precursor cells, which were assumed to be negative for CD3, CD4, and CD8 molecules, actually do express low levels of CD4 and can be infected with HIV in vitro. In addition, human thymic epithelial cells transplanted into an immunodeficient mouse can be infected with HIV by direct inoculation of virus into the thymus. Since these cells may play a role in the normal regeneration of CD4+ T cells, it is possible that their infection and depletion contribute, at least in part, to the impaired ability of the CD4+ T cell pool to completely reconstitute itself in certain infected individuals in whom cART has suppressed viral replication to <50 copies of HIV RNA per milliliter (see below). In addition, CD34+ monocyte precursor cells have been shown to be infected in vivo in patients with advanced HIV disease. It is likely that these cells express low levels of CD4, and therefore it is not essential to invoke


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InternalMed_Harrison. precursor cells have been shown to be infected in vivo in patients with advanced HIV disease. It is likely that these cells express low levels of CD4, and therefore it is not essential to invoke CD4-independent mechanisms to explain the infection.


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InternalMed_Harrison. ABNORMALITIES OF MONONuCLEAR CELLS CD4+ T Cells The primary immunopathogenic lesion in HIV infection involves CD4+ T cells, and the range of CD4+ T cell abnormalities in advanced HIV infection is broad. The defects are both quantitative and qualitative and ultimately impact virtually every limb of the immune system, indicating the critical dependence of the integrity of the immune system on the inducer/helper function of CD4+ T cells. In advanced HIV disease, most of the observed immune defects can ultimately be explained by the quantitative depletion of CD4+ T cells. However, T cell dysfunction can be demonstrated in patients early in the course of infection, even when the CD4+ T cell count is in the low-normal range. The degree and spectrum of dysfunctions increase as the disease progresses, reflecting the range of CD4+ T cell functional heterogeneity, especially in lymphoid tissues. One of the first sites of intense HIV replication is in the GALT where CD4+ TH17 cells reside; they


InternalMed_Harrison

InternalMed_Harrison. reflecting the range of CD4+ T cell functional heterogeneity, especially in lymphoid tissues. One of the first sites of intense HIV replication is in the GALT where CD4+ TH17 cells reside; they are important for host defense against extracellular pathogens in the intestinal mucosa and help maintain the integrity of the gut epithelium. In HIV infection, they are depleted by direct and indirect effects of viral replication and cause loss of gut homeostasis and integrity, as well as a shift to a more TH1 phenotype. Studies have shown that even after many years of cART, normalization of the CD4+ T cells in the GALT remains incomplete. In lymph nodes, HIV perturbs another important subset of the CD4+ helper T lineage, namely TFH cells (see “Lymphoid Organs and HIV Pathogenesis,” above). TFH cells, which are either derived directly from naïve CD4+ T cells or other TH precursors, migrate into B follicles during germinal center reactions and provide help to antigen-specific B cells through


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InternalMed_Harrison. cells, which are either derived directly from naïve CD4+ T cells or other TH precursors, migrate into B follicles during germinal center reactions and provide help to antigen-specific B cells through cell–cell interactions and secretion of cytokines to which B cells respond, the most important of which is IL-21. As with TH17 cells, TFH cells are highly susceptible to HIV infection. However, in contrast to TH17 and most other CD4+ T cell subsets, the number of TFH cells is increased in lymph nodes of HIV-infected individuals, especially those who are viremic. It is unclear whether this increase is helpful to responding B cells, although the likely outcome is that the increase in numbers is detrimental to the quality of the humoral immune response against HIV (see “Immune Response to HIV,” below). In addition, defects of central memory cells are a critical component of HIV immunopathogenesis. The progressive loss of antigen-specific CD4+ T cells has important implications for the


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InternalMed_Harrison. HIV,” below). In addition, defects of central memory cells are a critical component of HIV immunopathogenesis. The progressive loss of antigen-specific CD4+ T cells has important implications for the control of HIV infection. In this regard, there is a correlation between the maintenance of HIV-specific CD4+ T cell proliferative responses and improved control of infection. Essentially every T cell function has been reported to be abnormal at some stage of HIV infection. Loss of polyfunctional HIV-specific CD4+ T cells, especially those that produce IL-2, occurs early in disease, whereas IFN-producing CD4+ T cells are maintained longer and do not correlate with control of HIV viremia. Other abnormalities include impaired expression of IL-2 receptors, defective IL-2 production, reduced expression of the IL-7 receptor (CD127), and a decreased proportion of CD4+ T cells that express CD28, a major co-stimulatory molecule necessary for the normal activation of T cells, which is also


InternalMed_Harrison

InternalMed_Harrison. expression of the IL-7 receptor (CD127), and a decreased proportion of CD4+ T cells that express CD28, a major co-stimulatory molecule necessary for the normal activation of T cells, which is also depleted as a result of aging. Cells lacking expression of CD28 do not respond normally to activation signals and may express markers of terminal activation including HLA-DR, CD38, and CD45RO. As mentioned above (“Immune Activation, Inflammation, and HIV Pathogenesis”), a subset of CD4+ T cells referred to as T regulatory cells, or T-regs, may be involved in damping aberrant immune activation that propagates HIV replication. The presence of these T-reg cells correlates with lower viral loads and higher CD4+/CD8+ T cell ratios. A loss of this T-reg capability with advanced disease may be detrimental to the control of virus replication.


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InternalMed_Harrison. It is difficult to explain completely the profound immunodeficiency noted in HIV-infected individuals solely on the basis of direct infection and quantitative depletion of CD4+ T cells. This is particularly apparent during the early stages of HIV disease, when CD4+ T cell numbers may be only marginally decreased. In this regard, it is likely that CD4+ T cell dysfunction results from a combination of depletion of cells due to direct infection of the cell and a number of virus-related but indirect effects on the cell (Table 226-5). Several of these effects have been demonstrated ex vivo and/or by the analysis of cells isolated from the peripheral blood. However, as explained above, many of the defects are related to specialized CD4+ T cells that reside in lymphoid tissues. Furthermore, since the main targets of HIV infection are immunocompetent cells, these responses may contribute to immune cell depletion and immunologic dysfunction by eliminating both infected cells and “innocent


InternalMed_Harrison

InternalMed_Harrison. since the main targets of HIV infection are immunocompetent cells, these responses may contribute to immune cell depletion and immunologic dysfunction by eliminating both infected cells and “innocent bystander” cells. Soluble viral proteins, particularly gp120, can bind with high affinity to the CD4 molecules on uninfected T cells and monocytes; in addition, virus and/ or viral proteins can bind to DCs or FDCs. HIV-specific antibody can recognize these bound molecules and potentially collaborate in the elimination of the cells by ADCC. HIV envelope glycoproteins gp120 and gp160 manifest high-affinity binding to the CD4 molecule as well as to various chemokine receptors. Intracellular signals transduced by gp120 through both CD4 and CCR5/CXCR4 have been associated with a number of immunopathogenic processes including anergy, apoptosis, and abnormalities of cell trafficking. The molecular mechanisms responsible for these abnormalities include dysregulation of the T cell


InternalMed_Harrison

InternalMed_Harrison. of immunopathogenic processes including anergy, apoptosis, and abnormalities of cell trafficking. The molecular mechanisms responsible for these abnormalities include dysregulation of the T cell receptor–phosphoinositide pathway, p56lck activation, phosphorylation of focal adhesion kinase, activation of the MAP kinase and ras signaling pathways, and downregulation of the co-stimulatory molecules CD40 ligand and CD80.


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InternalMed_Harrison. The inexorable decline in CD4+ T cell counts that occurs in most HIV-infected individuals may result in part from the inability of the immune system to regenerate over an extended period of time the rapidly turning over CD4+ T cell pool efficiently enough to compensate for both HIV-mediated and naturally occurring attrition of cells. In this regard, the degree and duration of decline of CD4+ T cells at the time of initiation of therapy is an important predictor of the restoration of these cells. A person who maintains a very low CD4+ T cell count for a considerable period of time before the initiation of cART almost invariably has an incomplete reconstitution of such cells. At least two major mechanisms may contribute to the failure of the CD4+ T cell pool to reconstitute itself adequately over the course of HIV infection. The first is the destruction of lymphoid precursor cells, including thymic and bone marrow progenitor cells; the other is the gradual disruption of the lymphoid


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InternalMed_Harrison. over the course of HIV infection. The first is the destruction of lymphoid precursor cells, including thymic and bone marrow progenitor cells; the other is the gradual disruption of the lymphoid tissue microenvironment, which is essential for efficient regeneration of immunocompetent cells. Finally, during the advanced stages of CD4+ T lymphopenia, there are increased serum levels of the homeostatic cytokine IL-7. It was initially felt that this elevation was a homeostatic response to the lymphopenia; however, recent findings suggest that the increase in serum IL-7 was a result of reduced utilization of the cytokine related to the loss of cells expressing the IL-7 receptor, CD127, which serves as a normal physiologic regulator of IL-7 production.


