Human Immunodeficiency Virus (HIV) is a lentivirus, a group of retroviruses, that causes slow development of acquired immunodeficiency syndrome (AIDS). This results in immune system failure and increased suscepibility to life-threatening infections. HIV occurs as two types: HIV-type 1 (HIV-1) and HIV-type 2 (HIV-2). The HIV-2 strain is limited to Western and Central Africa.[1] The HIV-1 type acts as the primary cause of (AIDS) throughout the world.[1] The focus of this text is on HIV-1. Virus transmission occurs through transfer of blood, vaginal fluid, semen, pre-ejaculate, or breast milk. The primary modes of transmission are unprotected sex, breast milk, contaminated needles, and transmission at birth by an infected mother.

The most recently reported prevalence in the United States of those living with diagnosed or undiagnosed HIV infection was 1.1 million adults and adolescents (prevalence rate: 447.8 per 100,000 population). [2] The latest number of new cases per year in the United States has been reported at an incidence of 56,300.[3]


In order to thoroughly understand HIV/AIDs, it is paramount to understand the normal immune system response to infection and thus, how the HIV virus disrupts this system. The human body has typical physical barriers which protect us from pathogens including the gut, skin, urinary tract and mucous membranes of the bronchi. The organism is protected from infection and disease when the immune system is working properly; however, failure of the system can result in infection or disease that is localized or systemic. Due to the diversity of existing pathogens, the immune system has to respond in a variety of ways and the response depends on the type of antigen presented. Two immune responses work together to prevent entry of pathogens and destroy them upon penetration into the organism: Innate immunity and Adaptive/Acquired immunity.[4]

Innate Immunity

The innate immunity is the body’s first line of defense involving the skin and mucosal barriers as well as a nonspecific inflammatory response. [4] The main purpose of innate immunity is to rapidly contain an infection or pathogen once present in order to slow down the replication and spread of the pathogen. If the pathogen cannot be destroyed by the innate system alone, the adaptive immune system is mobilized. Once the adaptive response is initiated, the innate immunity also plays a critical role for amplifying, modulating, and sustaining the adaptive immune responses.[5]

The innate system cannot adapt to repeated exposure of a pathogen and does not distinguish between different invaders (non-specific).[4] Therefore, it responds the same way every time an antigen is encountered. The innate immune system uses structures known as pattern recognition receptors (PRRs) to identify pathogens by a few evolutionary structures presented on large groups of microorganisms, termed pathogen-associated molecular patterns (PAMP)s. Once the PRRs recognize a PAMP they activate a proinflammatory response that ultimately leads to production of cytokines, chemokines, and anti-viral type I interferon. (IFN)[6] IFNs use a variety of mechanisms to curb viral replication which include shutting-down protein synthesis and degrading foreign nucleic acid.[7]

The primary cells of the innate system are phagocytes (monocytes, macrophages, and neutrophills) which engulf the foreign material and release toxins to destroy them.[4] Dendritic cells are specialized cells that constantly sample their environment searching for pathogens and once found present these antigens to the lymphocytes(B and T cells) to initiate the adaptive immune response.[8]

Inflammatory mediators (mast cells, eosinophils, and basophils) and natural killer (NK) cellsare also involved in innate immunity. Inflammation plays a key role in triggering an immune response that consists of a physiological cascade of events that responds to injury or infection. [4] Once macrophages encounter damaged tissue or bacteria they release cytokines which perform three functions in inflammation. (1) Induce vasodilation to allow for more circulating immune cells to reach the area, leads to redness and heat (2) Increase permeability of blood vessels, resulting in edema (3) Act as chemoattractant for leukocytes (neutrophils and monocytes). [4] These immune cells then destroy the pathogens and promote healing. [4]

Adaptive Immunity

This system complements the innate immune response by developing more specific responses in order to protect the organism from those pathogens that get past the innate cells. The adaptive immunity initiates a highly selective and specific response which becomes more effective on repeated exposure (memory). The recognition of the antigen is the foundation of adaptive immunity and requires two responses within this system to work together to make this system effective: Humoral Immunity and Cell-Mediated Immunity.[4]

Humoral Immunity

Antibodies present in the saliva, blood, or vaginal secretions mediate the humoral response and are very effective against foreign substances that can be easily reached and neutralized. B lymphocytes (B cells) are coated in immunoglobulin, originate in the bone marrow, circulate in the extracellular fluid, and are responsible for producing the antibodies. An antibody is a receptor on each B cell that can recognize a specific antigen and immobilize it, thus preventing it from causing infection. B cells mature in the bone marrow where they change into plasma cells and memory B cells. The plasma cells produce a specific antibody to the antigen it meets and secretes the antibody into body fluids. Memory cells circulate for about 1 year or longer in the blood, lymph, and tissues to respond to repeated exposure to the same antigen for a more sustained and stronger immune response. The response of humoral immunity is quicker than cell-mediated immunity, thus more responsible for acute bacterial infections.[4]

Cell-Mediated Immunity

Like humoral immunity relies on B lymphocytes, cell-mediated immunity requires the function of T lymphocytes. (T cells) T cells are more specific than B cells and can recognize organisms that hide inside cells (where antibodies cannot reach them) and destroy them on a cell-to-cell basis. The precursors of T lymphocytes begin in the bone marrow but mature in the thymus where they learn to discriminate self from non-self. The T cells then circulate in the blood, lymph, and lymph nodes. The cell-mediated immunity is mostly responsible for fighting foreign organisms such as viruses, bacteria, fungi, etc.[4]

Once a T cell interacts with a specific antigen, it produces a number of additional lymphocytes such as helper T cells (CD4+) and cytotoxic T cells (CD8+). Helper T cells recognize foreign antigens (synthesized outside the cell) bound to host proteins and aid the B cells to produce antibodies. The CD4+ T cells also aid in the stimulation of the CD8+ T cells, through production of cytokines. The CD8+ T cells target and lyse virally infected cells by recognizing foreign antigens (synthesized within the cell) bound to host proteins. T lymphocytes therefore, are capable of turning the entire immune system on or off. This component is very important in regards to the immune response to HIV and will be discussed in further detail. [4]

In regards to the adaptive immune system, cytokines are responsible for proliferation and maturation of the lymphocytes that produce them. When an antigen binds to a B or T cell, they produce cytokines which in turn begin proliferation of the B and T cells in the lymph nodes. There is a 1000 fold expansion within 3-4 days of the responding cell allowing them to enter the circulatory system and be attracted to the site of infection by other cytokines and chemokines involved in the inflammatory response.[4] With repeated exposure to these antigens, the large population of B and T cells are maintained and are involved in the long-term memory for a more rapid response the next time the host is infected with that pathogen. [9]

General Immune Response to Infection

The immune system has a variety of responses based on the pathogen that is presented; therefore, it is difficult to define the typical response. There are overarching processes that occur and are described briefly here. When a pathogen gets past the innate immune system, the following are possible responses:

  • Humoral Response: B lymphocyte recognizes the bacteria and makes antibodies that bind to it and neutralize it (prevents them from replicating and invading host cells)
  • Cell-mediated Response to a bacteria: T lymphocyte recognizes the bacteria and produces cytokines which help the macrophages perform phagocytosis of the bacteria
  • Cell-mediated Response to a virus: T lymphocyte (cytotoxic T cells) recognizes the virus and destroys it (Cytotoxic Reaction)
  • Innate Immunity: Complement system recognizes foreign organism and destroys it.[4]

The innate and adaptive immunity can also work together with the following possible responses:

  • Antibodies produced by B cells (adaptive immunity) bind and coat the bacteria making it more available for the phagocytes of the innate immune system to initiate phagocytosis
  • Cytotoxic T cells (adaptive immunity) and NK cells (innate immunity) are activated and directly attack cells that have been mutated by a malignant process or virus.
  • T cell recognizes the foreign invader and produces hormones (lymphokines) to help the macrophages destroy it.[4]

Virus Structure - HIV

HIV is a lentivirus that causes slow development of disease. Lentiviruses are a group of retroviruses, which means that they require the enzyme reverse transcriptase for transcription of its ribonucleic acid (RNA) encoded genes into DNA. The human immunodeficiency virus is spherically shaped with an outer phospholipid bilayer that surrounds the inner contents.[10] Multiple couplets of glycoproteins (gp 120 and gp41) are embedded over the outer surface of the virus and act as receptors for binding to host cell membrane receptors. The gp41 portion crossing the viral phosphoplipid bilayer anchors the receptor to the membrane while the gp120 portion lies at the extracellular end of the gp41 stem. Inside the virus, a protein capsid surrounds the primary components of the virus that are essential for replication. Two single strands of identical RNA with reverse transcriptase, integrase, and protease enzymes lie within the capsid.[1], [10] Other necessary proteins are encoded on the viral RNA. The virus relies on host cell components and mechanisms to synthesize these proteins.

The viral RNA encodes genes for proteins and enzymes essential to HIV replication and survival. The gag gene encodes structural proteins of the virus core (p6, p7, p24) and matrix (p17).[1] The viral cell membrane glycoprotein codes (gp41 and gp 120) are found on the env gene.[1] The viral replication enzymes, reverse transcriptase and integrase, are encoded on the pol gene of the virus.[1] Reverse transcriptase changes viral RNA into DNA. Integrase integrates viral DNA into the chromosomal DNA of the host. Integrase also modifies viral proteins into their useable form.[1] Other viral genes encode for various other viral proteins and factors for survival.

The small HIV protein, Nef, is essential to viral production and infectivity. Without Nef, disease progression is virtually non-existent.[11] No person has been known to die of AIDS when infected with a Nef-deleted virus.[11] Targeting Nef in antiviral medication is difficult because of its many functions. A pharmaceutical against Nef may only interfere with one or two of its complex activities.[11] In vitro studies have discovered four key Nef functions that play possible roles in pathogenesis. 1) Nef downregulates cell surface levels of CD4 and induces degradation of internalized CD4 receptors in the cytoplasm.[11] 2) Nef downregulates cell surface levels of major histocompatibility class I (MHCI) molecules.[11] With fewer CD4 receptors and MHCI molecules, viral replication within the host cell could proliferate without less risk of attack by an intracellular or extracellular immune response.[11] 3) Nef mediates cellular signaling and activation, especially partially active T-cells.[11] Enhanced cellular signaling could augment viral production. 4) Nef enhances viral particle infectivity by overcoming normal cell barriers, such as cell entry blocked by an unknown surface protein and/or internal actin filaments or proteosomal degradation upon virus insertion into the host cell.[11] The exact in vivo mechanism of Nef’s contribution to HIV pathogenesis is not known, therefore pharmaceutical interventions have not been directed at Nef. Refer to Table 1 for major viral components of HIV-1.

