Characterization of clonal CD4+ effector cell expansions in HIV-1 disease

HIV-1 infection leads to CD4+ T cell depletion and alterations in CD4+ T cell phenotype, function, and repertoire. Highly active antiretroviral therapy (HAART) is generally effective in suppressing viral replication and enabling the recovery of CD4+ counts, but abnormalities in phenotype and repertoire can persist for several years after the initiation of therapy.; Preliminary investigations of patients with moderately advanced HIV-1 disease revealed large expansions of CD4+ T cell subsets expressing certain T cell receptor (TCR) beta chain variable regions (Vβ). In some cases, the expansions occupied up to 30 percent of a patient's CD4+ T cell repertoire. Detailed study of these expansions was undertaken in several patients before and during HAART. TCR sequencing showed that these large Vβ subsets contained large clonal populations of cells that had characteristics of highly differentiated effector cells and persisted during up to three years of therapy. Sequencing of individual Vβ-Jβ subsets showed that, by contrast, the remainder of the CD4+ repertoire retained near-normal levels of TCR diversity.; In response to mitogenic stimulation, these clones proliferated poorly but expressed high levels of interferon gamma. Flow cytometric analysis of the clones showed high levels of perforin expression and relatively low levels of the costimulatory molecule CD28 and the HIV-1 co-receptors CXCR4 and CCR5. Cells lacking CD28 were also found to contain low levels of HIV-1 DNA, suggesting that they were relatively protected from infection. The TCR genes from the largest clone were expressed in a chimeric TCR hybridoma system. Antigen specificity studies using this system suggested that the clone was not specific for HIV-1 antigens but failed to reveal the antigenic target.; These results support the existence of antigen-driven processes in HIV-1 infection that generate clonal CD4+ expansions without globally disturbing the repertoire. These expansions appear competent to carry out effector functions, including cytolysis. They are not necessarily involved in the immune response to HIV-1, but they may play an important role in the control of other chronic viral infections, including some opportunistic infections commonly associated with HIV-1.