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InternalMed_Harrison. CD8+ T Cells A relative CD8+ T lymphocytosis is generally associated with high levels of HIV plasma viremia and likely reflects an immune response to the virus as well as dysregulated homeostasis associated with generalized immune activation. During the late stages of HIV infection, there may be a significant reduction in the numbers of CD8+ T cells despite the presence of high levels of viremia. HIV-specific CD8+ CTLs have been demonstrated in HIV-infected individuals early in the course of disease, and their emergence often coincides with a decrease in plasma viremia—an observation that is a factor in 1237 the proposal that virus-specific CTLs can control HIV disease for a finite period of time in a certain percentage of infected individuals. However, emergence of HIV escape mutants that ultimately evade these HIV-specific CD8+ T cells has been described in the majority of HIV-infected individuals who are not receiving cART. In addition, as the disease progresses, the functional


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InternalMed_Harrison. that ultimately evade these HIV-specific CD8+ T cells has been described in the majority of HIV-infected individuals who are not receiving cART. In addition, as the disease progresses, the functional capability of these cells gradually decreases, at least in part due to the persistent nature of HIV infection that causes functional exhaustion via the upregulation of inhibitory receptors such as PD-1 on HIV-specific CD8+ T cells (see “Immune Activation, Inflammation, and HIV Pathogenesis,” above). As chronic immune activation persists, there are also systemic effects on CD8+ T cells, such that as a population they assume an abnormal phenotype characterized by expression of activation markers such as HLA-DR and CD38 with an absence of expression of the IL-2 receptor (CD25) and a reduced expression of the IL-7 receptor (CD127). In addition, CD8+ T cells lacking CD28 expression are increased in HIV disease, reflecting a skewed expansion of a less differentiated CD8+ T cell subset. This


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InternalMed_Harrison. of the IL-7 receptor (CD127). In addition, CD8+ T cells lacking CD28 expression are increased in HIV disease, reflecting a skewed expansion of a less differentiated CD8+ T cell subset. This skewing of subsets is also associated with diminished polyfunctionality, a qualitative difference that distinguishes nonprogressors from progressors. It has been reported that nonprogressors can also be distinguished from progressors by the maintenance in the former of a high proliferative capacity of their HIV-specific CD8+ T cells coupled to increases in perforin expression, characteristics that are markedly diminished in advanced HIV disease. It has been reported that the phenotype of CD8+ T cells in HIV-infected individuals may be of prognostic significance. Those individuals whose CD8+ T cells developed a phenotype of HLA-DR+/CD38– following seroconversion had stabilization of their CD4+ T cell counts, whereas those whose CD8+ T cells developed a phenotype of HLA-DR+/CD38+ had a more


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InternalMed_Harrison. cells developed a phenotype of HLA-DR+/CD38– following seroconversion had stabilization of their CD4+ T cell counts, whereas those whose CD8+ T cells developed a phenotype of HLA-DR+/CD38+ had a more aggressive course and a poorer prognosis. In addition to the defects in HIV-specific CD8+ CTLs, functional defects in other MHC-restricted CTLs, such as those directed against influenza and CMV, have been demonstrated. CD8+ T cells secrete a variety of soluble factors that inhibit HIV replication, including the CC-chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4) as well as potentially a number of unidentified factors. The presence of high levels of HIV viremia in vivo as well as exposure of CD8+ T cells in vitro to HIV envelope, both of which are associated with aberrant immune activation, have been shown to be associated with a variety of cellular functional abnormalities. Furthermore, since the integrity of CD8+ T cell function depends in part on adequate inductive signals


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InternalMed_Harrison. have been shown to be associated with a variety of cellular functional abnormalities. Furthermore, since the integrity of CD8+ T cell function depends in part on adequate inductive signals from CD4+ T cells, the defect in CD8+ CTLs is likely compounded by the quantitative loss and qualitative dysfunction of CD4+ T cells.


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InternalMed_Harrison. B Cells The predominant defect in B cells from HIV-infected individuals is one of aberrant cellular activation, which is reflected by increased propensity to terminal differentiation and immunoglobulin secretion and increased expression of markers of activation and exhaustion. As a result of activation and differentiation in vivo, B cells from HIV viremic patients manifest a decreased capacity to mount a proliferative response to ligation of the B cell antigen receptor and other B cell stimuli in vitro. B cells from HIV-infected individuals manifest enhanced spontaneous secretion of immunoglobulins in vitro, a process that reflects their highly differentiated state in vivo. There is also an increased incidence of EBV-related B cell lymphomas in HIV-infected individuals that are likely due to combined effects of defective T cell immune surveillance and increased turnover that increases the risk of oncogenesis. Untransformed B cells cannot be infected with HIV, although HIV or its


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InternalMed_Harrison. due to combined effects of defective T cell immune surveillance and increased turnover that increases the risk of oncogenesis. Untransformed B cells cannot be infected with HIV, although HIV or its products can activate B cells directly. B cells from patients with high levels of viremia bind virions to their surface via the CD21 complement receptor. It is likely that in vivo activation of B cells by replication-competent or defective virus as well as viral products during the viremic state accounts at least in part for their activated phenotype. B cell subpopulations from HIV-infected individuals undergo a number of changes over the course of HIV disease, including the attrition of resting memory B cells and replacement with several aberrant memory and differentiated B cell subpopulations that collectively express reduced levels of CD21


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1238 and either increased expression of activation markers or inhibitory receptors associated with functional exhaustion. The more activated and differentiated B cells are also responsible for increased secretion of immunoglobulins and increased susceptibility to Fas-mediated apoptosis. In more advanced disease, there is also the appearance of immature B cells associated with CD4+ T cell lymphopenia. Cognate B cell–CD4+ T cell interactions are abnormal in viremic HIV-infected individuals in that B cells respond poorly to CD4+ T cell help and CD4+ T cells receive inadequate co-stimulatory signals from activated B cells. In vivo, the aberrant activated state of B cells manifests itself by hypergammaglobulinemia and by the presence of circulating immune complexes and autoantibodies. HIV-infected individuals respond poorly to primary and secondary immunizations with protein and polysaccharide antigens. Using immunization


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InternalMed_Harrison. of circulating immune complexes and autoantibodies. HIV-infected individuals respond poorly to primary and secondary immunizations with protein and polysaccharide antigens. Using immunization with influenza vaccine, it has been demonstrated that there is a memory B cell defect in HIV-infected individuals, particularly those with high levels of HIV viremia. There is also evidence that responses to HIV and non-HIV antigens in infected individuals, especially those who remain viremic, are enriched in abnormal subsets of B cells that either are highly prone to apoptosis or show signs of functional exhaustion. Taken together, these B cell defects are likely responsible in part for the inadequate response to HIV as well as to decreased response to vaccinations and the increase in certain bacterial infections seen in advanced HIV disease in adults, as well as for the important role of bacterial infections in the morbidity and mortality rates of HIV-infected children, who cannot mount an


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InternalMed_Harrison. infections seen in advanced HIV disease in adults, as well as for the important role of bacterial infections in the morbidity and mortality rates of HIV-infected children, who cannot mount an adequate humoral response to common bacterial pathogens. The absolute number of circulating B cells may be depressed in HIV infection; this phenomenon likely reflects increased activation-induced apoptosis as well as a redistribution of cells out of the circulation and into the lymphoid tissue—phenomena that are associated with ongoing viral replication.