Table 1: Major Viral Components and Functions.[1]

Viral Component Function Encoding Gene
gp 120 (a glycoprotein) Located on gp 41 on external cell membrane for recognition and binding to host cell receptors env
gp 41 (a glycoprotein) Transmembrane glycoprotein that aids hostcell receptor binding env
p17 A protein that forms the structural matrix within the virus gag
p24 A protein that forms the capsid that holds the RNA components and reverse transcriptase within the virus gag
Reverse transcriptase An enzyme that converts single stranded viral RNA into double stranded DNA pol
Integrase An enzyme that integrates viral DNA into host cell (provirus) chromosomal DNA for eventual replication; also modifies proteins made by virus pol
RNA Single stranded viral RNA – two copies are stored in the capsid
Tat protein A regulatory protein found early after infection – promotes HIV gene expression into RNA transcripts in the nucleus tat
Rev protein A protein involved with exporting messenger RNA and genomic RNA from host cell nucleus to cytoplasm rev
Vpr (viral protein "r") A protein that halts cell cycle and allows viral DNA to enter host cell nucleus in non-dividing cells (e.g. macrophages) vpr
Vpu (viral protein "u") A protein that facilitates release of virions from the host cell vpu
Vif (viral infectivity factor) A protein for augmenting effectiveness of new virus particles vif
Nef (necessary and enforcing factor) A multiple function protein – Cell signal transduction, Host cell CD4 receptor and MHCI down-regulation to evade immune response nef
Protease Cleaves strands of viral peptide chains into final protein products pol

HIV Targets[1]

Any immune system or central nervous system (CNS) cells containing CD4 cell membrane receptors and the appropriate co-receptor on the plasma membrane.
 Circulating T-lymphocytes – co-receptor type: CCR5
 T-cell precursors in the thymus and bone marrow – co-receptor type: CXCR4
 Monocytes and macrophages – co-receptor type: CCR5
 Eosinophils
 Dendritic cells of CNS – co-receptor type: CCR5
 Microglial cells of CNS

The CD4 molecule normally acts as a co-receptor of the major histocompatibility complex class II molecule for recognition of extracellular foreign bodies (antigens) by the T-cell.[1] When HIV binds to CD4, the gp120 alters its structure so that it can attach to the chemokine receptors on the cell membrane. These chemokine receptors (CCR5 and CXCR4 mainly) are necessary for complete HIV binding. Next, the extracellular portion of gp41 forms a loop structure that brings the virus and host cell membranes close to each other. Fusion of the membrane occurs and the viral capsid enters the host cell.

HIV Tropism

Tropism refers to the receptors the HIV virus is attracted to. After the initial binding to a host cell by viral gp120 surface receptor onto CD4, the virus must bind to a co-receptor to secure it to the host cell membrane. The M-tropic (M indicates macrophage) strains of HIV-1 use the beta-chemokine receptor, CCR5, for cell entry into macrophages, CD4+ T-cells, and dendritic cells. The T-tropic (T for T-cell) HIV strains successfully bind to the alpha-chemokine receptor, CXCR4, for entry into CD4+ T-cells and macrophages. 1 HIV isolates that are M-tropic are known as R5 viruses, while those that are T-tropic are referred to as X4 viruses. 1 HIV isolates that can bind to both CXCR4 and CCR5 are called X4R5.1 Other co-receptors are used by HIV, but CXCR4 and CCR5 are the most commonly used.

HIV Replication (See Fig. 1)

Replication of HIV is carried out through 6 essential steps: 1) host cell binding and entry, 2) uncoating of the capsid, 3) reverse transcription of the viral RNA, 4) integration of the viral DNA complex into host DNA, 5) virus protein synthesis and assembly, 6) exocytosis or storage of viral RNA in the host cell.[1]

Step 1: Host cell binding and virus entry

The HIV gp120 surface receptor links to the CD4 membrane protein of immune system T-cells, monocytes/macrophages, eosinophils, dendritic cells in epithelial tissue, and mircoglial cells in the central nervous system.[1] To complete host cell binding, the gp 120 complex then transforms its shape to expose a domain specific for a chemokine receptor (e.g. CCR5 or CCXR4), which it must also bind to. This double receptor attachment firmly secures the virus on the target cell and the gp41 fuses with the host cell membrane.[1] The viral capsid subsequently is released into the host’s cytoplasm.[1]

Step 2: Uncoating the viral capsid

The two single strands of RNA, reverse transcriptase, integrase, and protease are released into the cytoplasm when the capsid of the virus dissembles.[1]

Step 3: Transcription

With the use of host cell machinery and components in the cytoplasm, reverse transcriptase creates a proviral complementary double-helix DNA (cDNA) copy of the original viral RNA.[1] Integrase then cleaves a guanine-thymine dinucleotide from the 3’ end of each long terminal repeat on the cDNA.[9], [1] These two “sticky ends” will be utilized during integration of the proviral DNA into the host genome.[1] A preintegration complex (PIC) consisting of the cDNA, integrase, matrix proteins, viral protein R (Vpr), and host cell proteins is transported to the nucleus.[9] The exact mechanism of transport to the nuclear membrane has not been identified, but a possible microtubule-actin network has been suggested with early research.[12]

Once at the surface of the nucleus, interaction of the PIC’s Vpr and integrase with various nuclear pore proteins allows entry into the nucleus.[12] The PIC is larger than nuclear pores. Thus, ATP is required to facilitate active transport of the PIC into the nucleus.[9]

Step 4: Integration into host cell DNA

Inside the nucleus, integrase controls attachment of the provirus’ 3’ hydroxyl groups (i.e. sticky ends) to the 5’ phosphate end of the target site on the host DNA.[13] Unpaired dinucleotides at the provirus’ 5’ ends are removed and any gaps between viral and host DNA are repaired by host DNA enzymes, which completes the integration process.[13]

Step 5: Virus protein synthesis and assembly

Host RNA polymerase transcribes the viral genome into RNA molecules. A long-terminal repeat (LTR) sequence located at the 5’ end of the integrated provirus has numerous binding sites for several transcription factors to ensure HIV-1 RNA transcription from the DNA complex.[12] One of the most commonly studied transcription factors is NF-KB (nuclear factor kappa-light-chain-enhancer of activated B-cells).[12] This factor controls transcription and is upregulated by LTR, which enhances recruitment of RNA polymerase to LTR.[9] Binding of the viral protein, transcriptional activator (Tat), at the LTR sequence promotes transcription of longer copies of the viral genome than would normally occur with basal activation and control of transcription.[9], [1], [12] Without Tat, short mRNA sequences would be produced. In other words, Tat takes over control of transcription from the host cell once NF-KB is bound to the LTR.

The transcribed viral RNA will either be spliced into smaller pieces (i.e. removal of noncoding nucleotide sequences called introns) to become mRNA or it will be partially spliced or remain unspliced. Early synthesis and adequate accumulation of the viral protein, Rev, assists in the export of viral RNA from the nucleus. Host ribosomes translate viral mRNA into viral proteins.1 HIV-1 protease, which was released into the cytoplasm earlier, cleaves translated strands to complete synthesis of gp120, gp 41, p24, p17, and other viral proteins.

Unspliced RNA contains the full HIV genome. Pairs of these RNA strands are brought together with replication enzymes and proteins while in the cytoplasm.[1], [12] The capsid around the replication materials will be formed by the protein, p24.[1] The viral protein, p17, eventually will assemble the matrix underlying the outer plasma membrane when the virion is released from the host cell.[1] These viral components make up the immature virion, which is shuttled to the host plasma membrane.

Step 6: Exocytosis or storage within the host cell

The immature virion is released into the extracellular space from the host cell by evagination of the host cell plasma membrane.[1] The virus matures while floating in the extracellular material and becomes ready to infect other cells.[1]

In T-lymphocytes, viral budding at the cell membrane results in release of virions into extracellular space.[1] In monocytes and macrophages, viral budding results in intracellular vacuoles which may be released into extracellular space or remain in the host cell resulting in latent reservoirs of HIV.[1] This latency creates one of the greatest challenges to combatting HIV infection because antiretroviral (ARV) medications are ineffective against the virus in this state.[9],[1]

Inhibition of release of viral products appears to be controlled by the host cell transmembrane protein, tetherin. Tetherin binds the virus/viral particles to the inner plasma membrane.[14] Viral protein “u” (Vpu) counteracts tetherin by degrading it to allow release of viral particles from the host cell.[15]
Figure 1: HIV Replication Process[16]


Mutations and latency as inhibiting factors of complete HIV eradication

HIV variability occurs due to regular mutations of the initial viral RNA.[1] Errors by reverse transcriptase or during rapid viral replication in the host nucleus account for these errors.[1] These mutations are beneficial to HIV survival in that HIV-1 specific CD4+ and CD8+ cells cannot eradicate new strains of the virus because they fail to recognize the gp120 residue alterations.[17], [18]
Preintegration latency can occur in CD4+ cells from three main host cell causes. First, insufficient ATP supply for PIC transport into the nucleus will prevent integration of viral DNA into the host genome.[9] Second, preintegration latency also can be affected by an inadequate supply of the host cell’s cytoplasmic nucleotide pool, since the virus relies on the host to provide these building blocks.[9] Third, the presence of polynucleotide-cytidine deaminases, APOBEC (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide), act in an antiviral capacity.[9] One host cell enzyme of this type, APOBEC3G, deaminates cytidine during reverse transcription that results ultimately in producing a stop codon to prevent subsequent viral life cycle stages.[19] Non-permissive cells, such as CD4+ T-cells, then are left with non-infectious HIV particles.[9], [19]


The innate and adaptive immune responses are both activated once HIV has infected the host, but they appear to be inadequate or too late to eradicate the virus.[4] The role of the adaptive immune response has been researched in greater detail as opposed to the more recent recognition and appreciation for the importance of the innate system in the pathogenesis of HIV. [6] Researchers are looking to answer the questions regarding HIV pathogenesis and why the host is unable to prevent the virus from establishing reservoirs of latent virus during acute HIV infection.[6]

