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The Body Covers: The 12th International AIDS Conference
The Body Fights Back -- Immune Responses and Reconstitution in HIV Infection

July 1-3, 1998


A symposium was held focusing on HIV specific immunity -- why it successfully controls virus replication in some individuals, but fails in others; how it may be preserved; and how it's effected by antiretroviral therapy. Highlights of the presentations by Bruce Walker and Brigitte Autran follow.

Session 425: Immune events in early HIV infection.

Bruce Walker discussed why patients with HIV infection typically lack the ability to control the virus' replication. He explained that during acute HIV infection, antigen presenting cells express fragments of HIV proteins that are recognized by the T cell receptor (TCR) on naive CD4+ lymphocytes. TCRs are preprogramed to recognize any amino acid sequence of any antigen that the body may encounter. Once the TCR processes this antigen the CD4+ lymphocyte becomes activated in order to coordinate the antibody and cellular immune response against the viral protein fragment that it recognizes. Unfortunately, the greatest concentration of virus is present in infected individuals during their acute HIV infection illness, and the cells that are most likely infected are the activated CD4+ lymphocytes. Therefore, these helper cells that are programmed to coordinate the immune response against the virus are destroyed during acute HIV infection. Because naive cells are already preprogrammed, once the cells that contain the unique TCR able to recognize a specific HIV protein fragment are destroyed, there are no cells able to identify that viral antigen. The ability to coordinate the immune response against that particular viral target is lost, at least until new generations of naive cells can replace the cells destroyed.

Session 598/31130: Control of HIV replication requires virus-specific helper and CTL function and levels of CTL activity are in equilibrium with viral burden.

According to Walker, many infected individuals have cellular immunity in the form of cytotoxic CD8+ T lymphocytes that could better control virus replication if it were not for the fact that most patients lack the CD4+ helper response required to coordinate the immune system's counterattack. In his overview talk and in another presentation from his lab, Walker showed that in untreated individuals, the ability of CD4+ lymphocytes to proliferate in response to HIV antigens was inversely correlated with patients' viral loads. In other words, the better the CD4+ helper response against HIV, the better the individual was at controlling his/her HIV infection in the absence of therapy. Patients with more vigorous CD4+ helper responses were more likely to have good cytotoxic T lymphocyte responses against the virus, and the numbers of cytotoxic T lymphocyte precursor cells were higher in patients with the better helper responses. Long term non-progressors, those individuals with normal CD4+ counts and low viral loads in the absence of treatment almost always have strong CD4+ helper responses and good cytotoxic T lymphocyte responses. Therefore, this CD4+ helper response may serve as a marker for a good HIV specific immune response, in general, and may be a way to assess the potential benefit of vaccine candidates.

The next step in Walker's research was to try to understand how a strong HIV-specific CD4+ helper response could be preserved in infected individuals. Eric Rosenberg, working in Walker's lab, was able to identify a group of patients experiencing their acute HIV syndrome, and monitored these individuals' CD4+ helper responses after being started on therapy. In these patients treated during their acute HIV syndrome, CD4+ helper responses were absent at the time treatment was initiatied, but improved steadily over the ensuing three to six months, such that the level of CD4+ lymphocyte proliferation against HIV antigens was similar to or higher than those patients with low viral loads off therapy. In patients who have been treated more than six months beyond their acute HIV illness, no augmentation of the CD4+ lymphocyte responses against HIV antigens occurred.

These observations in treated patients confirms the proposed hypothesis explaining the lack of CD4+ helper responses against HIV antigens outlined above. In most infected individuals, the depletion of CD4+ helper cells occurs during their acute HIV syndrome, and these responses, once lost, can not be restored. Two factors explain why these HIV-specific immune responses don't return with treatment. First, the repertoire of CD4+ lymphocytes with the TCR receptors capable of recognizing the HIV antigens has been lost, and may not be recoverable, except after prolonged periods of therapy when the population of naive cells increases. Secondly, no new HIV specific immune responses develop in individuals experiencing the benefit of active antiretroviral therapy because HIV antigens are not present in sufficient enough concentrations to elicit an immune response.

