February 25, 2002
The formation of a strong, effective immune response to HIV has proved to be one of the most elusive goals of antiretroviral therapy and remains the cornerstone of designing a candidate vaccine. Much has been learned about the reconstitution of the immune system that occurs after the use of successful combination antiretroviral therapy (ART). The work of Dr. Brigitte Autran and her colleagues has been critical in understanding these responses. In this plenary session Dr. Autran reviewed the state of knowledge and the problems inherent in maintaining HIV-specific immune reconstitution. She then described the rationale and design of therapeutic strategies to control HIV replication with the active participation of the immune system and briefly mentioned ongoing research in vaccine-based adjuncts to ART that will surely play a role in restoring HIV-specific host responses.
One key point crucial to understanding immune reconstitution is that these responses are antigen-dependent. Since ART does not directly affect opportunistic pathogens, after successful ART, enough of their antigens remain in the host, available to stimulate the development of a reconstituted memory response. The restoration of these responses and the emergence of naive T-cell responses allow patients to safely discontinue prophylactic antibiotics. After initiation of ART, however, HIV replication decreases dramatically, decreasing the amount of HIV antigens necessary to reconstitute HIV-specific CD4 responses that support the cytotoxic T-lymphocyte responses (CTL) of CD8 cells.
In acute infection, replicating HIV activates CD4 cells specific for HIV antigens inducing an initial CTL. However, these activated CD4 cells become a prime target for infection, rapidly causing their death. With the loss of these HIV-specific helper cells, the maintenance of effective HIV-specific CTL is not possible, and this is the central dilemma in HIV immunity. When suppressive ART is used, however, viral replication and antigen load disappears, and CTL can no longer target the latently infected CD4 cells that harbor replication-competent proviral DNA. Early therapy after acute HIV infection delays and reduces later CTL, as antigen load has been decreased, but preserves CD4 cells responsive to HIV. In chronically infected patients in whom most of the HIV-specific CD4 cells have been long infected and killed after initiation of ART, CD4 responses -- as measured by lymphoproliferative assays and ELISpot to IFN-g -- are significantly worse than seen after treatment in acute infection. Furthermore, as ART continues, any existing HIV-specific CD8 cells decline over time, as measured by tetramer assays and IFN-g.
The need for the ongoing presence of HIV antigens to stimulate CD4 Th1-help led to the concept of treatment interruptions (STIs) as a source of antigen for representation to the immune system. The use of STIs to produce CD4 responses have largely failed, however, with the early responses measurable after an STI waning rapidly, even prior to restarting ART. CD8 responses wane shortly after restarting ART as well. Furthermore, the rebounding CTL is often very narrowly focused on the single preexisting immunodominant clone, not sufficient to suppress HIV replication after therapy is later stopped.
Long-term non-progressors (LTNPs), defined as patients who maintain CD4 counts >600 for more than eight years without symptoms of HIV disease in the absence of ART, seem to have kept HIV in check through their own immune activity. Specifically, the CD8 responses of LTNPs seem to be more intense and more broadly aimed at HIV antigens than in patients whose infection progresses to immune dysfunction in the usual time course. HIV-specific CD4 Th1-helper responses correlate well with viral load and are strongest in LTNPs with low viral loads. IgG2 antibody responses against gag and gp41 antigens may also play a role in maintaining immune control of HIV in untreated LTNPs.
Since we have learned that strong, broad CD4 and CD8 responses -- in conjunction with antibodies -- seem to be correlates of LTNP status, but that STIs are not effective at inducing these responses, novel strategies using ART and therapeutic vaccines are currently under investigation. These strategies may represent the best current hope for reconstitution of HIV-specific responses. Recombinant viral vector vaccines, such as canarypox and attenuated cowpox strains, as well as adenovirus vectors may induce transcription of multiple HIV genes in target cells to stimulate the necessary strong, broad immune responses. Studies are currently underway by the European ANRS group to assess the efficacy of canarypox alone and combinations of canarypox, lipopeptides and IL-2 in both acutely and chronically-infected patients. Naked DNA vaccines taken up into cells may achieve this same goal without the use of viruses, and these vaccines are also being studied in combination with viral vectors vaccines. Small peptide and inactivated particle vaccines are also under investigation. Although final results of these trials are not yet available, Dr. Autran mentioned promising preliminary data indicating that canarypox, combined with inactivated virus particles when used in primary infection, can induce CD4 responses comparable to those seen in LTNPs. When used in chronic infection, slightly less strong responses were observed, and CTL data is not yet available.
Although the road to understanding the reconstitution of HIV-specific immune responses has been long, effective therapeutic vaccine strategies may be available in the near future. These strategies may ultimately allow for the development of improved immune control of HIV, lower viral set points and, perhaps, eventual decreases in the intensity and duration of conventional ART.
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