HIV infection’s natural history is characterized by very high levels of virus circulating with a rapid decline in CD4+ T cells during the acute phase.[6] The primary targets (which become host cells) for the HIV virus are the memory T cells in the mucosa that express CD4 and CCR5.[6] At this point, it is thought that the innate immune system is activated and may recruit macrophages and lymphocytes, which are also targets of the HIV virus.[6]

Once the virus has entered the host cells, the viral genome is transcribed and integrated with the host DNA and begins replicating many times[4], as described above. During this stage, the person is still asymptomatic. The presence of antibodies in the blood, known as seroconversion, takes place in the first 3-6 weeks of the replication process.[4]

Further infection is achieved when the virus and viral-infected cells reach the lymph nodes, where activated CD4+CCR5+ T cells are targeted by the virus.[6] Thus, the immune system’s response actually spreads the virus by presenting it to additional immune cells (T-cells) that can be further infected; resulting in the massive depletion of CD4+ memory T cells. The CD4 count is a way to track the progress of the HIV infection; at this stage the CD4 count is still above 500 cells/mm3.[4]

After 21-28 days, the virus enters the blood again to infect the remaining lymphocytes resulting in peak plasma viraemia along with decreased numbers of peripheral CD4+ T cells.[4][6] During this peak viral load, the virus now becomes clinically apparent (flu-like symptoms) as the CD4 count has decreased to 200-500 cells/mm3.[4]

Following the acute phase, the immune system responds strongly in order to decrease the viral load and increase the circulating CD4+ T cells; however, despite this attempt the host is not able to clear the infection[6]. Over 12-20 weeks, the viral load eventually decreases which begins a more chronic stage of infection.[6] Although circulating CD4+ T cells return to a near normal level, studies have found accelerated cell turnover and massive activation of the immune system during this chronic HIV infection.[6] When an individuals’ CD4 (T cell) count is below 200 cells/mm3, it is known as acquired immunodeficiency syndrome (AIDS) indicating profound immunosuppression and the individual is susceptible to opportunistic infections.[4]Refer to Figure 2.

Figure 2: CD4 and Viral Load Levels Throughout Disease Progression[20]


Immune Response to HIV-1

Innate Immune Response
Monocyte-Macrophage: The infection of the family of monocyte-macrophage cells by HIV-1 results in a persistant and chronic low-level infection. Cytokine interactions can manipulate the genomic activation of integrated viral DNA in these cells. Studies have found that in monocytes and macrophages that are infected, interleukin 1 (IL-1), IL-8, and tumor necrosis factor (TNF)-α strongly upregulates viral replication of HIV-1.[9] TNF-α is a cytokine secreted by T cells, NK cells, and macrophages; it is a powerful activator of the transcription factor NF-κB ([9]. NF-κB is translocated into the nucleus and ultimately makes the HIV-1 LTR more accessible and results in viral transcription. [9][6] This is one example of how HIV exploits the host cells’ machinery to its advantage. Further detail about the IL effects can be found in the Table 2.

NK Cells: During HIV-1 infection, NK cells proliferate in a typical pattern by early stimulation of type 1 interferons secreted by dendritic cells as well as increased expression of interleukin-15.[9] These NK cells are the first line of defense to control the virus by mediating the non-specific lysis of the targeted cells[9]. Through the release of various cytokines (IFN-γ, TNF-α, and chemokines), a strong adaptive immune response is activated that leads to T cell proliferation and a reduction in viral replication.[9] NK cells also produce IFN-γ when stimulated by IL-18, which in turn may lead to inhibition of viral replication in the affected monocytes and macrophages and could result in viral latency.[9] Disruption of the NK cell function can result in a general weakening of innate immunity of the host during the HIV infection; the precise role is not yet fully understood. [5]

Adaptive Immune Response

CD4+ T-cells: CD4 T cells are part of the second line of defense of the immune system along with CD8+ T cells and B cells. The CD4 T cells differentiate into effector T cells that activate their target cells through production of cytokines to help destroy pathogens [9]. Interleukin (IL)-2 is one type of cytokine secreted by an effector T cell that upregulates HIV-1 replication in certain cells but can also stimulate CD8+ T cells that result in suppression of HIV-1 replication in other cells. [9] IL-16 and IFN-α also have effects on T cells and can be seen in Table 2.


HIV-1 infection and replication is highly regulated by cytokines produced by a variety of cells. The effects of cytokines on HIV-1 can be inhibitory, stimulatory, or both.[21] The cytokines involved in HIV include Tumor Necrosis Factors (TNF), a variety of interleukins (IL), interferons (IFN), and macrophage-colony stimulating factors (M-CSF).[21][22] [9] The cells that produce, cells that are targeted by, and the mode of action of each cytokine are discussed in Table 2.

Table 2: Major Cytokines Involved in HIV-1 Infection

Stimulatory Cytokine Produced by Cell Targeted Mode of Action
TNF-α Monocytes, macrophages,T cells, B cells, NK cells, and neutrophils [9] Monocytes and macrophages Powerful activator of transcription factor NF-κB.[21][22] [9]Activation of NF-κB is followed by nuclear translocation and binding to HIV long-terminal repeat (LTR), which leads to initiation or increases in viral transcription[22].
M-CSF Fibroblasts and endothelial cells[21] Macrophages[21] Stimulates increased surface expression of CD4 and CCR5 receptors. Results in greater HIV-1 entry and replication.[21]
IL-1 Monocytes, macrophages, and neutrophils[9] Monocytes and macrophages[9] Upregulates HIV-1 viral replication in infected monocytes and macrophages. Stimulates HIV-1 expression in U1 latently-infected cells[9]
IL-6 T cells, B cells, and macrophages[21] Monocytes and macrophages[9] Synergizes with TNF-α to stimulate HIV expression in latently infected cell lines. Potentiates TNF-α-induced HIV-1 production and transcription of NF-κB.[9]
IL-12 Macrophages and dendritic cells[9] T cells[9] Stimulates HIV-1 replication in peripheral blood mononuclear cells (PBMC), CD4+ T cells, and T cell lines. It also triggers IFN-γ production. [9]
Inhibitory Cytokine Produced by Cell Targeted Mode of Action
IFN-α Leukocytes and dendritic cells[9] T cells, monocytes, macrophages Inhibits replication of HIV-1 by suppressing reverse transcriptase.[9]
IL-10 Monocytes, macrophages, T cells, and B cells[21] Macrophages[21] Inhibits replication of HIV-1 in the early stages of infection. Inhibition is associated with its ability to down-modulate production of IL-6 and TNF-α[21].
IL-13 Dendritic cells and T cells Macrophages[21] Inhibits HIV-1 infection and production by down-modulating CCR5 expression on macrophages, blocks revers transcription, and suppresses HIV-1 replication at the post-transcriptional level.[9]
IL-16 T cells, mast cells, eosinophils[9] CD4+ T cells[9] IL-16 is a natural ligand for the CD4 receptor, so it inhibits HIV-1 entry into CD4+ T cells^^1,[9]
Bifunctional Cytokine Produced by Cell Targeted Mode of Action
IL-4 CD4+ T cells, mast cells, NK cells, and basophils[21] Monocytes and macrophages[21] IL-4's role is determined by the state of maturation of monocytes into macrohpages. IL-4 induces NF-κB nuclear translocation stimulates HIV-1 replication in slowly maturing monocytes, but inhibits CCR5 expression and HIV-1 replication in young monocytes[21].
IFN-γ T cells and NK cells[21] Monocytes and macrophages[21] Inhibits viral entry through down-modulation of CD4 surface expression. However, it stimulates HIV-1 replication when stimulating chronically infected macrophages or when introduced in the presence of TNF-α.[21]

Mitochondria & Apoptosis in HIV infection

Mitochondria are often referred to as the power house of the cell, as it produces 90% of cellular ATP through the process of oxidative phosphorylation. The chemiosmotic theory states the energy gained by respiration is converted into an electrochemical gradient across the inner mitochondrial membrane, which is thus used for ATP production. [23] While mitochondria play a vital role for the survival of a cell through ATP synthesis, they also play a role in apoptosis (programmed cell death) initiation. Specifically, mitochondria initiate apoptosis through loss of membrane potential and alterations in mitochondrial membrane permeability. [24] Changes in permeability result in release of several molecules into the cytosol of the cell which include (1) direct caspase activators (ie: cytochrome c) (2) indirect caspase activators (ie:SMAC/DIABLO) (3) apoptotic activators independent of caspases (ie: apoptosis inducing factor). [25] It has been well documented that HIV-1 greatly affects the regulation of apoptotic pathways, both directly (through the action of viral gene products) or indirectly (through cell metabolism alterations which cause deregulation of extrinsic or intrinsic apoptotic pathways). [24] Apoptotic mechanisms can be distinguished as intrinsic or extrinsic cell signaling pathways. The intrinsic pathway is mediated by mitochondrial dysfunction, which is thought to be associated with translocation of members of the Bcl-2 protein family, including Bax. [25] Bcl-2 proteins promote cell survival and hinder apoptosis; Bax proteins promote cell death. These proteins are commonly used as markers of increased or decreased apoptosis cellular signaling. [25] The extrinsic pathway is mediated by the activation of cell surface receptors, which are members of the tumor necrosis factor receptor (TNF-1) family. Binding of these death receptors to their ligands activates initiator capsase-8, leading to apoptotic cell death. [25]

Recent studies have primarily focused on the effects of HIV pharmacological interventions on mitochondria. However, it has been shown that HIV directly affects mitochondrial function by impairment of complex 1 function of the electron transport chain. The ability of HIV to alter mtDNA remains highly debatable. [24] Two studies have documented a reduction of mtDNA in peripheral blood mononuclear cells among HIV+ patients, who have not undergone previous therapy. [26], [27] This suggests that the decline in mtDNA occurs secondary to the HIV infection, rather than as solely an effect of pharmaceutical interventions, which was previously thought to be true.