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InternalMed_Harrison. Monocytes/Macrophages Circulating monocytes are generally normal in number in HIV-infected individuals; however, there is evidence of increased activation within this lineage. The increased level of sCD14 and other biomarkers (see above) reported in HIV-infected individuals is an indirect marker of monocyte activation in vivo. A number of other abnormalities of circulating monocytes have been reported in HIV-infected individuals, many of which may be related directly or indirectly to aberrant in vivo immune activation. In this regard, increased levels of lipopolysaccharide (LPS) are found in the sera of HIV-infected individuals due, at least in part, to translocation across the gut mucosal barrier (see above). LPS is a highly inflammatory bacterial product that preferentially binds to macrophages through CD14 and Toll-like receptors, resulting in cellular activation. Functional abnormalities of monocyte/macrophages in HIV disease include decreased secretion of IL-1 and IL-12;


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InternalMed_Harrison. to macrophages through CD14 and Toll-like receptors, resulting in cellular activation. Functional abnormalities of monocyte/macrophages in HIV disease include decreased secretion of IL-1 and IL-12; increased secretion of IL-10 and IL-18; defects in antigen presentation and induction of T cell responses due to decreased MHC class II expression; and abnormalities of Fc receptor function, C3 receptor–mediated clearance, oxidative burst responses, and certain cytotoxic functions such as ADCC, possibly related to low levels of expression of Fc and complement receptors. Monocytes express the CD4 molecule and several co-receptors for HIV on their surface, including CCR5, CXCR4, and CCR3, and thus are potential targets of HIV infection. The degree of cytopathicity of HIV for cells of the monocyte lineage is low, and HIV can replicate in cells of the monocyte lineage with relatively little cytopathic effect. Hence, monocyte-lineage cells may play a role in the dissemination of HIV in the body


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InternalMed_Harrison. lineage is low, and HIV can replicate in cells of the monocyte lineage with relatively little cytopathic effect. Hence, monocyte-lineage cells may play a role in the dissemination of HIV in the body and can serve as reservoirs of HIV infection, thus representing an obstacle to the eradication of HIV by antiretroviral drugs. In vivo infection of circulating monocytes is difficult to demonstrate; however, infection of tissue macrophages and macrophage-lineage cells in the brain (infiltrating macrophages or resident microglial cells) and lung (pulmonary alveolar macrophages) can be demonstrated easily. Tissue macrophages are an important source of HIV during the inflammatory response associated with opportunistic infections. Infection of monocyte precursors in the bone marrow may directly or indirectly be responsible for certain of the hematologic abnormalities in HIV-infected individuals. However, as with DCs, monocytes and macrophages express high levels of host restriction factors


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InternalMed_Harrison. or indirectly be responsible for certain of the hematologic abnormalities in HIV-infected individuals. However, as with DCs, monocytes and macrophages express high levels of host restriction factors that likely help explain the low contribution of myeloid cells to the overall viral burden in HIV-infected individuals.


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InternalMed_Harrison. Dendritic and Langerhans Cells DCs and Langerhans cells are thought to play an important role in the initiation of HIV infection by virtue of the ability of HIV to bind to cell-surface C-type lectin receptors, particularly DC-SIGN (see above) and Langerin. This allows efficient presentation of virus to CD4+ T cell targets that become infected; complexes of infected CD4+ T cells and DCs provide an optimal microenvironment for virus replication. There was once considerable disagreement regarding the HIV infectibility and hence the depletion as well as the dysfunction of DCs themselves. However, since the recognition of myeloid (mDC) and plasmacytoid (pDC) subsets, there has been a better appreciation of specific DC dysfunction in HIV disease. pDCs are an important component of the innate immune system and secrete large amounts of IFN-α in response to viral infections. The numbers of circulating pDCs are decreased in HIV infection through mechanisms that remain unclear, and there are


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InternalMed_Harrison. immune system and secrete large amounts of IFN-α in response to viral infections. The numbers of circulating pDCs are decreased in HIV infection through mechanisms that remain unclear, and there are conflicting reports regarding the frequency of pDCs in lymphoid tissues, with some studies suggesting that their increased tissue presence and secretion of inflammatory cytokines such as IFN-α contributes to lymphoid hyperplasia. The mDCs or conventional DCs are involved in the initiation of adaptive immunity in draining lymph nodes by presenting antigen to T cells and B cells, as well as by secreting cytokines such as IL-12, IL-15, and IL-18 that activate other immune cells. There are also indications that the relatively low infectibility of DCs may be associated with the expression of host restriction factors, including APOBEC3G (see above).


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InternalMed_Harrison. Natural Killer Cells The role of NK cells is to provide immunosurveillance against virus-infected cells, certain tumor cells, and allogeneic cells (Chap. 372e). There are no convincing data that HIV productively infects NK cells in vivo; however, functional abnormalities in NK cells have been observed throughout the course of HIV disease, and the severity of these abnormalities increases as disease progresses. NK cells are part of the innate immune system and act by direct killing of infected cells and secretion of antiviral cytokines. In early HIV infection there is an increase in the activation of NK cells, and the capacity to secrete IFN-γ is maintained, although they manifest reduced cytotoxic function. During chronic HIV infection, both NK cell cytotoxicity and cytokine secretion become impaired. Given that HIV infection of target cells downregulates HLA-A and -B, but not HLA-C and -D molecules, this may explain in part the relative inability of NK cells to kill HIV-infected


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InternalMed_Harrison. become impaired. Given that HIV infection of target cells downregulates HLA-A and -B, but not HLA-C and -D molecules, this may explain in part the relative inability of NK cells to kill HIV-infected target cells. However, the NK cell impairments, especially in patients with high levels of virus replication, are associated with an expansion of an “anergic” CD56–/CD16+ NK cell subset. This abnormal subset of NK cells manifests an increased expression of inhibitory NK cell receptors (iNKRs) and a substantial decrease in expression of natural cytotoxicity receptors (NCRs) and shows a markedly impaired lytic activity. The overrepresentation of this abnormal subset of NK cells may explain in part the observed defects in NK cell function in HIV-infected individuals and likely begins to occur during primary infection. NK cells also serve as important sources of HIV-inhibitory CC-chemokines. NK cells isolated from HIV-infected individuals constitutively produce high levels of MIP-1α (CCL3),


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InternalMed_Harrison. primary infection. NK cells also serve as important sources of HIV-inhibitory CC-chemokines. NK cells isolated from HIV-infected individuals constitutively produce high levels of MIP-1α (CCL3), MIP-1β (CCL4), and RANTES (CCL5), although the impact of these chemokines on HIV replication in vivo is unclear. Finally, NK cell–DC interactions are important for normal immune function. NK cells and DCs reciprocally modulate each other’s activation and maturation. These interactions are markedly impaired in HIV-infected individuals with high levels of plasma viremia.


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InternalMed_Harrison. pHenotypes of sUsceptibility and response to Hiv infection It is well known that individuals vary in their susceptibility to acquiring HIV infection and that there is wide variation in both the steady-state level of HIV that is established soon after infection (virologic setpoint) as well as the rate at which HIV-infected patients progress to AIDS. Some striking examples include sex workers who remain uninfected despite repeated exposure to HIV; HIV-infected individuals who spontaneously control viral replication in the absence of cART (HIV controllers); patients who resist disease progression for at least 8–10 years, despite viremia; and those progressing to AIDS within 3 years. Investigators have hypothesized that genetic differences may partly explain this interindividual variation in risk of acquiring HIV infection and disease progression rates. In addition to these phenotypes, it has been hypothesized that genetic variation may partly underpin the risk of developing specific


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InternalMed_Harrison. in risk of acquiring HIV infection and disease progression rates. In addition to these phenotypes, it has been hypothesized that genetic variation may partly underpin the risk of developing specific AIDS-defining illnesses (e.g., renal and neurologic diseases) and non-AIDS comorbidities (e.g., cardiovascular disease), as well as the variable recovery in CD4+ T cell counts observed while receiving cART.


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InternalMed_Harrison. Candidate gene approaches and genome-wide association studies (GWAS) have demonstrated associations between gene variations and the above-mentioned phenotypes. A list of some of these associations is shown in Table 226-6. While in vitro genome-wide functional scanning using RNA interference has identified hundreds of host factors that may be involved in the HIV life cycle, the association of these genes with HIV susceptibility and/or disease progression remains largely undefined. Below is a discussion of a few key genes with strong associations and their implications for improving clinical care.


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InternalMed_Harrison. associations witH ccr5 and translation of genetic findings to tHe clinic Possibly, the most dramatic example of the importance of genetic studies for identifying host factors that influence HIV-AIDS pathogenesis is from studies related to the gene that encodes for CC chemokine receptor 5 (CCR5). While in vitro studies established that CCR5 is the major HIV co-receptor for the cell entry of HIV-1 into the host, it was genetic studies that established the seminal in vivo role of this receptor for the initial entry of HIV and AIDS pathogenesis. Genetic analysis revealed that the in vitro resistance to CCR5-using R5 strains of HIV is in some instances due to carriage of two defective CCR5 alleles. This defect is a 32-bp deletion in the coding sequence (designated as the Δ32 allele). The CCR5 Δ32 allele encodes a truncated protein that is not expressed on the cell surface.


