Epidemiology and Social: Editorial Comment
Immune-based interventions in HIV infection: doing the right studies, getting the right answers
Bart, Pierre-Alexandre; Pantaleo, Giuseppe
From the Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland.
Received 23 August, 2005
Accepted 27 October, 2005
Correspondence to Pr G. Pantaleo, Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland. E-mail: email@example.com
Strong immunological and medical rationales can be given for supporting the development of immune-based interventions in HIV-1 infection. Firstly, HIV-1 causes severe impairment of immune functions . In addition to the massive destruction of CD4 T cells, HIV-1 has developed a series of strategies that invariably allow the virus to evade the virus-specific immune response . Secondly, the current potent drug combination therapies are able to suppress virus replication effectively but not to eradicate it [3–5] and life-time therapies are just not possible due to the difficulties in maintaining optimal adherence to therapy and for the toxicity associated with long-term antiviral therapy .
In the last issue of the journal, Levy and his collaborators report the results of a clinical study investigating the effects of a therapeutic vaccination regimen on the control of HIV-1 replication . The immune-based interventions developed over the years have had three main objectives: (1) to compensate CD4 T-cell loss, for example, by interleukin (IL)-2 therapy ; (2) to reduce immune activation and target cells availability, for example, with cyclosporin A (CsA) , mycophenolate  and hydroxyurea ; and (3) to boost existing and/or to induce de novo HIV-1-specific T-cell responses, for example, by therapeutic immunization/vaccination [12,13]. IL-2 therapy has proven efficacy in preserving CD4 T-cell numbers but the long-term clinical benefit of this intervention has not yet been completely demonstrated. Immunomodulator agents such as CsA, mycophenolate and hydroxyurea have generated interesting observations when used either for a limited period of time during primary infection (CsA [9,14] and mycophenolate) or in structured treatment intervention therapeutic regimens . Therapeutic vaccine strategies included peptide-based vaccines (lipopeptides), inactivated virus-based vaccines (Remune®, The Immune Response Corporation, Carlsbad, California, USA) and recombinant virus vector-based vaccines (canarypox and more recently adenovirus type 5) expressing different HIV-1 proteins. With the exception of IL-2 therapy, the major limitations of the clinical studies investigating the above immunological interventions have been the non-controlled study design and the small number of patients enrolled in these studies. Other complicating factors in the interpretation of the clinical data were the lack of clearly defined study endpoints and criteria of successful response. Therefore, most of the studies have generated interesting scientific observations but were not powered or adequately designed to show clinical benefit.
Why is the report of Levy and collaborators an important study? This is an important study because it has the appropriate study design, namely a controlled randomized study; it has clear endpoints, namely cumulative time (days) off treatment; it is statistically powered as it included seventy subjects; it has comprehensive virologic and immunologic monitoring; and it has a long-term follow-up, namely 2 years. Seventy HIV-1 infected patients successfully treated with antiviral therapy were randomized to continue treatment alone or in combination with four boosts of ALVAC 1433 (recombinant canarypox expressing gag) and HIV-LIPO-6T vaccines followed by three cycles of subcutaneous IL-2. The effects of vaccination on virus replication were determined by treatment interruption. The results show that the cumulative time off treatment (primary endpoint of the study) was significantly greater in the vaccine group (177 days) in comparison with the control group (89 days). Similarly, viremia levels were significantly lower in the vaccine group after treatment interruption and HIV-1-specific immune responses significantly correlated with the time off treatment.
Levy and collaborators have provided evidence that immune-based interventions may have clinical benefit. One of the lessons we have learnt is that by doing the right study, you get the right answer. There are also another series of important considerations generated from this study. The beneficial effect observed has been obtained using three different (recombinant canarypox, peptides and IL-2) immune-based interventions. The present study does not address the relative importance of the three immune-based interventions in the therapeutic effects observed. This issue needs to be investigated in future studies. This however may indicate the need for the combination of multiple immune-based intervention strategies in order to achieve effective immune-mediated antiviral effects. The great complexity of the immunoregulatory mechanisms responsible for the generation and maintenance of effective T-cell responses supports the hypothesis that combining multiple immune-based intervention strategies preventing CD4 T-cell loss, stimulating HIV-1-specific T-cell responses and reducing T-cell activation and target cell availability may ultimately render less efficient both virus replication and virus escape mechanisms.
