349   Immunomodulation of Chronic HIV-1 Infection: Impact of HAART, Interleukin-2 and/or an Inactivated gp120-Depleted HIV-1 Immunogen (REMUNE).

G. Hardy*¹, N. Imami¹, A. Sullivan¹, M. Nelson¹, C. Burton¹, R. Moss², B. Gazzard¹, and F. Gotch¹.
¹Imperial Coll. Sch. of Med. Chelsea and Westminster Hosp., London, UK and²Immune Response Corp., San Diego, CA.

Background:Highly active antiretroviral therapy (HAART) fails to restore full immunocompetence as demonstrated by a lack of HIV-1-specific T cell responses in chronically infected individuals. Both HIV-1- specific CD8 cytotoxic T lymphocyte (CTL) and CD4 helper T lymphocyte (HTL) responses are pivotal in maintaining control of HIV-1 replication and are likely to play critical roles in depleting latent HIV-1 reservoirs in the context of HAART. Enhanced anti-viral responses, in addition to activation of latent viral reservoirs, may enable increased decay of residual virus and reduce the risk of viral rebound following discontinuation of HAART.

Methods:A randomised, phase I trial of treatment with interleukin-2 (IL-2) in combination with therapeutic vaccination (REMUNE) is being conducted. Forty patients are treated for 16 weeks with HAART before randomisation to A) HAART alone, B) HAART + IL-2, C) HAART + IL-2 + REMUNE, or D) HAART + REMUNE.

Results:While HAART alone does not lead to reconstitution of HIV-1-specific responses, restoration of some recall responses, such as to Candida antigen (p = 0.001), become highly significant. While the baseline mean CD4 T cell count of 286 cells/ml blood was lower than in other REMUNE studies, REMUNE was able to induce HIV-1-specific T cell responses in some patients. The addition of IL-2 to REMUNE in some cases reduced the number of vaccine doses required to achieve this effect and increased the number of HIV-1 antigens to which responses were induced. IL-2 with or without REMUNE substantially increases CD4 T cell counts, despite inducing transient viraemia. However, CD4 HTL and CD8 CTL responses to HIV-1 are also induced by virological breakthrough due to therapeutic failure, even without immunotherapy.

Conclusions:HIV-1-specific CD8 and CD4 T cell responses are inducible in HAART-treated patients with advanced HIV-1 disease by both therapeutic vaccination and IL-2 therapy. Combining these immunomodulatory approaches enhances their effectiveness. Such strategies for induction of T cell responses are likely to be safer than structured treatment interruptions.