It has also been well documented that apoptosis is a primary mechanism responsible for CD4 T cell decline in HIV infected patients. Both CD4+ and CD8+ T cells demonstrate a decrease in cell membrane potential, and subsequent apoptosis. [25] The env, nef, tat, and vpr genes produce important viral proteins, which play a key role in the death-inducing property of HIV. Env-induced apoptosis occurs through the intrinsic pathway of apoptosis. Env proteins have been associated with increased activation of caspase 3, increased Bax expression, and decreased Bcl-2 expression. [25] It has been hypothesized that Env proteins of infected cells interact with CD4/CXCR4 or CD4/CCR5 complex of uninfected cells, which results in a rapid decrease of inner mitochondrial membrane potential. Alterations of membrane potential change the passage of ions through the membrane, initiating apoptosis in lymphocytes. [28] Nef protein is necessary for the efficient replication of any virus. Nef has been shown to have both pro-apoptotic and anti-apoptotic properties. Nef can trigger apoptosis through the extrinsic pathway by Fas and Fas-L interactions (members of the tumor necrosis factor ligand family). In addition, Nef can trigger apoptosis through the intrinsic pathway by decreasing Bcl-2 expression in HIV infected cells. [29] Interestingly, Nef also blocks apoptosis in infected T cells, in order to maintain replication of the virus in the host cell. Tat-induced apoptosis involves the intrinsic pathway which results in decreased Bcl-2 expression, increased Bax expression, and increased activation of caspase 8 and 10. [24] In addition, Tat translates into the mitochondria, resulting in increased mitochondrial membrane permeability and decreased mitochondrial superoxide dismutase (SOD2). A decrease in SOD2 reduces the cell’s ability to neutralize reactive oxygen species (ROS) produced in the mitochondria, increasing the cell’s susceptibility to apoptosis. [30] Finally, Vpr initiates apoptosis by decreasing the expression of Bcl-2. Furthermore, Vpr causes increased permeability of the inner mitochondrial membrane, swelling of mitochondria, and subsequent bursting of the outer mitochondrial membrane. [24] See Table 2 for the effect of HIV proteins on apoptosis.

Table 2: HIV Proteins and Apoptosis[31]

HIV Protein Mode of Action Impact on Apoptosis
Env Stimulates activation of CD4 and chemokine receptors Increased
Nef 1)Activation of Fas-L expression 2)Down-regulation of CD4 1)Increased 2)Inhibited
Tat 1)Induces transduction in Fas- dependent manner 2)Increased Bax expression 1)Increased 2)Inhibited
Vpr Decreased expression of Bcl-2 Inhibited

HIV and Neuroendocrine System

HPA Axis (See Fig. 3)

The primary role of the Hypothalamic-Pituitary-Adrenal axis (HPA axis) is to maintain the basal and stress-related homeostasis of the central nervous system (CNS). When stimulated, a cascade of interactions is set off and any disruption has a significant impact on circulatory, behavioral, endocrine, immune, and cognitive functions. Several studies have shown that HIV-1 infection results in HPA axis activation and abnormality.[32] There are proposed mechanisms to explain this phenomenon.

Figure 3: HPA Axis[33]


Cytokines have a major role in activating the HPA axis in those infected with HIV. Cytokines act as inflammatory signals and they are produced as a result of the innate and adaptive immune system activation. The cytokines associated with HIV include tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 and IL-6.[32] They directly activate the hypothalamus. Cytokines also directly cause adrenocorticotropic hormone (ACTH) release from the pituitary gland and cortisol release from the adrenal glands. ACTH leads to secretion of glucocorticoids, such as cortisol. Simultaneously, the HIV envelope protein gp120 stimulates the HPA axis and causes additional glucocorticoid secretion. Additionally, one of the proteins associated with HIV, the HIV-viral protein R (vpr), can interact with corticosteroid receptors leading to glucocorticoid resistance or sensitivity depending on the tissue.[34] The overall effect of the increase in HPA axis and receptor stimulation is hypercortisolemia.[35]

A high concentration of serum glucocorticoids has been shown to cause atrophy and dysfunction of the hippocampus.[36] The hippocampus, found in the medial temporal lobe of the brain, helps regulate the secretion of trophic hormones, such as corticotrophic releasing hormone (CRH), from the hypothalamus. The primary purpose of CRH is to cause proopiomelanocortin (POMC) gene transcription to build the POMC peptide that allows formation of ACTH and other hormones.[36] The disruption in this mechanism results in further neuroendocrine dysfunction.

Furthermore, increased serum cortisol inhibits the production of cytokines, thus decreasing T-cell proliferation and function. A study performed by Christeff and colleagues[37] found a negative correlation between CD4 cell count and cortisol concentration in individuals infected with HIV. The adrenal androgen dehydroepiandosterone (DHEA), on the other hand, stimulates T-cell function and have been shown to be positively correlated with the number CD4 cells present in the body.[37]

Adrenal Androgens

As stated above, the adrenal androgen dehydroepiandosterone (DHEA) levels are often decreased in HIV-infected persons. DHEA is a precursor for male and female sex hormones. It also stimulates T-cell function and has been shown to be positively correlated with the number of CD4 cells present in the body.[36] Researchers believe that the high cortisol/low DHEA level that is typically associated with the HIV illness is indicative of a negative prognosis.[32] The combination of increased corticosteroids and decreased adrenal androgens puts the body in a state of catabolism. Glucocorticoids stimulate enzymes of amino-acid catabolism, while androgens increase amino-acid anabolism.[37],[38].

Heat Shock Proteins

Heat shock proteins (HSP) are intracellular proteins that are highly expressed during stress-related conditions within the cell, such as heat shock or bacterial/viral infection.[39] These proteins act as molecular chaperones to translocate proteins within the cell and prevent misaggregation of denatured proteins.[40] The HSPs ensure optimal function of proteins by folding them into their proper conformation.[40] In times of cellular environmmental stress especially, HSPs refold the denatured proteins to safeguard proper cellular function.[40] HSPs, namely Hsp70, also prevent apoptosis by interaction with Bcl-2 in the mitochondria.[41], [42] This anti-apoptotic effect contributes to cell survival in HIV infected cells.[42] The functions of HSPs are ATP dependent. When bound to ATP, they have a low affinity for binding substrates, but a high affinity when ATP is catalyzed to leave a bound ADP molecule.[43]

Several HSPs are involved with HIV infection. HIV research commonly studies HSP70 due to its prevalent interaction with the virus. HSP70, as mentioned earlier, can have anti-apoptotic effects. The previously mentioned Bcl-2 interaction with HSP70 occurs at the mitochondrial permeability transition pore to block Vpr’s apoptotic inducing capability.[41], [44] Consequently, caspase 3 activation is prevented and the host cell survives.[44]

Contradictory effects have been seen in regards to HSP70’s influence on HIV replication. HSP70 levels elevate in response to thermal changes in the cellular environment and with inflammatory or infection responses, such as with HIV. When HIV is in the preintegration complex (PIC) state, HSP70 can bind with Vpr on the PIC and prevent entry of PIC into the nucleus for integration with host cell DNA.[45] It is unclear if this is direct binding or involves an intermediate receptor.[45] In macrophages that are Vpr deficient, however, HSP70 can facilitate entry of the PIC into the nucleus, rather than inhibiting it.[45] This role of HSP70 as a PIC nuclear importer has occurred in vivo in cases of HIV infection with mutated Vpr, which permits HIV replication.[45] Patients who carry Vpr-deficient HIV mutants may have high levels of viral replication if HSP70 levels are elevated due to environmental stress. Iordanskiy et al.[45] suggested stressors should be minimized in patients who are typically of long-term nonprogressive disease status.

Association of HSP70 with a deaminating enzyme of the APOBEC family controls viral replication in the cytoplasm. APOBEC3G interferes with reverse transcription of both X4 and R5 strains of HIV RNA.[19] Degradation of APOBEC3G is induced by HIV Vif (viral infectivity factor), however.[19] HSP70 in the cytoplasm impedes this degradation, thus sustaining the host cell defense mechanism and leaving viral particles non-infectious.[19]

Extracellular HSP70 is present in a protective role as well. Direct binding to the co-receptor, CCR5, blocks entry of R5 HIV-1 strains into the CD4+ cell.[46] Chemokines are drawn to these receptors by HSP70, which prolongs inhibition at these sites.[46]

Association of HSP70 with viral particles can be found extracellularly, particularly in blood serum.[40] Viral budding dissociates the cell plasma membrane from the host to envelope the new HIV virion. HSP70s embedded in that membrane are carried away with the virion.[40] Antibodies against HSP70 naturally occur in human blood and they are elevated during HIV infection.[40] The HIV-1 Tat protein can transport extracellular HSP70 back into the cell.[47] This mechanism of return would benefit a Vpr deficient HIV to facilitate transport of the PIC into the nucleus for transcription, as mentioned previously.

The HSP70 can prompt immunological responses apart from the antibodies set against it. Chemokines, cytokines, and dendritic cell functions have binding sites on the HSP. TNF-α, interleukin 1 (IL-1), IL-6, IL-12, and nitric oxide all can be elicited by HSP70.[46] Additionally, HSP70 may present antigens to assist CD4+ T-cells and CD8+ cytotoxic T-lymphocytes with infection control.[46]

Other HSPs interact with HIV, but have been less studied than HSP70. HSP27 inhibits Vpr-induced cell cycle arrest and eventual cell death from prolonged arrest.[48] Stopping the cell cycle prevents T-cell clonal expansion and suppresses the immune response against the virus, particularly immune memory cells.[48] A proviral effect, however, has been seen with HSP40 as it is upregulated by Nef to enhance gene expression and viral production.[49] Early studies have suggested that HSP60-HSP10 complex may chaperone HIV integrase into the nucleus and thus support viral replication.[50] HSP60 also has been implicated in protecting integrase from denaturing under stressful conditions.[50] Few studies have been conducted on HSP60, so results have not been corroborated.

Clinical Manifestations

HIV has many clinical presentations that vary across age, gender, and race.[4] It is challenging to include all presentations in one list due to this variance in cellular effects of HIV; therefore, this is not an exhaustive list of all possible presentations. The following is a table, classified by system, of the symptoms that have been commonly found in patients diagnosed with HIV. Severity, duration and time in which the symptoms appear in the course of HIV also vary among individuals infected with HIV.

