Suppression of HIV replication in the resting CD4(+) T cell reservoir by autologous CD8(+) T cells: Implications for the development of therapeutic strategies

CD8(+) T cell-mediated antiviral activity against HIV has been described co nsistently in infected individuals; however, the role of this activity in c ontrolling replication of HIV in the latently infected, resting CD4(+) T ce ll reservoir is unclear. By using an ex vivo system, we show that replicati on of HIV in this viral reservoir is effectively suppressed in coculture by autologous CD8(+) T cells in long-term nonprogressors (LTNPs) and in patie nts whose viremia was controlled by highly active antiretroviral therapy (H AART), but not in therapy-naive patients who had substantial levels of plas ma viremia. This antiviral activity was largely independent of cytotoxic CD 8(+) T lymphocytes (CTL). When the role of soluble CD8(+) T cell-derived fa ctors was examined, we found that CC-chemokines played a major role in inhi bition of viral replication in the latent viral reservoir in some LTNPs and patients receiving HAART, but not in chronically infected patients who wer e not receiving antiretroviral therapy. Potent antiviral activity, independ ent of CC-chemokines, was found mainly in patients in whom HAART was initia ted shortly after the acute phase of HIV infection. These results indicate that CD8(+) T cells provide potent suppressive activity against HIV replica tion in the latent viral reservoir via direct cellular contact in patients who are naturally LTNPs or in those who are treated with HAART. Furthermore , the profound antiviral activity exerted by non-CC-chemokine soluble facto rs in infected patients who began HAART early in HIV infection suggests tha t preservation of this HIV-suppressive mechanism by early initiation of the rapy may play an important role in the containment of viral replication in infected patients following interruption of therapy.