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245 Immune Responses and Reconstitution in HIV-1-Infected Individuals: Impact of Antiretroviral Therapy, Cytokines, and Therapeutic Vaccines
F. Gotch*1, N. Imami1, G. Hardy1, C. Burton1, A. Pirez1, R. Moss2, and B. Gazzard3
1Imperial Coll. Sch. of Med., London, UK; 2Immune Response Corp., Carlsbad, CA, USA; and 3Chelsea and Westminster Hosp., London, UK
Background: High levels of HIV-specific cellular immune responses are demonstrable in long-term nonprogressor patients who are able to control viraemia for many years in the absence of chemotherapy. Reconstitution of such potentially useful HIV-specific cellular immune responses must be a therapeutic aim, so that chronically infected patients with progressive disease may eventually discontinue drug therapy and attain long-term nonprogressor status. Although highly active anti-retroviral therapy (HAART) results in diminished viraemia and reconstitution of immune responses to some opportunistic pathogens, responses specific for HIV have not been shown to be restored, and indeed some responses may diminish in the absence of viral antigen. Consequently several novel therapeutic immunomodulatory strategies designed to boost HIV-specific immune responses have been attempted in the context of HAART.
Methods: HIV-1-specific CD4 and CD8 T-cell responses have been quantified in vitro in HIV+ persons following the administration of cytokines and/or therapeutic vaccines in the context of HAART and following drug treatment interruption or drug therapy change.
Results: Administration of cytokines ((therapeutic vaccines) improves both CD4+ and CD8+ HIV-1-specific T-cell responses even in late stage disease. Virus-specific T-cell responses are also induced by auto-immunisation (occurring during transient viraemia or during treatment interruption) and following therapy change from a PI- to a nonnucleoside-based HAART regimen. However, reconstitution of HIV-1-specific immune responses is mostly transient and reversal to the previous anergic state is rapid.
Conclusions: Viral reservoirs in the latently infected resting CD4+ T cells, on follicular dendritic cells or infected thymic epithelium may be involved in clonal suppression/anergy, which present major obstacles to the long-term maintenance of useful HIV-1-specific immune responses induced by immunomodulation. Nevertheless we believe that immunotherapy in the context of limited HAART may eventually offer hope to 30 million people currently infected with HIV.
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