How can we link these immunological observations with the experience of the Berlin patient and those patients receiving hydroxyurea who experienced augmentation of their HIV specific immune response over time? Walker presented data on the Berlin patient and showed that this individual had a strong CD4+ helper response against HIV antigens, similar to what can be seen in long term non-progressors. [Recall that the Berlin patient was started on therapy less than two months after his acute HIV syndrome.] The experiences of those patients with improved CD4+ helper responses on only ddI and hydroxyuea therapy are more difficult to explain. These patients were treated beyond their acute illness, at the time their infection was already established, and had ongoing viral replication for prolonged periods until their viral loads eventually were reduced below quantifiable levels. Because these patients were on hydroxyurea, a drug that stops the virus' replication by targeting a cellular enzyme not a viral enzyme, the virus did not become resistant to the medication. For this reason the viral loads did not rebound despite ongoing viral replication. While HIV replication was being slowly inhibited, immune reconstitution in the form of an increase in the naive CD+ cell counts occurred. In conjuction with the improved immune function, there was a small amount of viral antigen present which was able to boost the HIV specific immune response. That's the theory, but at this point there is much more work to be done to substantiate the hypothesis.

The future direction of this avenue of investigation is to try to figure out how to restore the HIV-specific immune responses that are lost in those individuals who are treated with already established HIV infection. As an initial approach, Walker will be trying to improve on the immune functions of patients treated with established infection by vaccinating them after their naive CD4+ cells increase in number.

Poster Session 60414: Inhibition of HIV-1 by CD8+ cells from seropositive individuals is antigen processing-dependent.

There were two other reports from Walker's lab focusing on the cytolytic and noncytolytic functions of CD8+ lymphocytes. One report examined the requirement that CD8+ cells recognize HIV antigens in order to inhibit HIV replication by noncytolytic mechanisms. As background, there is evidence that CD8+ cells can inhibit HIV replication by producing soluble factors such as chemokines or other molecules that have not yet been identified. This activity is in addition to their potential to destroy infected cells by direct cytolytic attack. Individual CD8+ clones from infected and uninfected individuals were expanded and tested for their ability to recognize HIV antigens. HIV-specific CD8+ cells were able to inhibit HIV replication by noncytolytic mechanisms, but not CD8+ cells from infected individuals that did not recognize HIV antigens. CD8+ cells from uninfected individuals did not inhibit HIV replication. Inhibition of HIV replication only occurred when the CD8+ cells and the infected cell targets were HLA matched (a requirement for antigen processing). Therefore, it seems that ability of CD8+ cells to inhibit HIV replication by any mechanism is dependent upon these cells being able to recognize HIV antigens. This is additional in vitro confirmation that maintaining a healthy HIV-specific immune response is critical for individuals to maintain the most effective immunologic control of their infection as is possible.

Poster Session 31135: Recognition of two overlapping CTL epitopes by CTL from a long-term non-progessing HIV-1 infected individual.

The final report from Walker's lab was a study of the targets of the cytotoxic T lymphocyte (CTL) response in a long-term non-progressor. As yet, we have not determined whether there is an immune response directed against a specific fragment of viral protein (epitope) that may be associated with better control of HIV replication than immune responses made against other epitopes. For this reason the dominant CTL responses against targets expressing a diverse array of HIV protein fragments was determined in one long-term non-progressor. The strongest CTL responses in this individual were directed against overlapping amino acid sequences that are a part of p17 and are known to be essential for HIV replication. To help ascertain whether this individual was a long-term non-progressor because he was making an immune response against two overlapping regions of the same protein which could potentially limit the virus' ability to replicate, this portion of the virus was sequenced from plasma and cellular samples. HIV genotypes with different sequences from that recognized by the CTL were identified. Virus with these sequences was not recognized by the patients' CTL, but could replicate as efficiently as virus with the sequences recognized by the CTL. This observation demonstrates that the virus can escape immune recognition by CTL without impairing its ability to replicate. In this regard, HIV demonstrates another form of resistance other than resistance to antiretroviral therapy, the ability to evade the immune response of the host. This study did not provide any insight into why this patient is a long-term non-progressor.

