| |
HIV Immunopathogenesis and Correlates of Protection: treatment during acute HIV
|
| |
| |
Bruce D. Walker, MD
Director, Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Source: www.medscape.com
Over the past few years there has been increasing evidence that the viral set point is influenced by HIV-specific immune responses, and this has led to considerable interest in and exploration of immune-based approaches to anti-HIV therapy.[1] However, the enthusiasm of some in this regard has been tempered by the skepticism of others, and final proof that meaningful immune augmentation might be achieved remains to be delivered. Several important studies presented at the Second IAS Conference on HIV Pathogenesis and Treatment not only addressed some of the current controversies concerning the prospect of immune-based therapy for HIV infection, but also provided further insights into why, at a fundamental level, immune control of HIV may be difficult to achieve.
Evidence of Cellular Immune Control of HIV
Some of the most exciting data demonstrating the influence of the immune system on viral evolution come from recently published studies involving a cohort of HIV-infected patients from Perth, Australia.[2] Updates and discussions of these studies were presented at the IAS Conference.[3] These findings showed that, on a population level, HIV is evolving to evade human CD8+ cell responses. In a State-of-the-Art Lecture, Simon Mallal of Royal Perth Hospital described sequence polymorphisms in HIV that were specifically found in persons with certain HLA types, indicating that immune selection pressure was being applied on the virus with respect to HIV's interaction with these sites. These data add additional and compelling evidence that HIV feels the effects of immune selection pressure, and suggest that evasion through sequence variation is a common consequence of this pressure. This emerging field of viral immunogenetics is likely to be an area of intense interest, and one that is particularly relevant to vaccine development because gradual viral evolution under immune selection pressure may influence the potential efficacy of vaccines based on current consensus sequences.
Augmentation of Immune Control in Acute and Chronic HIV Infection
Attempts to boost immune control in chronic HIV infection through the use of structured treatment interruptions (STI) have been disappointing, but interest remains in the possibility of boosting immunity with a combination of antiretroviral (ARV) treatment and immunization to augment CD8+ and/or CD4+ cell responses. Some new evidence that this may be possible was presented, but clinical benefit remains to be determined; larger studies of this approach are planned, and will involve the use of more potent immunogens.[4]
In contrast to the results of such studies in chronically infected patients, studies in persons with acute HIV infection have suggested that immediate treatment with ARV therapy leads to augmentation of virus-specific immune responses, and raise the possibility that this might result in improved control of HIV once therapy is halted, or that transient interruptions of therapy might lead to a regulated boosting of immunity and subsequent viral control once therapy is stopped. In an initial STI trial performed in 8 patients treated for acute HIV infection, all 8 certain HLA types, indicating that immune selection pressure was being applied were able to achieve at least transient control of viremia to < 5000 HIV-1 RNA copies/mL after discontinuation of ARV therapy following 1 or 2 treatment periods.[5] At the time of publication of that study (2000), 5 of 8 subjects remained off therapy with plasma viral loads of < 500 copies/mL after a median 6.5 months.
More recent follow-up data on these subjects and an additional 6 patients were presented at the conference by Bruce Walker[6] of Harvard Medical School, Boston, Massachusetts. These new findings showed that 12 of 14 persons, following initial viral rebound, were able to achieve at least transient immune control of viral replication upon interruption of ARV therapy. However, in an intention-to-treat analysis, only 3 of 14 did not ultimately meet the protocol-determined criteria for reinitiation of therapy (viral load > 5000 copies/mL for 3 weeks, or > 50,000 copies on a single occasion). In some patients, though, viral breakthrough occurred more than 600 days after treatment interruption. Of note, the majority of failures occurred with slow, gradual rises in viral load. These data provide further impetus for larger clinical trials to determine whether the viral set point can be altered, and whether disease progression can be affected by limited early treatment. Such studies are under way.
Correlates of Immune Control of HIV (And Lack Thereof)
The correlates of protection in HIV infection remain unclear. There is no question that cellular immune responses are important, and that these include both CD4 T-helper cell and CD8+ cytotoxic T lymphocyte (CTL) responses. Other host and immunologic factors must also be considered, including natural killer cell activity, as certain of these are clearly affected by genetic polymorphisms that may contribute to differences in disease outcome.[7] As demonstrated by Amalio Telenti[8] of the University of Lausanne, Switzerland, there are specific HLA alleles, such as HLA B57, that are strongly associated with persistent containment of viremia. Further, as Nathaniel Landau[9] of the Salk Institute discussed in his plenary lecture, host genetic factors such as APOBEC3G, which may limit productive infection within cells, may play an important role as innate, intracellular components of immunity; such factors may also be genetically polymorphic and expressed to different degrees in different patients/populations.
Alterations in adaptive immune responses also clearly affect viral control. New data linking viral evolution and immune escape to increases in viremia were discussed by Marcus Altfeld[10] of Massachusetts General Hospital, Boston, Massachusetts. These were derived from studies of persons who failed to control HIV following cessation of early ARV therapy for acute infection: Viral isolates from these patients revealed progressive, escape-related mutations within CTL epitopes. In the few cases presented, it was clear that escape occurred in a stepwise fashion, and that substantial differences in plasma viremia were associated with the number of mutant epitopes. Moreover, amino acid changes other than those associated with these epitopes were shown to affect the ability of an epitope to be presented, complicating analysis of sequence variation and immune escape.
