Immune responses and reconstitution in HIV-1 infected individuals: impact of anti-retroviral therapy, cytokines and therapeutic vaccination

Most patients with chronic HIV-1 infection lack functional CD4(+) and CD8() HIV-1-specific T cells with proliferative and cytolytic capacity, respect ively. This is despite being able to produce intracellular cytokines in res ponse to viral antigens. Protease inhibitor (PI)-based highly active anti-r etroviral therapy (HAART) is unable to completely eradicate virus and fails to enable total restoration of immunity including induction of anti-HIV-1 responses. We have taken novel approaches towards the treatment of chronic HIV-1 disease with the aim of instigating long-term non-progressor status a nd depletion of virus reservoirs. HIV-1-specific CD4(+) and CD8(+) T cell r esponses were measured following the administration of cytokines, during th erapeutic vaccination, and following treatment interruption (TI) or drug th erapy change. Administration of cytokines, with or without therapeutic vacc ination, in HAART treated patients, improved both CD4(+) and CD8(+) HIV-1-s pecific T cell responses even in late-stage disease. Virus-specific T cell responses were also seen during TI or when transient viraemia was apparent, and following therapy change from a PI- to a non-nucleoside-based HAART re gimen. Reconstitution of HIV-1-specific immune responses was found to be tr ansient and reversal to the previous anergic state was rapid. Viral reservo irs in the latently infected resting CD4(+) T cells, on follicular dendriti c cells of germinal centers or even in infected thymic epithelium may be in volved in clonal suppression and anergy. These may present major obstacles to the maintenance of HIV-1-specific responses and the eventual eradication of HIV-1. (C) 2001 Published by Elsevier Science B.V.