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.
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