Immune reconstitution and viral stimulation are required to restore HIV-specific CD8 T cell responses following advanced infection.

The extent to which highly active antiretroviral therapy (HAART) restores human immunodeficiency virus (HIV)-specific immunity in advanced infection is unknown. Therefore, we studied how effective therapy affected HIV-specific CD8(+) T cell responses in 4 individuals who had progressed to advanced infection. CD8(+) T cell responses were assessed by cytotoxicity and interferon-gamma (IFN-gamma) production. Proliferative CD4(+) T cell responses against HIV, Candida and mitogen were measured by (3)H-thymidine incorporation. Substantial immune reconstitution indicated by increased CD4(+) and CD8(+) T cell numbers followed suppression of viral replication. This was associated with emergence of HIV-specific cytotoxic T lymphocytes (CTL), but only concurrent with detectable viral replication. Emergent anti-HIV CTL were similar to those at earlier stages of infection in terms of their specificity, function, and CD28 phenotype. However, they were very short-lived in the absence of detectable HIV replication. Antigen-specific CD4(+) T cell responses remained severely compromised. Thus, effective antiretroviral therapy restores the capacity for HIV-specific CTL responses after advanced infection. However, the transient nature of these responses suggests failure to generate stable long-lived memory cells in the absence of HIV-specific helper T cell responses.