Table 4: Clinical Manifestation of HIV Across Systems[4],[51],[52],[53],[54],[55],[56]

Integumentary System Neuromuscular System Cardiopulmonary System Musculoskeletal System Psychological Symptoms
Hives Brachial neuropathy Vasculitis Muscle pain Depression
Hair loss Peripheral neuropathy Cardiomyopathy Joint pain Anxiety
Basal cell carcinoma Radiculopathy Endocarditis Inflammatory joint disorders Chronic stress
Kaposi's sarcoma Osteomyelitis Pericardial effusion Inflammation of skeletal muscle Irritability
Rash Headache Hypoxia Connective tissue disease Confusion/disorientation
Mucocutaneous ulcers Seizures Dyspnea, particularly during exertion Avascular necrosis Memory impairments
Encephalitis Nonproductive cough Pelvic inflammatory disease Dementia
Paraplegia Pulmonary opportunistic infections Extrapulmonary tuberculosis
Guillain Barre syndrome Decreased bone density
Ataxia/gait disturbances

Opportunistic infections are highly likely in people with HIV.[4],[51] Examples of common infections can be found in Table 7. They are called “opportunistic infections” because the immune system is already functioning at a compromised level and unable to fight off infections that a healthy individual would otherwise be able to defend. Constitutional symptoms including fever, sore throat, weight loss, lethargy, fatigue, and night sweats are common.[4] Other organs in the body are not immune to the effect of HIV. Lymphedema, renal failure, hepatic failure, visual disturbances, lipodystrophy, gingivitis, and oral thrush attack the host body as well.[4] The most common forms of malignancy caused by HIV include Non-Hodgkin’s lymphoma, Kaposi’s sarcoma, and cervical cancer[4]. The gastrointestinal tract is affected causing wasting syndrome.[51] Both decreased bone density and wasting syndrome result in a decreased ability to function at an energy level conducive to participate in activities of daily living without injury and/or devastating levels of fatigue.

Decreased bone density is 3 to 3.7 times more prevalent in people with HIV versus the unaffected population.[57][58] The actual HIV virus is involved directly in bone demineralization through activation of inflammatory cytokines and HIV viral proteins.[57] Pharmacological treatment has been linked to bone mineral density decrease. Recently, Tenofovir (TDF), a nucleoside reverse transcriptase inhibitor (NRTI), has been proven to be the most commonly involved antiretroviral agent causing bone demineralization in patients undergoing highly active anti-retroviral therapy (HAART).[57] Research with protease inhibitors has yielded controversial evidence on their involvement with bone density loss and varies according to protease inhibitor studied.[57] In general, protease inhibitors increase osteoclast differentiation which then inhibits osteoblastic differentiation because of lipid abnormalities and changes the metabolism of vitamin D in the body.[57] A decrease in vitamin D levels potentially linked to bone density loss is also found with non-nucleoside reverse transcriptase inhibitors (NNRTI).[57] These cellular components all contribute to decreased bone mineral density in patients with HIV however there is still much research to be done to determine all contributing factors.[58]

Wasting syndrome, as it is defined related to HIV by the Center for Disease Control (CDC), USA, is: (A) involuntary weight loss greater than 10% of baseline weight associated with either chronic diarrhea for at least 30 days or chronic weakness or (B) documented fever for at least 30 days in the absence of a concurrent illness or condition other than HIV infection that could explain findings (e.g., tuberculosis, cryptosporidiosis, or other specific enteritis).[59] Loss of body weight is caused by many things including inadequate intake, malabsorptive disorders in the gastrointestinal (GI)tract, metabolic alterations, hypogonadism, and excessive cytokine production.[60] This excessive cytokine production leads to a decrease in absorption of nutrients from the GI tract and causes chronic diarrhea and decreased nutrient uptake. One study found that a lower CD4 count at diagnosis of HIV and lower BMI were prognostic factors of wasting syndrome for those with HIV.[61] Body weight and composition must be closely monitored during HIV treatment.

In addition to the physical symptoms affecting individuals with HIV, psychological symptoms appear that greatly affect the course of the disease. The psychological effect of HIV takes a toll on both the quality of life and the cellular response to HIV. [52],[53],[54],[55],[56] People who have HIV and also have depression and anxiety show a decrease in natural killer cells, increased viral load, and elevated CD8+ T lymphocytes compared to their non depressed or anxious counterparts.[51] Chronic stress also causes the immune system to decrease glucocorticoid receptors activity on immune cells and in the limbic region of the brain resulting in an increased secretion of proinflammatory cytokines and augmented HPA axis activity.[51] Studies show that participation in mental health care increases an individual’s quality of life and therefore their adherence to medical treatment and improved control of HIV.[56] Because of these affects, psychological symptoms must be treated in addition to physical symptoms.

Psychological disorders found in patients with diagnosed HIV vary based on stage of the disease, social support, and stigma surrounding the individual. The major diagnoses reported are depression, anxiety, chronic stress, irritability, confusion, disorientation, memory loss, and dementia.[51], [56] A study by Basta et al. [56] has shown that somatization, obsessive compulsive behavior, interpersonal sensitivity, hostility, phobic anxiety, paranoid ideation, and psychoticism are also commonly found in people diagnosed with HIV, especially those who live in rural areas compared to urban areas.

Animal Models

Although animal models can not identically replicate infections in humans, the use of these models are essential for understanding the pathogenesis of many infectious diseases, including AIDS. In addition, these models provide an opportunity to examine potential AIDS vaccines and therapies, which are not yet appropriate to be trialed within humans. Joag [62] identified six characteristics of an ideal animal model of AIDS, which include the following: (1) the infectious virus used in the model should inevitably result in human AIDS (2) the affected structures (cells, tissues, and/or organs) should be analogous to those affected in humans (3) transmission methods used in the model should be the same as for HIV in humans (4) immune system responses to infection and immunization should be analogous to human response (5) the disease course should be a shorter time span than human HIV, but similar in the course of the disease (6) the species used in the model should be financially and ethically responsible in nature [62]. Models can be divided into two classifications: models developed from chimeric viruses (viruses created in the laboratory) and models developed from natural viruses (viruses present in nature). Chimeric viruses can be created in the laboratory by combination of two viruses, combination of two strains of the same virus, or through recombinant DNA techniques. [62]

Animal models of HIV have been researched in a variety of species; however, the clinical relevance remains debatable in many. The only species susceptible to the experimental HIV-1 infection include the chimpanzee, gibbon ape, and rabbit.[63] Large efforts have been made to experimentally adapt the HIV-1 infection in other species, although these have been largely unsuccessful until recently. Several human-mouse chimeric models have been developed, by transplantation of human lymphoid organs into immunodeficient mice, in order to study HIV-1 infection and T cell depletion in vivo. [64] In addition, a newer model has been developed which involves injection of CD34+ human HSC (hematopoietic stem cells) directly into the liver of new born mice .[64] Following this injection, long term development of human T, B, NK, and dendritic cells were identified in peripheral lymphoid tissues (ie: spleen, lymph nodes, and peripheral blood). These species serve as valuable subjects to study the mechanisms of HIV pathogenesis, because of the establishment of a functional human immune system.[64] It has been shown that HIV-1 can be successfully established within these mice, and results in decline of human CD4+ T cells.[64] These current mouse models allow researchers to translate immunological results in mice to the immune system of humans.

Non-human primates serve as ideal models for human diseases secondary to physiological, anatomical, and endocrine system similarities. Chimpanzees, in regard to genetic similarity, serve as a valuable model for pathogenesis and vaccine studies of HIV-1, because they share 98% of DNA coding sequences with humans. The benefits of the chimpanzee model include the similar infection course as seen in humans. Following inoculation of HIV-1 in chimpanzees, a chronic infection is established, resulting in both cellular and humoral immune system responses.[65] Similar to humans, the HIV-1 infection is characterized by seroconversion, the ability to recover active virus from peripheral blood lymphocytes.[65] Unfortunately, only one chimpanzee infected with the HIV-1 virus has developed AIDS and the associated significant loss of CD4+ T-cells and increased viral loads in plasma.[62] Typically, infected chimpanzees present asymptomatic, with no detectable decline in CD4+ cells. CD8+ cytotoxic T lymphocyte (CTL) activity to anti-HIV-1 antigens were significantly lower than the vigorous responses observed within HIV-1 infected humans.[65] Although there is some hope for future studies, the lack of active infections within other species significantly limits the usefulness of studying pathogenesis and vaccine development. The value of the chimpanzee model is also limited by cost, animal welfare, availability of chimpanzees, and number of animal facilities. The immune system of the gibbon ape appears to respond similarly to chimpanzees, creating the same limitations of animal models.[63]

Because of the limitations of animal models created from HIV-1 inoculation, models based on other natural viruses have been of significant importance to the current understanding of HIV. Simian immunodeficiency virus (SIV) is the animal lentivirus most closely related to HIV, and has been identified from several species of monkeys. The SIV infection within rhesus macaques has served as a useful model for HIV-1, secondary to its similar disease manifestations and immune system responses.[65] Infection of SIV results in increased viral load, decreased CD4+ lymphocyte count, and development of symptoms similar to AIDS.[65] The SIV-macaque model has served as a model for pathogenesis, virus-host cell interactions, and transmission. This model has provided some important information about the role of CTL activity in the protection and suppression of viral infections. A study conducted by Schmitz et al reported the significance of CTL activity and CD8+ lymphocytes to control viral replication in the macaque model.[66] Depletion of CD8+ lymphocytes was directly associated with increased viral replication. Conversely, as CD8+ lymphocyte count was increased, viral replication was suppressed. [66] In a different study, Kimata et al [67] demonstrated the genetic variations of HIV and SIV that evolve over the course of the infection increase the pathogenicity using the macaque model. These variant strains, which are antigenetically and phenotypically distinct from the initial, infecting strain, represent strains which are increasingly capable of replication within the individual host. Thus, these viral strains propel disease progression rather than disease onset in SIV and HIV infection, through increased pathogenicity.[67] Finally, using the SIV-macaque model, Zhang et al determined that SIV propagates in active, proliferating T cells, as well as resting CD4+ T cells. More importantly, most resting infected T cells remained following antiretroviral therapy. [68] Developing a vaccination and completely eliminating the virus from the body becomes increasingly difficult secondary to these chronically infected resting T cells. [68]

In order to investigate the unique immune system responses to HIV, two analyses, tetramer analysis and cytokine flow cytometry, have been utilized to study the SIV infection in macaques. These analyses have revealed a direct correlation between tetramer binding and CD8+ T-cell production of interferon (an intracellular cytokine) to CD8+ effector cell function.[65] Thus, continuous monitoring of CD4+ and CD8+ T-cell responses is vital in both HIV-1 and SIV infections and treatment possibilities. These analyses provide hope to replace the more timely, labor-intensive bulk-CTL and lymphoproliferative assays which are currently utilized.[65]