Other factors likely to affect immune control include infection and impairment of HIV-specific CD4+ cells in vivo,[11] aberrant CD8+ cell activation and premature senescence of HIV-specific CD8 T cells,[12] and skewed maturation of antigen-specific CD4+ cells, which, in one study, led to an impaired ability to produce interleukin (IL)-2.[13] It is likely that all of these factors contribute in varying degrees to the relative control or escape of HIV, and that the contribution of individual or multiple factors may differ depending on host genetics. It is important to remember from animal models of chronic disease that even small nucleotide changes can dramatically alter outcomes in murine models of viral infection, such as murine lymphocytic choriomeningitis virus infection, and that changes in the genetic background of the mice can similarly affect disease outcomes. The genetic heterogeneity of human populations affected by HIV confounds attempts to define a simple explanation of the correlates of protection against HIV infection, since the relative contributions of a multitude of host genetic factors may vary significantly in different persons and different populations. One aspect of this that is in need of greater attention is the specific impact of such host factors on viral replicative fitness, and how that relationship may influence steady-state viral load.
Cytokines and Immune Reconstitution
There has been increasing interest in IL-7, a stromal cell-derived cytokine, as a possible immunotherapeutic agent in HIV infection, since it plays an important part in thymopoiesis. In a small study in SIV-infected animals, IL-7 was infused for 3 weeks, and the effects of this therapy on viral load and T lymphocyte subsets were evaluated, as was the rate of peripheral expansion of CD4+ and CD8+ cells.[14] IL-7 was shown to be reasonably well tolerated, to increase central renewal and peripheral expansion of T lymphocytes, and to effect no alterations in viral load in blood or lymph nodes. Trials of IL-7 have are under way in cancer patients, and IL-7 will soon be tested in the setting of HIV infection.
The study of IL-2 as an immunotherapeutic agent continues, and the preliminary results of ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) were presented by Laurence Weiss[15] of Hospital European Georges Pompidou, Paris, France. The study has enrolled about 4000 patients with baseline CD4+ cell counts of > 300 cells/mcL, and at least 8 months of follow-up are available for the majority of subjects. Of persons completing 3 cycles of subcutaneous IL-2, nearly 10% were classified as nonresponders because CD4+ cell counts fell below baseline values. However, nearly two thirds had increases in CD4+ cell counts of 200 cells or more. Higher nadir CD4+ cell count, higher baseline CD4+ cell count at the time treatment with IL-2 was started, and younger age were all associated with positive CD4 changes. However, the demonstration that there is or is not any clinical benefit to IL-2 therapy is still anxiously awaited.
Conclusions
Immunopathogenesis studies presented at this conference add to our growing understanding that the immune system plays a significant, albeit insufficient, role in containing viral replication. Determining the correlates of immune protection will be difficult given the genetic heterogeneity of HIV-infected populations, but large-scale studies will help. Host genetic factors and viral variation in the face of potent immune responses may limit the prospects for immune control of infection and for immune augmentation, but therapeutic immunization studies using potent immunogens capable of inducing strong augmentation of immune responses in infected persons have yet to be conducted, and preliminary studies with less potent immunogens suggest that immune responses can be induced in this setting. As trials continue and increase in number, more data will be forthcoming that will hopefully provide proof of principle that immune augmentation is a therapeutic option.
References
1. Letvin NL, Walker BD. Immunopathogenesis and immunotherapy in AIDS virus infections. Nat Med. 2003;9:861-866.
2. Moore CB, John M, James IR, Christiansen FT, Witt CS, Mallal SA. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science. 2002;296:1439-1443.
3. Mallal S. HIV mutational escape from CTL responses and antiretrovirals; parallels and differences. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 133.
4. Autran B. Rationale for HIV-specific immunotherapy: lessons from chronic HIV infection and immune restoration. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 11.
5. Rosenberg ES, Altfeld M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000;407:523-526.
6. Walker BD. Prospects for immunotherapy of HIV infection: lessons from acute infection. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 12.
7. Carrington M. Dissecting the effects of HLA and KIR genetic polymorphism on HIV disease. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 132.
8. Telenti A. Genetic predisposition of HIV disease progression. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 133a.
9. Landau NR. Host/virus mechanisms in the molecular pathogenesis of HIV. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 4.
10. Altfield M. Impact of HIV-1 specific T-cell responses on viral sequence variations and control of viral replication. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 45.
11. Douek D, Hill B, Ambrozak D, et al. T-cells that harbour HIV in vivo: implications for pathogenesis. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 177.
12. Appay V. CD8+ T-cell differentiation towards senescence following aberrant CD8+ activation in HIV-1 infection. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 48.
13. Harari A. Skewed representation of functionally distinct populations of virus-specific CD4 T-cells in HIV-1-infected subjects with progressive disease. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 44.
14. Nugeyre MT, Monceaux V, Beq S, et al. Inerleukin-7 stimulates T cell renewal without increasing viral replication in SIV-infected macaques. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 14.
15. Weiss L, Aboulhab J, Babiker GA, et al. Preliminary results of ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomised International Trial): baseline predictors of CD4 T-cell response to interleukin-2. Program and Abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 13.
|
|
| |
| |
|
|
|