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InternalMed_Harrison. Approximately 1% of individuals of European ancestry are homozygous for the CCR5 Δ32 allele. Depending on the geographic region in Europe, up to 20% of individuals are heterozygous for the CCR5 Δ32 allele. The CCR5 Δ32 allele is either absent or extremely rare in other populations. The evolutionary pressure that resulted in the emergence of the CCR5 Δ32 allele in the European population remains unknown and has been speculated to be secondary to an ancestral pandemic such as the plague.


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InternalMed_Harrison. Individuals homozygous for the CCR5 Δ32 allele (Δ32/Δ32) lack CCR5 surface expression and are highly resistant to acquiring HIV infection. Heterozygosity for the CCR5 Δ32 allele is also associated with a reduced risk of acquiring HIV. Consequently, the frequency of the CCR5 Δ32 allele is enriched in individuals of European descent who remain uninfected despite exposure to the virus. Although the CCR5 Δ32/Δ32 genotype is associated with profound resistance to acquiring HIV, a few individuals with this genotype have become infected with the X4 HIV strain and, in some instances, experienced an accelerated disease course. In general, CCR5 Δ32 heterozygosity is associated with a slower HIV disease course.


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InternalMed_Harrison. Subsequent studies identified single nucleotide polymorphisms (SNPs) in the promoter (regulatory region) of CCR5 that influence its expression levels. Alleles bearing specific cassettes of linked polymorphisms (haplotypes) were identified and designated as human haplogroups A to G*2 (HHA to HHG*2). The CCR5 Δ32 is found on the HHG*2 haplotype. The CCR5 HHE haplotype was associated with higher CCR5 expression, and genetic association studies have shown that homozygosity for the CCR5 HHE haplotype is associated with an increased risk of acquiring HIV, progressing rapidly to AIDS, and reduced immune recovery on cART. The CCR2-64I-bearing HHF*2 haplotype is associated with a slower HIV disease course. The CCR5 HHA haplotype is the ancestral CCR5 haplotype and is associated with a lower CCR5 expression. The HHA haplotype was associated with slower disease progression in African populations and has been speculated to be a basis for why SIV-infected chimpanzees (who all carry the ancestral


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InternalMed_Harrison. expression. The HHA haplotype was associated with slower disease progression in African populations and has been speculated to be a basis for why SIV-infected chimpanzees (who all carry the ancestral CCR5 HHA haplotype) may resist disease progression. The CCR5 haplotypes also influence cell-mediated immunity and immune 1239 recovery on cART.


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InternalMed_Harrison. The association of variations in the CCR5 gene with HIV-AIDS phenotypes is also an example of how discoveries made in the laboratory (bench) have been translated to improve health outcomes (bedside). The discovery that the CCR5 Δ32/Δ32 genotype is associated with strong resistance to HIV infection, and that uninfected Caucasians bearing this genotype did not appear to have impaired immunity, led to the development of two kinds of therapies. First, it spurred the development of a new class of FDA-approved therapies, entry inhibitors (e.g., maraviroc), that block the interaction of CCR5 with the HIV envelope. Second, it led to the development of novel experimental cellular therapies. An HIV-infected patient with acute myelogenous leukemia was given an allogeneic stem-cell transplantation from an HLA-compatible person whose cells lacked expression of CCR5 due to the Δ32/Δ32 genotype. There has been no evidence of HIV-1 infection in the transplanted patient thus far (6 years). This


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InternalMed_Harrison. from an HLA-compatible person whose cells lacked expression of CCR5 due to the Δ32/Δ32 genotype. There has been no evidence of HIV-1 infection in the transplanted patient thus far (6 years). This observation spurred the hope of an HIV cure and led to the development of additional novel cellular therapies involving autologous transplantation of CD4+ T-cells in which the CCR5 gene is inactivated ex vivo using new gene editing procedures.


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InternalMed_Harrison. discovery of Hla class i alleles tHat associate witH virologic control of Hiv infection There is a strong association between variations within the HLA-B gene with protective (e.g., HLA-B*57 and -B*27 alleles) or detrimental (e.g., HLA-B*35 allele) outcomes during HIV infection. Carriage of the HLA-B*57 and/or HLA-B*27 alleles is associated with slower disease progression. The beneficial effects of these alleles may relate in part to their consistent associations with a lower virologic setpoint as well as to higher cell-mediated immunity. The protective effect of the HLA-B*57 and -B*27 alleles on HIV disease course is underscored by the finding that the prevalence of these alleles is higher among long-term nonprogressors and HIV elite controllers (see above). On the other hand, the HLA-B*35 allele has been associated with faster progression to AIDS and higher viral load. The prevalence of the HLA-B alleles differs between populations. HLA


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InternalMed_Harrison. B*57:01 in Europeans and HLA-B*57:03 in African Americans are the protective alleles. In some populations (e.g., Japanese) where the HLA-B*57/-B*27 alleles are absent, HLA-B*51 is associated with a protective phenotype. Possession of the protective HLA-B alleles is associated with broader and stronger CD8+ T cell responses to HIV epitopes. The mechanisms underlying the differential effects of the HLA-B alleles on HIV disease course may relate to differences in the ability of antigen-presenting cells to present immunodominant HIV epitopes to T helper or cytotoxic T lymphocytes in the context of MHC-encoded molecules. This may result in differential immune responses that influence viral replication. In this regard, the HLA-B alleles that impact HIV disease course differ in their amino acid residues in the HLA-B peptide-binding groove—and this may play a critical role in virologic control.


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InternalMed_Harrison. Investigators have also examined the influence of extended HLA haplotypes (linked alleles) on HIV disease course. The extended HLA ancestral haplotype (AH) 8.1 is defined by the presence of HLA-A1, HLA-B8, and HLA-DR3 alleles. AH 8.1 is the most common ancestral haplotype in Caucasians (present in 10%) and is associated with multiple autoimmune diseases in HIV-uninfected persons. These associations of AH 8.1 are thought to be due to a genetically determined hyperresponsiveness characterized by high TNF-α production and lack of complement C4A. Strong epidemiologic data indicate that carriage of AH 8.1 in HIV-infected persons is associated with a rapid decline in CD4+ T cells and faster progression to AIDS development. Gene–gene interactions between HLA alleles and other genes (e.g., killer cell immunoglobulin-like receptors) also may influence HIV disease progression rates.


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InternalMed_Harrison. polymorpHisms identified by gwas tHat associate witH virologic control Large-scale GWASs have been conducted for the phenotype of viral load, including in a large group of HIV controllers. GWAS in HIV-infected persons of European ancestry identified four SNPs in genes in the HLA class I loci that associated with virologic control. Human Immunodeficiency Virus Disease: AIDS and Related Disorders KIR+HLA KIR3DS1 + HLA-Bw4-80Ile Altered NK cell activity required to eliminate KIR3DS1 with HLA Bw4-80I +: delayed AIDS HIV-infected cells onset HLA-C1 + KIR2DL3, Reduction of inhibitory KIR likely results in HLA-C1+/KIR2DL3+: better immune recovery LILRB2+HLA LILRB2 + HLA class I Regulation of dendritic cells by LILRB2-HLA Control of HIV-1 engagement aRepresentative genes and polymorphisms and bpossible mechanisms are listed. cSome of the associations are population specific and may display cohort-specific effects.


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InternalMed_Harrison. Note: Apobec, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like; ApoE, apolipoprotein E; ART, antiretroviral therapy; CCL, CC ligand; CCL3L, CCL3-like; CCR5, CC chemokine receptor 5; CRP, C-reactive protein; CXCR6, chemokine (C-X-C motif ) receptor 6; DARC, Duffy antigen receptor for chemokines; HCP5, HLA class I histocompatibility antigen protein P5; HHE, human haplogroup E; HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; LILRB2, leukocyte immunoglobulin-like receptor B2; KIR, killer cell immunoglobulin-like receptors; KS, Kaposi’s sarcoma; MBL, mannose-binding lectin; MHC, major histocompatibility complex; MICA: MHC class I polypeptide-related sequence A; ORF, open reading frame; PARD3B, par-3 family cell polarity regulator beta; PROX1, prospero homeobox 1; PSORS1C3, psoriasis susceptibility 1 candidate 3; SNP, single nucleotide polymorphism; rs#, SNP identification number in SNP database from NCBI; UTR, untranslated region; ZNRD1, zinc ribbon domain


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InternalMed_Harrison. 1; PSORS1C3, psoriasis susceptibility 1 candidate 3; SNP, single nucleotide polymorphism; rs#, SNP identification number in SNP database from NCBI; UTR, untranslated region; ZNRD1, zinc ribbon domain containing 1; +, present, –, absent.