Chimeric SHIV viruses, created by combining portions of SIV and HIV-1 (SHIV), provide research advantages of infecting macaques with viruses which cause immune deficiency and express various HIV-1 envelope protein isolates.[65] SHIV has been shown to produce disease in many macaque species, typically resulting in decreased CD4+ T-cell declines within several weeks and AIDS within several weeks to two years.[62] Organ-specific diseases, such as encephalitis, and histological changes in the lymphoid and other tissue sites that occur in the SHIV-macaque model closely resemble those in HIV-1 infected humans.[62] Since envelope proteins are vital for virus transmission, the SHIV-macaque model is more biologically applicable to examining vaccine and immunization possibilities, because the HIV-1 env gene is incorporated within its composition. In a research study conducted by Lu et al [69], monkeys vaccinated with whole inactivated HIV-1 antigens were protected against SHIV (containing HIV-1 envelope glycoproteins). The ability to define specific immune responses which elicited SHIV protection in these monkeys may prove valuable to the development of a HIV-1 vaccine. [69] In another study, Pauza et al [70]immunized macaques with chemically inactivated Tat toxoid, an essential protein for HIV-1 replication, and then inoculated these animals with a strain of SHIV. Animals which had been immunized expressed significantly weakened disease, with decreased viral RNA, interferon, and chemokine receptor expression on CD4+ T cells. Thus, this study confirms that immunization with Tat toxoid may hinder essential steps in HIV-1 pathogenesis, and may serve as a key element of HIV-1 vaccinations and therapies.[70] Mascola et al [71]administered a combination of human anti-Env antibodies to macaques 24 hours prior to mucosal exposure to the SHIV through vaginal transmission. Although it has been shown that passive infusion of antibodies protects individuals from intravenous challenges of SHIV, this study demonstrated full or partial protection from SHIV transmission across mucosal surfaces. Although three out of the six monkeys did become infected by the virus, decreased viral loads and near-normal CD4+ T-cell counts were observed in comparison to control monkeys.[71] Three out of the six monkeys were completely protected from SHIV following administration of the anti-Env antibodies. [71]


There is currently no cure for HIV/AIDS, but there are more than 20 anti-retroviral (ARV) drugs that have been approved by the U.S. Food and Drug Administration (FDA).[72] These drugs have the potential to reduce morbidity and mortality rates as well as improve quality of life in HIV-infected people. The standard treatment for suppressing HIV replication consists of the combination of at least 3 ARV drugs referred to as highly active antiretroviral therapy (HAART).[73][74] Combining drugs decreases the likelihood of drug resistant HIV (commonly called drug resistance) which is a strain of HIV that is less likely to be affected by treatment due to mutations on parts of the virus that are targeted by the drugs.[73][74] Rates of AIDS or death were halved after approximately one year of combination therapy compared with rates in patients treated with drugs from only one ARV drug class.[75] The most common ARV drug combination for people beginning HAART includes 2 nucleoside reverse transcriptase inhibitors (NRTIs) combined with either a non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitor (PI) (See Table 5 for ARV drugs).[73] [74] A common example is the combination of zidovudine and lamivudine with efavirenz.[73][74] To decrease the amount of pills taken daily, multiple ARV drugs have been combined into one pill referred to as a “fixed dose combination”.[72] If the first line of therapy is not effective due to factors including drug resistance and severe side effects, a second line of therapy is attempted in order to increase the likelihood of HAART success. A minimum of 3 drugs is still recommended where at least one of the drugs comes from a new class.[73][74] Even among people who respond well to HAART, virus replication does not stop completely but continues at a slower pace.

Starting HAART is a life-long commitment. Discontinuation of therapy may result in viral rebound, immune decompensation, and clinical progression.[74] Adverse effects have been reported with all ARV drugs and it is one of the most common reasons for switching or discontinuing therapy as well as medication non-adherence.[76] Nausea, vomiting, and diarrhea are just a few of the side effects one can experience with HAART (See Table 6 for further side effects).[74] [76][77] Adherence to drug therapy has been strongly correlated with HIV viral suppression, reduced rates of drug resistance, an increase in survival, and improved quality of life.[73][74][78] To assure drug adherence, it is extremely important that information about HIV/AIDS and the specific regimen prescribed are clearly explained to the individual.

CD4 cell count is one of the key factors in deciding whether to initiate HAART and prophylaxis for opportunistic infections, and evidence shows it is the strongest predictor of subsequent disease progression and survival.[79][80] When a person is first diagnosed with HIV, CD4 cell count is ordered with the viral load test (discussed in the following paragraph) as part of a baseline measurement.[73][74] Normal ranges for CD4 cell count are between 500-1,200 x 106/L.[73][74] A person infected with HIV is defined as having AIDS when CD4 count is less than or equal to 200 cells/mm3.[73][74] It is strongly recommended that HAART be initiated in all adolescents and adults, including pregnant women, with a history of an AIDS-defining illness or with a CD4 count less than or equal to 350 cells/mm3 regardless of clinical symptoms.[73][74][81] Conversely, evidence suggests that deferral of treatment until the patient’s CD4 count is < 350 cells/mm3 is associated with increased rates of the combined endpoint of AIDS or death when compared with starting in the range 351–450 cells/mm3.[75] Although there are benefits associated with earlier initiation of HAART, concerns about long-term toxicity and the development of drug resistance have served as a rationale for the deferral of HIV therapy.[73][74] Approximately 2-8 weeks after HAART is implemented, CD4 cell count and viral load are re-evaluated to determine treatment effectiveness.[74] To monitor long-term therapy, both tests are re-administered every 3-4 months.[74] However, if the patient’s CD4 cell count has increased well above the threshold for opportunistic infection risk, monitoring can take place less frequently than the viral load, typically every 6-12 months unless there is a change in health status.[74]

A viral load test reports the number of HIV copies per milliliter (copies/mL) of blood.[74] During treatment and monitoring, a high viral load can range from 5,000-10,000 copies/mL and a low viral load usually ranges from 40-500 copies/mL.[74] If HAART is successful, the viral load will drop to the undetectable level of 50 copies/ml.[74] This can take up to 3-6 months and some people may never reach this level.[74] It is important to note that an undetectable level does not mean the person is cured. It may mean that HIV RNA is not present in the blood at the time of testing or that the level of HIV RNA is below the threshold needed for detection. If there is an increase in viral load, it is pertinent to determine if it is due to worsening infection, drug resistance, poor drug adherence, or drug interactions. A decrease in CD4 cell count and a greater risk for developing opportunistic infections can follow an increase in viral load.

As mentioned earlier, opportunistic infections (OI) take advantage of weakness in the immune system. A list of more than 20 OIs that are considered AIDS-defining conditions has been developed by the Centers for Disease Control and Prevention (CDC).[82] An individual with HIV is diagnosed with AIDS if he/she has one or more of the listed OIs (See Table 7 for several of the most common OIs).[82] To combat the occurrence or recurrence of an OI, a prophylaxis is usually administered. One particular drug called co-trimoxazole is effective at preventing a number of OIs and has been shown to significantly reduce mortality among HIV-positive individuals.[82]

When selecting an ARV drug regimen, factors such as drug-drug and/or drug-food interactions, co-morbid conditions, pregnancy or pregnancy potential, and patient adherence potential should be taken into consideration. To help reduce undesirable effects, a thorough review of the medications as well as consultation with the appropriate health care professional is highly recommended. In addition, the potential for drug interactions should be evaluated when any new drug, including over-the-counter agents, is added to an existing ARV drug combination.[74] The Liverpool HIV Pharmacology Group (LHPG) is a major research unit within the School of Biomedical Sciences at the University of Liverpool.[83] LHGP provides a comprehensive, up-to-date, and evidence-based drug-drug interaction resource that is available at[83]

A recent, major breakthrough in HIV prevention research involved a study that examined pre-exposure prophylaxis (PrEP).[84] PrEP is an approach that uses a “fixed dose combination” strategy where multiple ARV drugs are combined into one pill.[84] The goal of PrEP is to prevent the transmission of HIV rather than treat the infection.[84] Results showed that with consistent use of PrEP, HIV infection among gay and bisexual men, and transgendered women who have sex with men was reduced.[84] Numerous clinical trials are currently being conducted around the world to determine the effectiveness of PrEP in other populations. PrEP should never be seen as the first line of defense in HIV transmission because it has only been shown to be partially effective when used in combination with regular HIV testing, condoms, and other proven prevention methods.[84] FDA has yet to approve this drug, but the CDC is in the process of developing U.S. Public Health Service Guidelines. As more promising results arise from clinical studies examining pharmacology in HIV/AIDS, there is hope that the number of infected individuals and deaths due to this disease can be decreased.

Table 5: Antiretroviral (ARV) Drugs[73][74]

ARV Drug Class First Approved by the U.S. FDA Examples (Generic Name) Mechanism of Action
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 1987 lamivudine, abacavir, zidovudine, stavudine, didanosine, tenofovir, emtricitabine Inhibits reverse transcription by adding faulty nucleotides to viral DNA strand resulting in DNA termination
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) 1997 delavirdine, efavirenz, etravirine, nevirapine Inhibits reverse transcriptase by binding directly to the enzyme and interfering with its function
Protease Inhibitors (PIs) 1995 amprenavir, fosamprenavir, atazanavir, darunavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, lopinavir/ritonavir Hinders viral assembly by inhibiting protease
Entry/Fusion Inhibitors (EIs/FIs) 2003/2007 enfuvirtide, maraviroc Inhibits HIV infection from binding to or entering into host cell by blocking receptors
Integrase Strand Transfer Inhibitors (INSTIs) 2007 raltegravir Inhibits integration of viral DNA into host cell’s DNA

Table 6: Common and/or Severe Side Effects of ARV Drugs[74][76][77]

