T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity

The immunological correlates of highly active antiretroviral therapy (HAART)-induced suppression of human immunodeficiency virus type 1 (HIV-1) replication have been investigated. 20 HIV-1-infected patients with mean CD4(+) T cell count of 298/mul, plasma viral load of 4.7 log(10) copies/ml and naive for protease inhibitors (PI) were studied during 12 months of HAART. An increased number of both CD4(+) and CD8(+) naive T cells and a normalization of the frequency of CCR5- and CXCR4-expressing CD4(+) T cells were readily observed after starting therapy. Single cell analysis of cytokine production after 12 months of HAART showed an increased number of interleukin (IL)-2-, but not IIL-4- and (IFN)-gamma-, producing T cells and a decreased percentage of CD8+ TFN-gamma + cells. A correlation between the frequency of IFN-gamma-producing T cells and that of memory, CCR5(+) and CD95(+) T cells was demonstrated in both CD4(+) and CD8(+) subsets. The diversity of T cell receptor (TCR) variable beta (BV) chain repertoire significantly increased after 12 months of HAART within the CD4(+) but not the CD8(+) T cell subset. However, the level of perturbation of the third complementarity-determining region (CDR3), was not significantly modified by effective therapy. The number of anti-HIV Gag and Pol cytotoxic T lymphocytes precursors (CTLp) decreased during HAART and highly correlated with the CD8 IFN-gamma response. Ameliorated clinical conditions were observed in all patients in absence of any opportunistic infections during all the study period. These observations indicate that a better restoration of immunity may be obtained in patients starting HAART at less advanced stages of the disease.