A critical issue for the future development of immune-based interventions in HIV-1 infection will be to understand the causes of the heterogeneity of the response to immune-based interventions . Recent studies have shed new light on the host factors influencing the course of HIV-1 infection and on the functional characteristics of protective T-cell responses. In particular, it has become clear that the HLA genotype probably through the T-cell immune response influences HIV-1 infection and disease evolution [17,18]. In addition, polyfunctional CD4 and CD8 T-cell responses, as defined by the proliferation capacity and the secretion of multiple cytokines (IL-2, IFN-γ and MIP-1β), have consistently been associated with virus control in a number of virus infections including HIV-1 [19,20]. Future clinical studies will have to investigate these parameters in order to determine qualitative signatures of T-cell responses that may serve as predictors of the response to therapy and to identify groups of patients that may better respond to immune-based interventions.
In conclusion, Levy and his collaborators have provided solid clinical data that may generate a new impetus for further developing and expanding the investigation of immune-based interventions in HIV-1 infection.
1. Graziosi C, Soudeyns H, Rizzardi GP, Bart PA, Chapuis A, Pantaleo G. Immunopathogenesis of HIV infection. AIDS Res Hum Retroviruses 1998; 14(suppl 2):S135–S142.
2. Letvin NL, Walker BD. Immunopathogenesis and immunotherapy in AIDS virus infections. Nat Med 2003; 9:861–866.
3. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al
. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278:1295–1300.
4. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, et al
. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997; 278:1291–1295.
5. Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, et al
. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med
:727–728. Epub 2003 May 18.
6. Enanoria WT, Ng C, Saha SR, Colford JM Jr. Treatment outcomes after highly active antiretroviral therapy: a meta-analysis of randomized controlled trials. Lancet Infect Dis 2004; 4:414–425.
7. Lévy Y, Durier C, Lascaux A-S, Meiffrédy V, Gahéry-Ségard H, et al
. Sustained control of viremia following therapeutic immunization in chronically HIV-1 infected individuals. AIDS 2006; 20:405–413.
8. Arduino RC, Nannini EC, Rodriguez-Barradas M, Schrader S, Losso M, Ruxrungtham K, et al
. CD4 cell response to 3 doses of subcutaneous interleukin 2: meta-analysis of 3 Vanguard studies. Clin Infect Dis
:115–122. Epub 2004 Jun 14.
9. Rizzardi GP, Harari A, Capiluppi B, Tambussi G, Ellefsen K, Ciuffreda D, et al
. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J Clin Invest 2002; 109:681–688.
10. Chapuis AG, Rizzardi GP, D'Agostino C, Attinger A, Knabenhans C, Fleury S, et al
. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nat Med 2000; 6:762–768.
11. Lori F, Foli A, Groff A, Lova L, Whitman L, Bakare N, et al
. Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic (‘virostatic’) mechanisms. AIDS 2005; 19:1173–1181.
12. Boaz MJ, Waters A, Murad S, Easterbrook PJ, Vyakarnam A. Presence of HIV-1 Gag-specific IFN-gamma+IL-2+ and CD28+IL-2+ CD4 T cell responses is associated with nonprogression in HIV-1 infection. J Immunol 2002; 169:6376–6385.
13. Lu W, Arraes LC, Ferreira W, Andrieu JM. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med 2004; 10:1359–1365.
14. Rizzardi GP, Vaccarezza M, Capiluppi B, Tambussi G, Lazzarin A, Pantaleo G. Cyclosporin A in combination with HAART in primary HIV-1 infection. J Biol Regul Homeost Agents 2000; 14:79–81.
15. Garcia F, Plana M, Arnedo M, Brunet M, Castro P, Gil C, et al
. Effect of mycophenolate mofetil on immune response and plasma and lymphatic tissue viral load during and after interruption of highly active antiretroviral therapy for patients with chronic HIV infection: a randomized pilot study. J Acquir Immune Defic Syndr 2004; 36:823–830.
16. Pantaleo G, Koup RA. Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know. Nat Med 2004; 10:806–810.
17. Nolan D, James I, Mallal S. HIV: experiencing the pressures of modern life. Science 2005; 307:1422–1424.
18. Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D, Thobakgale C, Chetty S, et al
. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 2004; 432:769–775.
19. Harari A, Vallelian F, Meylan PR, Pantaleo G. Functional heterogeneity of memory CD4 T cell responses in different conditions of antigen exposure and persistence. J Immunol 2005; 174:1037–1045.
20. Zimmerli SC, Harari A, Cellerai C, Vallelian F, Bart PA, Pantaleo G. HIV-1-specific IFN-g/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells. Proc Natl Acad Sci USA 2005; 102:7239–7244.
This article has been cited 1 time(s).
AIDS Research and Human RetrovirusesInterruption of antiretroviral therapy initiated during primary HIV-1 infection: Impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 randomized studyAIDS Research and Human Retroviruses
HIV-1; treatment interruption; vaccine
© 2006 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.