Side Effect Description Signs and Symptoms Associated Drug Class
Dyslipidemia Elevation of lipids in the bloodstream; can lead to heart disease and pancreatitis No signs or symptoms NRTIs, NNRTIs, PIs
Hepatotoxicity Specific conditions: Hepatitis—inflammation of the liver; Hepatic necrosis—death of liver cells; Hepatic steatosis—too much fat in the liver, may be associated with lactic acidosis Nausea, vomiting, abdominal pain, loss of appetite, diarrhea, fatigue, weakness, jaundice, hepatomegaly NRTIs, NNRTIs, PIs
Hyperglycemia Increased blood glucose level due to insulin resistance or if the pancreas does not make enough insulin Increased urination, excessive thirst or hunger, unexplained weight loss PIs
Lactic Acidosis Life-threatening condition caused by lactic acid building up in the bloodstream faster than it can be removed Persistent nausea, vomiting, and abdominal pain; unexplained tiredness; shortness of breath; rapid breathing; enlarged or tender liver; cold or blue hands and feet; abnormal heart beat; weight loss NRTIs
Lipodystrophy Also called fat redistribution; disturbance in the way the body produces, uses, and stores fat Fat accumulation- back of neck and upper shoulders (“buffalo hump”), breasts, abdomen (“protease paunch” or “crixivan potbelly”), lipomas (fatty growths in different parts of the body); Fat wasting- face (sunken cheeks), arms and legs: veins become more prominent (“roping”), buttocks NRTIs, NNRTIs, PIs, INSTIs
Osteonecrosis, Osteopenia, Osteoporosis Osteonecrosis- bone death due to poor blood supply to the area; Osteopenia- lower than normal bone mineral density (BMD); Osteoporosis- reduced BMD over time Osteonecrosis- pain in affected area, limited range of motion (ROM), joint stiffness, muscle spasms; Osteopenia- no signs or symptoms; Osteoporosis- back pain, loss of height over time, stooped posture, fractures NRTIs, NNRTIs, PIs
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) Life-threatening condition affecting the skin where the epidermis separates from the dermis. TEN differs from SJS in the extent of skin damage-Ten involves at least 30% of total body skin area Flat or raised red spots on the skin that develop blisters in the center; blisters in the mouth, eyes, genitals, or other moist areas of the body; peeling skin that results in painful sores, fever, headache, malaise NRTIs, NNRTIs, PIs

Table 7: Common Opportunistic Infections (OIs) related to HIV/AIDS[73][82]

OI Description Symptoms
Candidiasis Fungal infection of the mouth (thrush), throat (esophagitis), or vagina (yeast infection or vaginitis) Cracking at the corners of the mouth; sore throat; nausea; loss of appetite; vaginal itching, burning, discharge
Cytomegalovirus (CMV) Member of the herpes virus family; affects the whole body; commonly causes retinitis that can lead to blindness; can cause pneumonia, polyradiculopathy, colitis, encephalitis, hepatitis, esophagitis Fever, swollen glands, sore throat, blurred vision, pneumonia-like symptoms, abdominal pain, headache
Cryptococcosis Systemic or central nervous system fungal infection; primarily affects the brain and spinal cord; often appears as meningitis and can be fatal if left untreated; can affect almost all organs in the body Headache, confusion, nausea with or without vomiting, malaise
Herpes Simplex Virus (HSV) Types I and II cause both primary and recurrent oral and genital disease; typically appears as a vesicular eruption of the mucous membranes of the oral or perioral area, vulva, perianal skin, rectum, and occasionally the inguinal or buttock areas Eruption of red, painful vesicles or ulcers ("fever blisters") with or without an exudate in the mouth, on the genitals, or in the perianal area; burning, tingling, or itching before eruption of the lesions
Herpes Zoster/Shingles Shingles is a skin or mucosal infection caused by the varicella-zoster virus (VZV) that occurs along a dermatome and represents a reactivation of varicella (chickenpox) Painful skin blisters or ulcerations along one side of the face or body, loss of vision, facial lesions, pain in a dermatomal distribution
Histoplasmosis Fungal infection that occurs through inhalation of fungal spores in soil; primarily affects the lungs but can affect other organs Fever, weight loss, fatigue, cough, dyspnea
Kaposi’s Sarcoma (KS) Type of cancer that usually occurs as skin and mouth lesions; can also affect mucous membranes, GI tract, lungs, lymph nodes; most common AIDS associated neoplasm Red or purplish nodules/lesions on skin; painful swelling in legs, groin area, or face
Mycobacterium Avium Complex (MAC) Bacteria usually enters through respiratory or GI tract and disseminate to cause multisystem infection; can also cause local disease such as soft tissue or bone infections Fever, weight loss, sweats, abdominal pain, chronic diarrhea
Pneumocystis Pneumonia (PCP) Fungal infection that primarily affects the lungs resulting in pneumonia; life-threatening Nonproductive cough, fever, night sweats, weight loss, fatigue, dyspnea
Tuberculosis (TB) Bacterial infection that primarily affects the lungs; accounts for 11% of AIDS deaths worldwide; occurs earlier in the course of HIV infection Chest pain, coughing up blood, weight loss, fever, chills, night sweats, pallor
Toxoplasmosis (toxo) Caused by a protozoan found in uncooked meat and cat feces; infects the central nervous system; life-threatening Headache, vomiting, confusion, fever, motor weakness

HIV Controllers vs. Progressors & Future Research

Not all individuals with HIV-1 infection progress to AIDS. Less than 0.2% of individuals infected with HIV have been found to spontaneously control the HIV-1 replication without the use of antiretroviral treatment and maintain a long term healthy status.[7] HIV control has been defined as having a viral load <50 copies HIV-1 RNA/ml for more than 10 years.[7] These individuals have an astonishingly low risk of progressing to AIDS and have been called HIV controllers, natural virus suppressors, or long-term nonprogressors.[7] There is much to learn from these individuals and may provide the keys to finding a vaccine for this deadly virus.

A review by Chakrabarti and Simon[7] summarized the recent advances reported on the immune mechanisms associated with HIV control early in the infection process. Findings suggest that the status of HIV controller can be established within months of the infection; therefore there has been an emphasis on the importance of the very early events that occur and help determine the outcome of the HIV-1 replication and host response competition.[7] Any way for the host to accelerate the early development of the antiviral response or delay the viral replication may result in HIV controller status.

HIV controllers, as opposed to progressor patients, have been found to achieve an optimal IFN response while also limiting IFN-dependent immunopathology; the exact mechanisms have not yet been determined.[7] Chronic IFN production has been found to be deleterious to the infected host cell by increasing expression of CCR5 (coreceptor of HIV), inducing death receptors, and activating an abnormal immune response.[7] Thus, if controllers have an improved IFN response, they may be able to decrease the amount of HIV replication that occurs early on.

When looking at CD8+ T-cell response, they have revealed that controllers’ differentiation of HIV-specific CD8+ cells and cytokine secretion have a high degree of heterogeneity. Early on, there is a high proliferation of specific CD8+ T-cells resulting in optimal survival and expansion capacity. HIV controllers have also been found to show signs of persisting immune activation even though they have low viral loads. It has been suggested that there is a presence of a high avidity memory CD4+ T-cell population for Gag in controllers. Gag is an encoding gene for a few major viral components for HIV. This may play a key role resulting in an increased capacity of the CD4 cells to recognize this gene, which in turn keeps the immune system in constant alert allowing rapid recall responses and the ability to detect minimal amounts of the virus.[7]

Overall, studies of HIV controllers are beginning to provide a wealth of information regarding the aspects of a proficient response against HIV. Future studies are required to elucidate the underlying mechanisms of these components in order to one day be able to provide an HIV vaccine and eradicate the virus altogether.


HIV is a complex retrovirus that primarily attacks immune cells in the body with CD4 receptors. Infection stimulates a cascade of cellular events and results in numerous deleterious effects on the cardiovascular, integumentary, neuromuscular, and musculoskeletal systems of the body. As the virus degrades the body's ability to fight foreign bodies, individuals with HIV become increasingly susceptible to life-threatening opportunistic infections. While there is currently no cure for the disease, anti-retroviral pharmacological interventions are available that help slow the progression from HIV to AIDS. With both current and future research findings along with prevention education, scientists hope to drastically decrease and eventually eradicate the incidence and prevalence of HIV/AIDS.