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InternalMed_Harrison. Sources: Sunil K Ahuja, MD, Weijing He, MD, and Gabriel Catano, MD. Reviews for additional information: P An et al: Trends Genet 26:119, 2010; J Fellay: Antivir Ther 14:731, 2009; RA Kaslow et al: J Infect Dis 191:S68, 2005; D van Manen et al: Retrovirology 9:70, 2012; MP Martin et al: Immunol Rev 254:245, 2013; S Limou et al: Front Immunol 4:118, 2013.


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InternalMed_Harrison. These SNPs are within or in the vicinity of HCP5, HLA-C, MICA, and PSORS1C3 genes. The protective effects of the SNPs in HCP5 and MICA may relate to their linkage with known protective HLA-B alleles. The protective HCP5 allele is in linkage disequilibrium with the HLAB*57:01, and the protective MICA allele tags with the HLA-B*57:01 and B*27:05 alleles. The protective HLA-C SNP is associated with higher HLA-C expression, and this effect is thought to be due to the altered binding of a microRNA to the HLA-C mRNA. Higher HLA-C expression has been associated with beneficial HIV phenotypes. The mechanism associated with the SNP in PSORS1C3 is unknown. GWAS in African Americans identified a SNP that tags the HLA-B*57:03 allele that is known to associate with lower virologic setpoint and slower disease course. Together these GWAS data underscore the importance of variations in HLA class I loci in control of viral replication.


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InternalMed_Harrison. GENETIC ASSOCIATIONS WITH SPECIFIC AIDS AND NON-AIDS CONDITIONS • carotid artery disease Many of the non-AIDS events in HIV-infected individuals resemble those related to immune senescence and those found in the HIV-uninfected aging population. A functional SNP in the ryanodine receptor 3 (RYR3) gene was found to be associated with an increased risk of common carotid intima–media thickness (cIMT), which is a surrogate for subclinical atherosclerosis. Functional studies on RYR3 and its isoforms demonstrate a major role of these receptors in modulating endothelial function and atherogenesis via calcium signaling pathways, providing a biologically plausible mechanism by which the SNP in RYR3 may associate with increased cIMT risk.


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InternalMed_Harrison. renal disease HIV-1-associated nephropathy (HIVAN) is a form of focal sclerosing glomerulonephritis caused by direct infection of kidney epithelial cells with HIV. HIVAN is more common in persons of African descent. There is evidence that polymorphisms in the MYH9 gene and in the neighboring APOL1 gene are a strong determinant of susceptibility to HIVAN in African Americans. The effect of carrying two APOL1 risk alleles explains nearly 35% of HIVAN. The mechanisms by which MYH9/APOL1 variants predispose to HIVAN are currently unknown.


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InternalMed_Harrison. The mechanisms by which MYH9/APOL1 variants predispose to HIVAN are currently unknown. Hiv-associated neurocognitive disorder HIV-associated neurocognitive disorder (HAND) comprises a spectrum of neurocognitive deficits due to HIV infection. Variations in the apolipoprotein E (ApoE) gene have strong associations with Alzheimer’s disease in the HIV-uninfected population. In HIV-infected persons, possession of the ApoE4 allele has been associated with several cognitive outcomes including dementia, peripheral neuropathy, and impairment in cognition and immediate and delayed verbal memory. Macrophage recruitment and activation plays a central role in the development of many of the HAND syndromes. Variations in chemokines that play an influential role in macrophage activation and recruitment, namely CCL2 (MCP-1) and CCL3 (MIP-1α), have been shown to alter the risk of developing HAND. Variations in mitochondrial genes also have been associated with risk of AIDS and HAND.


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InternalMed_Harrison. associations witH art-related adverse events Abacavir, an effective antiretroviral agent, is associated with significant risk of hypersensitivity reactions (2–9% of cases). Interestingly, while the HLA-B*57:01 allele is associated with a slower HIV disease course, possession of this allele is associated with a higher risk of abacavir-associated hypersensitivity. Pharmacogenetic screening for the HLA-B*57:01 allele is recommended before initiation of abacavir treatment.


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InternalMed_Harrison. While there has been a remarkable decrease in the incidence in the severe forms of HIV encephalopathy among those with access to treatment in the era of effective cART, HIV-infected individuals can still experience milder forms of neurocognitive impairment despite adequate cART. A variety of factors may contribute to the neurocognitive decline, which includes lack of complete control of HIV replication in the brain, production of HIV proteins that may be neurotoxic, low CD4+ T cell nadir, chronic immune activation, comorbidities such as


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1242 drug abuse, and the potential for neurotoxicity of certain of the antiretroviral drugs. HIV has been demonstrated in the brain and CSF of infected individuals with and without neuropsychiatric abnormalities. As opposed to lymphoid tissues, there are no resident lymphocytes in the brain. The main cell types that are infected in the brain in vivo are the perivascular macrophages and the microglial cells; low-level viral replication is also seen in perivascular astrocytes. Monocytes that have already been infected in the blood can migrate into the brain, where they then reside as macrophages, or macrophages can be directly infected within the brain. The precise mechanisms whereby HIV enters the brain are unclear; however, they are thought to relate, at least in part, to the ability of virus-infected and immune-activated macrophages to induce adhesion molecules such as E-selectin and vascular cell adhesion molecule 1


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InternalMed_Harrison. they are thought to relate, at least in part, to the ability of virus-infected and immune-activated macrophages to induce adhesion molecules such as E-selectin and vascular cell adhesion molecule 1 (VCAM-1) on brain endothelium. Other studies have demonstrated that HIV gp120 enhances the expression of intercellular adhesion molecule 1 (ICAM-1) in glial cells; this effect may facilitate entry of HIV-infected cells into the CNS. Virus isolates from the brain are preferentially R5 strains as opposed to X4 strains; in this regard, HIV-infected individuals who are heterozygous for CCR5-Δ32 appear to be relatively protected against the development of HIV encephalopathy. Once HIV enters the brain due to pressures of the local environment, it evolves to develop distinct sequences in the env, tat, and LTR genes. These unique sequences have been associated with neurocognitive dysfunction; however, it is unclear if they are causal (see below). HIV-infected individuals may manifest white matter


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InternalMed_Harrison. and LTR genes. These unique sequences have been associated with neurocognitive dysfunction; however, it is unclear if they are causal (see below). HIV-infected individuals may manifest white matter lesions as well as neuronal loss. The white matter lesions are due to axonal injury and a disruption of the blood-brain barrier and not due to demyelination. Given the absence of evidence of HIV infection of neurons either in vivo or in vitro, it is highly unlikely that direct infection of these cells accounts for their loss. Rather, the HIV-mediated effects on neurons are thought to involve indirect pathways whereby viral proteins, particularly gp120 and Tat, trigger the release of endogenous neurotoxins from macrophages and to a lesser extent from astrocytes. In addition, it has been demonstrated that both HIV-1 Nef and Tat can induce chemotaxis of leukocytes, including monocytes, into the CNS. Neurotoxins can be released from monocytes as a consequence of infection and/or immune


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InternalMed_Harrison. demonstrated that both HIV-1 Nef and Tat can induce chemotaxis of leukocytes, including monocytes, into the CNS. Neurotoxins can be released from monocytes as a consequence of infection and/or immune activation. Monocyte-derived neurotoxic factors have been reported to kill neurons via the N-methyld-aspartate (NMDA) receptor. In addition, HIV gp120 shed by virus-infected monocytes could cause neurotoxicity by antagonizing the function of vasoactive intestinal peptide (VIP), by elevating intracellular calcium levels, and by decreasing nerve growth factor levels in the cerebral cortex. A variety of monocyte-derived cytokines can contribute directly or indirectly to the neurotoxic effects in HIV infection; these include TNF-α, IL-1, IL-6, TGF-β, IFN-γ, platelet-activating factor, and endothelin. Furthermore, among the CC-chemokines, elevated levels of monocyte chemotactic protein-1 (MCP-1 or CCL-2) in the brain and CSF have been shown to correlate best with the presence and degree of HIV