Session 426: Immune responses and reconstitution.

A lecture by Brigitte Autran from Paris followed that of Bruce Walker. She presented data generated from immunologic investigations of 150 infected individuals at varying stages of disease. Her data demonstrated that individuals with CTL responses against a wide assortment of HIV epitopes have lower viral loads off therapy than individuals with more vigorous responses against a smaller number of viral targets. Her data suggests that the number of CTL epitopes recognized is influenced by stage of disease, time, viral load, and CD4+ counts. The immune system loses its ability to recognize one CTL target every five years an individual is infected, or every 1.5 years following an AIDS-defining diagnosis; every 2 log difference in viral load; and every 200 cell/mm3 decline in CD4+ count.

Data from a group of long-term non-progressors with a mean CD4+ count of 849 cells/mm3 and viral load of 5,900 copies/mL was presented. These individules could be stratified into two subgroups: one group who had strong HIV-specific immunity and good immunity against recall antigens, and a second group with good immunity against recall antigens but a poorer HIV-specific immune response. The mean viral load in those with good HIV-specific immunity was 50 copies/mL, compared to 11,400 copies/mL in those with poorer HIV-specific immunity. This data confirmed Walker's observations that the integrity of the HIV-specific immune response determines one's ability to control HIV replication in the absence of therapy.

Dr. Autran went on to describe the immune reconstitution experienced by another cohort of 317 patients, all of whom were studied at advanced stages of disease, with a mean CD4+ count of 50 cells/mm3. On antiretroviral therapy these patients experienced a mean increase of 150 CD4+ cells/mm3 over an average two year follow-up period. The initial increase in CD4+ cells that occurred during the first several months after beginning active therapy was comprised predominantly of memory cells, while a greater increase in the proportion of naive CD4+ cells were seen during the slower increase in counts that followed the early, rapid rise. If one considers just the CD4+ count increases, were these patients' CD4+ counts to continue to rise at the current rate, it will take seven to eight years before their counts return to normal levels.

The immunologic targets of these reconstituted CD4+ cells were analyzed in these patients with improved CD4+ counts. There was good recovery of CD4+ lymphoproliferative responses against recall antigens such as tetanus, and restoration of responses against antigens of opportunistic pathogens, such as cytomegalovirus and candida. Unfortunately, there was no recovery of CD4+ responses against HIV antigens. Although these patients were quite advanced at the time they were begun on active antiretroviral therapy, their lack of improvement in HIV-specific immunity supports the emerging concept that once lost, the HIV-specific immune response can not be recovered. Given the fact that there is a population of latently infected cells are to survive for years, there is little hope that individuals lacking strong HIV-specific immunity will be able to control any HIV replication in the absence of antiretroviral therapy. Therefore, unless other strategies can be identified that can boost HIV-specific immunity, there is little hope that these individuals will be able to stop therapy anytime soon.



Abstract: Immune events in early HIV infection (Session 425)
Authored by: Bruce D. Walker

Abstract: Control of HIV replication requires virus-specific helper and CTL function and levels of CTL activity are in equilibrium with virall burden (Poster 31130)
Authored by: Spyros Kalams, S.P. Buchbinder, M.J. Billingsley, E.S. Rosenberg, N. Jones, A.K. Trolha, B.D. Walker

Abstract: Inhibition of HIV-1 by CD8+ cells from seropositive individuals is antigen processing-dependent (Poster 60414)
Authored by: Otto Yang, B. Wilkes, S.A. Kalams, B.D. Walker

Abstract: Recognition of two overlapping CTL epitopes by CTL from a long-term non-progessing HIV-1 infected individual (Poster 31135)
Authored by: Thomas Harrer, E. Harrer, P. Barbosa, R. Wagner, M. Feinberg, S. Buchbinder, B.D. Walker

Abstract: Immune responses and reconstitution (Session 426)
Authored by: Brigitte Autran

See Also
More Research on HIV Long-Term Nonprogressors

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