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1. Fanales-Belasio E, Raimondo M, Suligoi B, Butto S. HIV virology and pathogenic mechanisms of infection: a brief review. Ann Ist Super Sanita. 2010; 46: 5-14.
2. Campsmith ML, Rhodes P, HI Hall, Green T. HIV prevalence estimates – United States, 2006. MMWR. 2008; 57: 1073-1076. Centers for Disease Control Web site. Available at: Accessed January 18, 2011.
4. Goodman C, Fuller K, Boissonnault W. Pathology: Implications for the Physical Therapist, 2nd ed. Philadelphia: Saunders; 2003.
5. Eger KA. Unutmaz D. The innate immune system and HIV pathogenesis. Current HIV/AIDS Reports. 2005; 2:10-15.
6. Mogensen TH, Melchjorsen J, Larsen CL, Paludan SR. Innate immune recognition and activation during HIV infection. Retrovirology. 2010; 7: 54.
7. Chakrabarti LA, Simon V. Immune mechanisms of HIV control. Curent Opinion in Immunology. 2010; 22: 488-496.
8. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998; 392: 245–52.
9. Shah S, Nonnemacher MR, Pirrone V, Wigdahl B. Innate and adaptive factors regulating Human Immunodeficiency Virus type 1 genomic activation. J Neuroimmune Pharmacol. 2010; 5: 278-293.
10. Gelderblom HR. Fine structure of HIV and SIV. Part III. HIV Compendium. HIV databases - Los Alamos National Laboratory Web site. 1997. Available at: Accessed January 25, 2011.
11. Foster JL, Garcia JV. HIV-1 Nef: at the crossroads. Retrovirology. 2008; 5: 84.
12. Lever AML, Jeang KT. Insights into cellular factors that regulate HIV-1 replication in human cells. Biochemistry. Just Accepted Manuscript. DOI: 10.1021/bi101805f. Publication Date (Web): 10 January 2011.
13. Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z. Cellular co-factors of HIV-1 integration. Trends BiochemSci. 2006; 31:98–105.
14. Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. 2008; 451: 425-430.
15. Douglas JL, Viswanatha, K, McCarrol, MN, Gustin JK, Fruh K, Moses AV. Vpu directs the degradation of the human immunodeficiency virus restriction factor
BST-2/Tetherin via a {beta}TrCP-dependent mechanism. J Virol. 2009; 83: 7931-7947.
17. Streeck H, Nixon DF. T cell immunity in acute HIV-1 infection. J Infect Dis. 2010; 202 Suppl 2:S302-308.
18. Poveda E, Soriano V. Resistance to entry inhibitors. In: Geretti AM, ed. Antiretroviral Resistance in Clinical Practice. London: Mediscript; 2006. PMID: 21249775.
19. Sugiyama R, Nishitsuji H, Furukawa A, et al. Heat shock protein 70 inhibits HIV-1 Vif-mediated ubiquitination and degradation of APOBEC3G. J Biol Chem. 2011 Jan 12. [Epub ahead of print] PMID: 21228271
21. Kedzierska K, Crowe SM, Turville S, Cunningham AL. The influence of cytokines, chemokines and their receptors on HIV-1 replication in monocytes and macrophages. Rev Med Virol. 2003; 13: 39-56.
22. Vicenzi E, Biswas P., Mengozzi M, Poli G. Role of pro-inflammatory cytokines and β-chemokines in controlling HIV replication. Journal of Leukocyte Biology. 1997; 62:34-40.
23. Taylor S, Fahy E, Zhang B, Glenn G, Warnock D, Wiley S, Murphy A, et al. Characterization of the human heart mitochondrial proteome. Nat Biotechnol 2003; 21: 281-6.
24. Pinti M, Nasi M, Gibellini L, Roat E, Biasi S, Bertoncelli L, Cossarizza A. The role of mitochondria in HIV infection and its treatment. J Exp Clin Med. 2010; 2(4): 145-155.
25. Lotocki G and Keane R. Inhibitor of apoptosis proteins in injury and disease. Life. 2002; 54: 231-240.
26. Maagaard A, Holberg-Petersen M, Kvittingen E, Sandvik L, Bruun J. Depletion of mitochondrial DNA/copies in peripheral blood mononuclear cells in HIV-1 infected treatment-naïve patients. HIV Med. 2006; 7: 497-505.
27. Miura T, Goto M, Hosoya N, Odawara T, Kitamura Y, Nakamura T, Iwamoto A. Depletion of mitochondrial DNA in HIV-1 infected patients and its amelioration by antiretroviral therapy. J Med Virol. 2003; 70: 497-505.
28. Fermin C, Garry R. Membrane alterations linked to early interactions of HIV with the cell surface. Virology. 1992; 191: 941-6.
29. Rasola A, Gramaglia D, Boccacio C, Comoglio P. Apoptosis enhancement by HIV-1 Nef protein. J Immunol. 2001; 166: 81-8.
30. Westendorp M, Shatrov S, Schulze-Osthoff J, Frank R, Kraft M, Los M, Krammer P, et al. HIV-1 Tate potentiates TNF-induced NK-kappa B activation and cytotoxicity by altering the cellular redox state. EMBO J. 1995; 14: 546-54.
31. Ross TM. Using death to one’s advantage: HIV modulation of apoptosis. Leukemia. 2001; 15: 332-341.
32. Zapanti E, Terzidis K, Chrousos G. Dysfunction of the Hypothalamic-Pituitary-Adrenal axis in HIV infection and disease. Hormones. 2008; 7: 205-216.
34. Kumar M, Kumar AM, Waldrop D, Antoni MH, Eisdorfer C. HIV Infection and its Impact on the HPA Axis, Cytokines, and Cognition.
35. Mayo J, Collazos J, Martinez E, Ibarra S. Adrenal Function in the Human Immunodeficiency Virus-Infected Patient. AMA. 2002; 162:1095-1098.
36. Kumar M, Kumar A, Waldrop D, Antoni M, Schneiderman N, Eisdorfer C. The HPA Axis in HIV-1 Infection. JAIDS. 2002; 31: S89-S93.
37. Christeff N, Gherbi N, Mammes O, et al. Serum Cortisol and DHEA Concentrations During HIV Infection. Psychoneuroendocrinology. 1997; 22: S11-S18.
38. Romagnani S: Biology of human TH1 and TH2 cells. J Clin Immunol. 1995, 15:121–129.
39. Soti C, Csermely P. Chaperones and aging: role in neurodegeneration and in other civilization diseases. Neurochemistry International. 2002; 41: 383-389.
40. Fust G, Beck Z, Banhegyi D, Kocsis J, Biro A, Prohaszka Z. Antibodies against heat shock proteins and cholesterol in HIV infection. Molecular Immunology. 20005; 42: 79-85.
41. Doong H, Vrailas A, Kohn EC. What's in the 'BAG'?—A functional domain analysis of the BAG-family proteins. Cancer Lett. 2002;188:25-32.
42. Rosati A, Khalili K, Deshmane SL, et al. BAG3 protein regulates caspase-3 activation in HIV-1-infected human primary microglial cells. J Cell Physiol. 2009;218:264-267.
43. Young J. Mechanisms of the Hsp70 chaperone system. Biochem Cell Biol. 2010; 88: 291-300.
44. Jacotot E, Ravagnan L, Loeffler M, et al. 2000; The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondria permeability transition pore. J. Exp. Med. 2000; 191: 33−46.
45. Iordanskiy S, Zhao Y, DiMarzio P, AgostiniI, Dubrovsky L, Bukrinsky M. Heat-shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages. Blood. 2004; 104:1867-1872.
46. Babaahmady K, Oehlmann W, Singh M, Lehner T. Inhibition of human immunodeficiency virus type 1 infection of human CD4+ T cells by microbial HSP70 and the peptide epitope 407-426. J Virol. 2007; 81: 3354-3360.
47. Wheeler DS, Dunsmore KE, Wong HR. Intracellular delivery of HSP70 using HIV-1 Tat protein transduction domain. Biochem Biophys Res Commun. 2003; 301:54-59.
48. Liang D, Benko Z, Agbottah E, Bukrinsky M, Zhao RY. Anti-vpr activities of heat shock protein 27. Mol Med. 2007;13:229-239.
49. Kumar M, Mitra D. Heat shock protein 40 is necessary for human immunodeficiency virus-1 Nef-mediated enhancement of viral gene expression and replication. J Biol Chem. 2005; 280: 40041-50.
50. Al-Mawsawi LQ, Neamati N. Blocking interactions between HIV-1 integrase and cellular cofactors: an emerging anti-retroviral strategy. Trends Pharmacol Sci. 2007; 28:526-535.
51. Dudgeon WD, Phillips KD, Bopp CM, Hand GA. Physiological and psychological effect of exercise interventions in HIV disease. AIDS Patient Care and STDs. 2004;18:81-98.
52. Penzak SR, Reddy YS, Grimsley SR. Depression in patients with HIV infection. Am J Health Syst Pharm 2000;57:376–386.
53. Maes M, Van Bockstaele DR, Gastel A, et al. The effects of psychological stress on leukocyte subset distribution in humans: Evidence of immune activation. Neuropsychobiology 1999;39:1–9.
54. Evans DL, Ten Have TR, Douglas SD, et al. Association of depression with viral load, CD8 T lymphocytes, and natural killer cells in women with HIV infection. Am J Psychiatry 2002;159:1752–1759.
55. Leserman J, Petitto JM, Gu H, et al. Progression to AIDS, a clinical AIDS condition and mortality: Psychosocial and physiological predictors. Psychol Med 2002;32:1059–1073.
56. Basta TB, Shacham E, Reece M. Symptoms of psychological distress: a comparison of rural and urban individuals enrolled in HIV-related mental health care. AIDS Patient Care and STDs. 2009;23:1053-1057.
58. Cazanave C, Dupon M, Lavignolle-Aurillac V, et al. Reduced bone mineral density in HIV infected patients: prevalence and associated factors. AIDS. 2008;22:395-402.
59. Centre for Disease Control, USA. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report. 1992;41(RR-17):1–19.
60. Grinspoon S, Mulligan K. Weight loss and wasting in patients infected with human immunodeficiency virus. Clin Infect Dis. 2003;36:569-578.
61. Smit E, Skolasky RL, Dobs AS, et al. Changes in the incidenc and predictors of wasting synbdrome related to human immunodeficiency virus infection, 1987-1999. Am. J. Epidemiol. 2002;156:211-218.
62. Joag S. Primate models of AIDS. Microbes and Infection. 2000; 2: 223-229.
63. Gardner M and Luciw P. Animal models of AIDS. The FASEB Journal. 1989; 3: 2593-2606.
64. Zhang L, Meissner E, Chen J, LiShan S. Current humanized mouse models for studying human immunology and HIV-1 immuno-pathogenesis. Science China: Life Sciences. 2010; 53 (2): 195-203.
65. Nath B, Schumann K, Boyer J. The chimpanzee and other non-human-primate models in HIV-1 vaccine research. Trends in Microbiology. 8 (9): 426-431.
66. Schmitz J, Kuroda M, Santra S, Sasseville V, Simon M, Lifton M. Control of viremia in simian immunodeficiency virus infection by CD8 lymphocytes. Science. 1999; 283: 857-60.
67. Kimata JT, Kuller L, Anderson DB, Dailey P, and Overbaugh J. Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression. Nat. Med. 1999; 5: 535- 541.
68. Zhang Z, Schuler T, Zupancic M, et al. Sexual transmission and propagation of SIV/HIV in resting and activated CD4 T cells. Science. 1999; 286: 1353-1357.
69. Lu Y, Salvato MS, Pauza CD et al. Utility of SHIV for testing HIV-1 vaccine candidates in macaques. J. Aids. 1996; 12: 99-106.
70. Pauza D, Trivedi P, Wallace M, Ruckwardt T, Buanec H, Lu W, et al. Vaccination with Tat toxoid attenuates disease in simian/HIV-challenged macaques. Proc. Natl. Acad. Sci. 2000; 97: 3515-3519.
71. Mascola J, Stiegler G, Vancott T, et al. Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J. Virol. 1999; 73: 4009-4018.
72. U.S. Department of Health & Human Services: U.S. Drug and Food Administration. Antiretoviral drugs used in the treatment of HIV infection. Accessed January 2011. Available at:
73. World Health Organization (WHO). Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach. 2010; 1-156. Accessed January 2011. Available at:
74. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2011; 1–166. Accessed January 2011. Available at:
75. Sterne JAC, May M, Costagliola D, de Wolf F, Phillips AN, et al. Timing of initiation in antiretroviral therapy in AIDS-free HIV-1-infected patients : a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373(9672): 1352–1363.
77. Montessori V, Press N, Harris M, Akagi L, Montaner J. Adverse effects of antiretroviral therapy for HIV infection. CMAJ. 2004; 170(2): 229-238.
78. Chesney MA. The elusive gold standard. Future perspectives for HIV adherence assessment and intervention. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S149-155.
81. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009; 4(5): 5575.
82. CDC Mortality and Morbidity Weekly Report. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. 2009; 58: 1-216. Accessed January 2011. Available at:
83. University of Liverpool. Drug Interaction Charts. Accessed January 2011. Available at:
84. Centers for Disease Control and Prevention (CDC). HIV/AIDS: Pre-Exposure Prophylaxis (PrEP). Accessed January 2011. Page updated January 2011. Available at:


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