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InternalMed_Harrison. Furthermore, among the CC-chemokines, elevated levels of monocyte chemotactic protein-1 (MCP-1 or CCL-2) in the brain and CSF have been shown to correlate best with the presence and degree of HIV encephalopathy. In addition, infection and/or activation of monocyte-lineage cells can result in increased production of eicosanoids, quinolinic acid, nitric oxide, excitatory amino acids such as l-cysteine and glutamate, arachidonic acid, platelet activating factor, free radicals, TNF-α, and TGF-β, which may contribute to neurotoxicity. Astrocytes may play diverse roles in HIV neuropathogenesis. Reactive gliosis or astrocytosis has been demonstrated in the brains of HIV-infected individuals, and TNF-α and IL-6 have been shown to induce astrocyte proliferation. In addition, astrocyte-derived IL-6 can induce HIV expression in infected cells in vitro. Furthermore, it has been suggested that astrocytes may downregulate macrophage-produced neurotoxins. Treatment with cART leads to improvement in


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InternalMed_Harrison. can induce HIV expression in infected cells in vitro. Furthermore, it has been suggested that astrocytes may downregulate macrophage-produced neurotoxins. Treatment with cART leads to improvement in neuropsychiatric manifestations and a decrease in these cytokine levels in CSF, suggesting that they are driven by the virus or by its products. However, even in patients on long-term cART, there may be evidence of persistently activated lymphocytes in the CSF. It is unclear if these lymphocytes may contribute to neuronal injury in the brain or are critical for controlling the CNS viral reservoir. The contribution of host genetic factors to development of neuropsychiatric manifestations of HIV infection has not been well studied. However, evidence supports the role of the E4 allele for apoE in an increased risk of HIV-associated neurocognitive disorders and peripheral neuropathy.


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InternalMed_Harrison. It has also been suggested that the CNS may serve as a relatively sequestered site for a reservoir of latently infected cells that might be a barrier for the eradication of virus by cART (see “Reservoirs of HIV-Infected Cells: Obstacles to the Eradication of Virus,” above).


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InternalMed_Harrison. There are at least four distinct epidemiologic forms of KS: (1) the classic form that occurs in older men of predominantly Mediterranean or eastern European Jewish backgrounds with no recognized contributing factors; (2) the equatorial African form that occurs in all ages, also without any recognized precipitating factors; (3) the form associated with organ transplantation and its attendant iatrogenic immunosuppressed state; and (4) the form associated with HIV-1 infection. In the latter two forms, KS is an opportunistic disease; in HIV-infected individuals, unlike typical opportunistic infections, its occurrence is not strictly related to the level of depression of CD4+ T cell counts. The pathogenesis of KS is complex; fundamentally, it is an angioproliferative disease that is not a true neoplastic sarcoma, at least not in its early stages. It is a manifestation of excessive proliferation of spindle cells that are believed to be of vascular origin and have features in common with


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InternalMed_Harrison. neoplastic sarcoma, at least not in its early stages. It is a manifestation of excessive proliferation of spindle cells that are believed to be of vascular origin and have features in common with endothelial and smooth-muscle cells. In HIV disease the development of KS is dependent on the interplay of a variety of factors including HIV-1 itself, human herpes virus 8 (HHV-8), immune activation, and cytokine secretion. A number of epidemiologic and virologic studies have clearly linked HHV-8, which is also referred to as Kaposi’s sarcoma–associated herpesvirus (KSHV), to KS not only in HIV-infected individuals but also in individuals with the other forms of KS. HHV-8 is a γ-herpesvirus related to EBV and herpesvirus saimiri. It encodes a homologue to human IL-6 and, in addition to KS, has been implicated in the pathogenesis of body cavity lymphoma, multiple myeloma, and monoclonal gammopathy of undetermined significance. Sequences of HHV-8 are found universally in the lesions of KS, and


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InternalMed_Harrison. implicated in the pathogenesis of body cavity lymphoma, multiple myeloma, and monoclonal gammopathy of undetermined significance. Sequences of HHV-8 are found universally in the lesions of KS, and patients with KS are virtually all seropositive for HHV-8. HHV-8 DNA sequences can be found in the B cells of 30–50% of patients with KS and 7% of patients with AIDS without clinically apparent KS.


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InternalMed_Harrison. Between 1 and 2% of eligible blood donors are positive for antibodies to HHV-8, while the prevalence of HHV-8 seropositivity in HIV-infected men is 30–35%. The prevalence of HHV-8 seropositivity in HIV-infected women is ~4%. This finding is reflective of the lower incidence of KS in women. It has been debated whether HHV-8 is actually the transforming agent in KS; the bulk of the cells in the tumor lesions of KS are not neoplastic cells. However, it has been demonstrated that endothelial cells can be transformed in vitro by HHV-8. In this regard, HHV-8 possesses a number of genes, including homologues of the IL-8 receptor, Bcl-2, and cyclin D, that can potentially transform the host cell. Despite the complexity of the pathogenic events associated with the development of KS in HIV-infected individuals, HHV-8 is the etiologic agent of this disease. The initiation and/or propagation of KS requires an activated state and is mediated, at least in part, by cytokines. A number of factors,


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InternalMed_Harrison. individuals, HHV-8 is the etiologic agent of this disease. The initiation and/or propagation of KS requires an activated state and is mediated, at least in part, by cytokines. A number of factors, including TNF-α, IL-1β, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), basic fibroblast growth factor, and oncostatin M, function in an autocrine and paracrine manner to sustain the growth and chemotaxis of the KS spindle cells. In this regard, KSHV-derived IL-6 has been demonstrated to induce proliferation of lymphoma cells and to inhibit the cytostatic effects of IFN-α on KSHV-infected lymphoma cells.


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InternalMed_Harrison. As detailed above and below, following the initial burst of viremia during primary infection, HIV-infected individuals mount robust immune responses that in most cases substantially curtail the levels of plasma viremia and likely contribute to delaying the ultimate development of clinically apparent disease for a median of 10 years in untreated individuals. This immune response contains elements of both humoral and cell-mediated immunity involving both innate and adaptive immune responses (Table 226-7; Fig. 226-26). It is directed against multiple antigenic determinants of the HIV virion as well as against viral proteins expressed on the surface of infected cells. 1243


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InternalMed_Harrison. Ironically, those CD4+ T cells with T cell receptors specific for HIV are theoretically those CD4+ T cells most likely to be activated—and thus to serve as early targets for productive HIV infection and the cell death or dysfunction associated with infection. Thus, an early consequence of HIV infection is interference with and decrease of the helper T cell Abbreviation: MHC, major histocompatibility complex. population needed to generate an effective immune response. Although a great deal of investigation has been directed toward delineating and better understanding the components of this immune response, it remains unclear which immunologic effector mechanisms are most important in delaying progression of infection and which, if any, play a role in the pathogenesis of HIV disease. This lack of knowledge has also hampered the ability to develop an effective vaccine for HIV disease.


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InternalMed_Harrison. Antibodies to HIV usually appear within 3–6 weeks and almost invariably within 12 weeks of primary infection (Fig. 226-27); rare exceptions are in individuals who have defects in the ability to produce HIV-specific antibodies. Detection of these antibodies forms the basis of most diagnostic screening tests for HIV infection. The appearance of HIV-binding antibodies detected by ELISA and Western blot assays occurs prior to the appearance of neutralizing antibodies; the latter generally appear following the initial decreases in plasma viremia and are more closely related to the appearance of HIV-specific CD8+ T lymphocytes. The first antibodies detected are those directed against the immunodominant region of the envelope gp41, followed by the appearance of antibodies to the structural or gag protein p24 and the gag precursor p55. Antibodies to p24 gag are followed by the appearance of antibodies to the outer envelope glycoprotein (gp120), the gag protein p17, and the products of the pol


InternalMed_Harrison

InternalMed_Harrison. protein p24 and the gag precursor p55. Antibodies to p24 gag are followed by the appearance of antibodies to the outer envelope glycoprotein (gp120), the gag protein p17, and the products of the pol gene (p31 and p66). In addition, one may see antibodies to the low-molecular-weight regulatory proteins encoded by the HIV genes vpr, vpu, vif, rev, tat, and nef. On rare occasion, levels of HIV-specific antibodies may decline during treatment of acute HIV infection.


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InternalMed_Harrison. While antibodies to multiple antigens of HIV are produced, the precise functional significance of these different antibodies is unclear. The only viral proteins that elicit neutralizing antibodies are the envelope proteins gp120 and gp41. Antibodies directed toward the envelope proteins of HIV have been characterized both as being protective and as possibly contributing to the pathogenesis of HIV disease. Among the protective antibodies are those that function to neutralize HIV directly and prevent the spread of infection to Human Immunodeficiency Virus Disease: AIDS and Related Disorders Activation, proliferation, cytokine and chemokine release additional cells, as well as those that participate in ADCC. The first neutralizing antibodies are directed against the autologous infecting 700 1:25,600 600 1:12,800 Levels of Anti-HIV antibody 1:6400 400 1:3200 300 1:1600 1:800200 100 1:400


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InternalMed_Harrison. Levels of Anti-HIV antibody 1:6400 400 1:3200 300 1:1600 1:800200 100 1:400 FIGuRE 226-27 Relationship between antigenemia and the devel-FIGuRE 226-26 Schematic representation of the different opment of antibodies to HIV. Levels of plasma HIV parallel those immunologic effector mechanisms thought to be active in the of p24 antigen. Antibodies to HIV proteins are generally seen 6–12 setting of HIV infection. Detailed descriptions are given in the weeks following infection and 3–6 weeks after the development of text. ADCC, antibody-dependent cellular cytotoxicity; MHC, major plasma viremia. Late in the course of illness, antibody levels to p24 histocompatibility complex; TCR, T cell receptor. decline, generally in association with a rising titer of p24 antigen.


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InternalMed_Harrison. 1244 virus and appear after approximately 12 weeks of infection. Due to its high rate of mutation the virus is usually able to quickly escape these (and subsequent) neutralizing antibodies. One important mechanism of immune escape is the addition of N-linked glycosylation sites, forming a glycan shield that interferes with envelope recognition by these initial antibodies. A number of broad and potent HIV-neutralizing envelope-specific antibodies have been isolated from HIV-infected individuals in studies designed to better understand the host response to HIV infection. Approximately 20% of patients develop antibodies capable of neutralizing highly diverse strains. These studies have revealed at least five major sites within the HIV envelope that are able to elicit broadly-neutralizing antibodies. These sites include antibodies directed toward the CD4 binding site (CD4bs) of gp120, those binding glycandependent epitopes in the V1/V2 region of gp120, those near the base of the V3 region


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InternalMed_Harrison. These sites include antibodies directed toward the CD4 binding site (CD4bs) of gp120, those binding glycandependent epitopes in the V1/V2 region of gp120, those near the base of the V3 region of gp120, those binding to the gp120/gp41 bridge, and those binding to the membrane-proximal region of gp41 (Fig. 226-28). Several of these antibodies contain unique features including high levels of somatic hypermutation, selective germline gene usage (especially for CD4bs antibodies) and long heavy chain complementary determining regions (especially CDRH3). Of note, while these antibodies are broadly neutralizing in vitro, their precise in vivo significance is unclear and the patients from whom they were derived demonstrate evidence of ongoing viral replication unless treated with cART. The other major class of protective antibodies are those that participate in ADCC, a form of cell-mediated immunity (Chap. 372e) in which NK cells that bear Fc receptors are armed with specific anti-HIV


InternalMed_Harrison

InternalMed_Harrison. other major class of protective antibodies are those that participate in ADCC, a form of cell-mediated immunity (Chap. 372e) in which NK cells that bear Fc receptors are armed with specific anti-HIV antibodies that bind to the NK cells via their Fc portion. These armed NK cells then bind to and destroy cells expressing HIV antigens. The levels of anti-envelope antibodies capable of mediating ADCC are highest in the earlier stages of HIV infection. Antibodies to both gp120 and gp41 have been shown to participate in ADCC-mediated killing of HIV-infected cells. In vitro, IL-2 can augment ADCC-mediated killing. In addition to playing a role in host defense, HIV-specific antibodies have also been implicated in disease pathogenesis. Antibodies directed to gp41, when present in low titer, have been shown in vitro to be capable of facilitating infection of cells through an Fc receptor– mediated mechanism known as antibody enhancement. Thus, the same regions of the envelope protein of HIV that


InternalMed_Harrison

InternalMed_Harrison. shown in vitro to be capable of facilitating infection of cells through an Fc receptor– mediated mechanism known as antibody enhancement. Thus, the same regions of the envelope protein of HIV that give rise to antibodies capable of mediating ADCC can also elicit the production of antibodies that can facilitate infection of cells in vitro. In addition, it has been postulated that anti-gp120 antibodies that participate in the ADCC killing of HIV-infected cells might also kill uninfected CD4+ T cells if the uninfected cells had bound free gp120, a phenomenon referred to as bystander killing. One of the most primitive components of the humoral immune system is the complement system (Chap. 372e). This element of innate immunity consists of ~30 proteins that are found circulating in blood or associated with cell membranes. While HIV alone is capable of directly activating the complement cascade, the resulting lysis is


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InternalMed_Harrison. FIGuRE 226-28 Known targets of broadly neutralizing antibodies against HIV-1. (Adapted from PD Kwong, JR Mascola: Immunity 37:412, 2012.) weak due to the presence of host cell regulatory proteins captured in the virion envelope during budding. It is possible that complementopsonized HIV virions have increased infectivity in a manner analogous to antibody-mediated enhancement. Given that T cell–mediated immunity is known to play a major role in host defense against most viral infections (Chap. 372e), it is generally thought to be an important component of the host immune response to HIV. T cell immunity can be divided into two major categories: that mediated by helper/inducer CD4+ T cells and that mediated by cytotoxic/immunoregulatory CD8+ T cells.


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InternalMed_Harrison. HIV-specific CD4+ T cells can be detected in the majority of HIV-infected patients through the use of flow cytometry to measure intracellular cytokine production in response to MHC class II tetramers pulsed with HIV peptides or through lymphocyte proliferation assays utilizing HIV antigens such as p24. These cells likely play a critical role in the orchestration of the immune response to HIV by providing help to HIV-specific B cells and CD8+ T cells. They may also be capable of directly killing HIV-infected cells. HIV-specific CD4+ T cells may be preferential targets of HIV infection by HIV-infected antigen-presenting cells during the generation of an immune response to HIV (Fig. 226-26). However, they also are likely to undergo clonal expansions in response to HIV antigens and thus survive as a population of cells. No clear correlations exist between levels of HIV-specific CD4+ T lymphocytes and plasma HIV RNA levels; however, in the setting of high viral loads, CD4+ T cell responses


InternalMed_Harrison

InternalMed_Harrison. as a population of cells. No clear correlations exist between levels of HIV-specific CD4+ T lymphocytes and plasma HIV RNA levels; however, in the setting of high viral loads, CD4+ T cell responses to HIV antigens appear to shift from one of proliferation and IL-2 production to one of IFN-γ production. Thus, while a reverse correlation exists between the level of p24-specific proliferation and levels of plasma HIV viremia, the nature of the causal relationship between these parameters is unclear.


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InternalMed_Harrison. MHC class I–restricted, HIV-specific CD8+ T cells have been identified in the peripheral blood of patients with HIV-1 infection. These cells include CTLs that produce perforins and T cells that can be induced by HIV antigens to express an array of cytokines such as IFN-γ, IL-2, MIP-1β, and TNF-α. CTLs have been identified in the peripheral blood of patients within weeks of HIV infection and prior to the appearance of plasma virus. The selective pressure they exert on the evolution of the population of circulating viruses reflects their potential role in control of HIV infection. These CD8+ T lymphocytes, through their HIV-specific antigen receptors, bind to and cause the lytic destruction of target cells bearing autologous MHC class I molecules presenting HIV antigens. Two types of CTL activity can be demonstrated in the peripheral blood or lymph node mononuclear cells of HIV-infected individuals. The first type directly lyses appropriate target cells in culture without prior in vitro


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InternalMed_Harrison. can be demonstrated in the peripheral blood or lymph node mononuclear cells of HIV-infected individuals. The first type directly lyses appropriate target cells in culture without prior in vitro stimulation (spontaneous CTL activity). The other type of CTL activity reflects the precursor frequency of CTLs (CTLp); this type of CTL activity can be demonstrated by stimulation of CD8+ T cells in vitro with a mitogen such as phytohemagglutinin or anti-CD3 antibody.


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InternalMed_Harrison. In addition to CTLs, CD8+ T cells capable of being induced by HIV antigens to express cytokines such as IFN-γ also appear in the setting of HIV-1 infection. It is not clear whether these are the same or different effector pools compared with those cells mediating cytotoxicity; in addition, the relative roles of each in host defense against HIV are not fully understood. It does appear that these CD8+ T cells are driven to in vivo expansion by HIV antigen. There is a direct correlation between levels of CD8+ T cells capable of producing IFN-γ in response to HIV antigens and plasma levels of HIV-1 RNA. Thus, while these cells are clearly induced by HIV-1 infection, their overall ability to control infection remains unclear. Multiple HIV antigens, including Gag, Env, Pol, Tat, Rev, and Nef, can elicit CD8+ T cell responses. Among patients who control viral replication in the absence of antiretroviral drugs are a subset of patients referred to as elite nonprogressors (see “Long-Term


InternalMed_Harrison

InternalMed_Harrison. Nef, can elicit CD8+ T cell responses. Among patients who control viral replication in the absence of antiretroviral drugs are a subset of patients referred to as elite nonprogressors (see “Long-Term Survivors and Long-Term Nonprogressors,” above) whose peripheral blood contains a population of CD8+ T cells that undergo substantial proliferation and perforin expression in response to HIV antigens. It is possible that these cells play an important role in HIV-specific host defense.


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InternalMed_Harrison. At least three other forms of cell-mediated immunity to HIV have been described: non-cytolytic CD8+ T cell–mediated suppression of HIV replication, ADCC, and NK cell activity. Non-cytolytic CD8+ T cell–mediated suppression of HIV replication refers to the ability of CD8+ T cells from an HIV-infected patient to inhibit the replication of HIV in tissue culture without killing infected targets. There is no requirement for HLA compatibility between the CD8+ T cells and the HIV-infected cells. This effector mechanism is thus nonspecific and appears to be mediated by soluble factor(s) including the CC-chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4). These CC-chemokines are potent suppressors of HIV replication and operate at least in part via blockade of the HIV co-receptor (CCR5) for R5 (macrophage-tropic) strains of HIV-1 (see above). ADCC, as described above in relation to humoral immunity, involves the killing of HIV-expressing cells by NK cells armed with specific antibodies


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InternalMed_Harrison. R5 (macrophage-tropic) strains of HIV-1 (see above). ADCC, as described above in relation to humoral immunity, involves the killing of HIV-expressing cells by NK cells armed with specific antibodies directed against HIV antigens. Finally, NK cells alone have been shown to be capable of killing HIV-infected target cells in tissue culture. This primitive cytotoxic mechanism of host defense is directed toward nonspecific surveillance for neoplastic transformation and viral infection through recognition of altered class I MHC molecules.


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InternalMed_Harrison. The establishment of HIV as the causative agent of AIDS and related syndromes early in 1984 was followed by the rapid development of sensitive screening tests for HIV infection. By March 1985, blood donors in the United States were routinely screened for antibodies to HIV. In 1996, blood banks in the United States added the p24 antigen capture assay to the screening process to help identify the rare infected individuals who were donating blood in the time (up to 3 months) between infection and the development of antibodies. In 2002, the ability to detect early infection with HIV was further enhanced by the licensure of nucleic acid testing (NAT) as a routine part of blood donor screening. These refinements decreased the interval between infection and detection (window period) from 22 days for antibody testing to 16 days with p24 antigen testing and subsequently to 12 days with NAT. The development of sensitive assays for monitoring levels of plasma viremia ushered in a new era of


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InternalMed_Harrison. days for antibody testing to 16 days with p24 antigen testing and subsequently to 12 days with NAT. The development of sensitive assays for monitoring levels of plasma viremia ushered in a new era of being able to monitor the progression of HIV disease more closely. Utilization of these tests, coupled with the measurement of levels of CD4+ T lymphocytes in peripheral blood, is essential in the management of patients with HIV infection.


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InternalMed_Harrison. The CDC has recommended that screening for HIV infection be performed as a matter of routine health care. The diagnosis of HIV infection depends on the demonstration of antibodies to HIV and/or the direct detection of HIV or one of its components. As noted above, antibodies to HIV generally appear in the circulation 3–12 weeks following infection.


InternalMed_Harrison

InternalMed_Harrison. The standard blood screening tests for HIV infection are based on the detection of antibodies to HIV. A common platform is the ELISA, also referred to as an enzyme immunoassay (EIA). This solid-phase assay is an extremely good screening test with a sensitivity of >99.5%. Most diagnostic laboratories use commercial kits that contain antigens from both HIV-1 and HIV-2 and thus are able to detect antibodies to either. These kits use both natural and recombinant antigens and are continuously updated to increase their sensitivity to newly discovered species, such as group O viruses (Fig. 226-1). The fourth-generation EIA tests combine detection of antibodies to HIV with detection of the p24 antigen of HIV. EIA tests are generally scored as positive (highly reactive), negative (nonreactive), or indeterminate (partially reactive). While the EIA is an extremely sensitive test, it is not optimal with regard to specificity. This is particularly true in studies of low-risk individuals, such as


InternalMed_Harrison

InternalMed_Harrison. indeterminate (partially reactive). While the EIA is an extremely sensitive test, it is not optimal with regard to specificity. This is particularly true in studies of low-risk individuals, such as volunteer blood donors. In this latter population, only 10% of EIA-positive individuals are subsequently confirmed to have HIV infection. Among the factors associated with false-positive EIA tests are antibodies to class II antigens (such as may be seen following pregnancy, blood transfusion, or transplantation), autoantibodies, hepatic disease, recent influenza vaccination, and acute viral infections. For these reasons, anyone suspected of having HIV infection based on a positive or inconclusive EIA result should 1245 ideally have the result confirmed with a more specific assay such as the Western blot. One can estimate whether an individual has a recent infection with HIV-1 by comparing the results on a standard EIA test that will score positive for all infected individuals with the


InternalMed_Harrison

InternalMed_Harrison. Western blot. One can estimate whether an individual has a recent infection with HIV-1 by comparing the results on a standard EIA test that will score positive for all infected individuals with the results on an assay modified to be less sensitive (“detuned assay”) that will score positive for individuals with established HIV infection and negative for individuals with recent infection. In rare instances, an HIV-infected individual treated early in the course of infection may revert to a negative EIA. This does not indicate clearing of infection; rather, it signifies levels of ongoing exposure to virus or viral proteins insufficient to maintain a measurable antibody response. When these individuals have discontinued therapy, viruses and antibodies have reappeared.


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InternalMed_Harrison. The most commonly used confirmatory test is the Western blot (Fig. 226-29). This assay takes advantage of the fact that multiple HIV antigens of different, well-characterized molecular weights elicit the production of specific antibodies. These antigens can be separated on the basis of molecular weight, and antibodies to each component can be detected as discrete bands on the Western blot. A negative Western blot is one in which no bands are present at molecular weights corresponding to HIV gene products. In a patient with a positive or indeterminate EIA and a negative Western blot, one can conclude with certainty that the EIA reactivity was a false positive. On the other hand, a Western blot demonstrating antibodies to products of all three of the major genes of HIV (gag, pol, and env) is conclusive evidence of infection with HIV. Criteria established by the U.S. Food and Drug Administration (FDA) in 1993 for a positive Western blot state that a result is considered positive if


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InternalMed_Harrison. is conclusive evidence of infection with HIV. Criteria established by the U.S. Food and Drug Administration (FDA) in 1993 for a positive Western blot state that a result is considered positive if antibodies exist to two of the three HIV proteins: p24, gp41, and gp120/160. Using these criteria, ~10% of all blood donors deemed positive for HIV-1 infection lacked an antibody band to the pol gene product p31. Some 50% of these blood donors were subsequently found to be false positives. Thus, the absence of the p31 band should increase the suspicion that one may be dealing with a false-positive test result. In this setting it is prudent to obtain additional confirmation with an RNA-based test for HIV-1 and/ or a follow-up Western blot. By definition, Western blot patterns of reactivity that do not fall into the positive or negative categories are considered “indeterminate.” There are two possible explanations for an indeterminate Western blot result. The most likely explanation in a


InternalMed_Harrison

InternalMed_Harrison. do not fall into the positive or negative categories are considered “indeterminate.” There are two possible explanations for an indeterminate Western blot result. The most likely explanation in a low-risk individual is that the patient being tested has antibodies that cross-react with one of the proteins of HIV. The most common patterns of cross-reactivity are antibodies that react with p24 and/or p55. The least likely explanation in this setting is that the individual is infected with HIV and is in the process of mounting a classic antibody response. In either instance, the Western blot should be repeated in 1 month to determine whether the indeterminate pattern is a pattern in evolution. In addition, one may attempt to confirm a diagnosis of HIV infection with the p24 antigen capture assay or one of the tests for HIV RNA (discussed below). While the Western blot is an excellent confirmatory test for HIV infection in patients with a positive or indeterminate EIA, it is a poor