A clear understanding of the antiviral effects of CD8؉ T cells in the context of chronic human immunodeficiency virus (HIV) infection is critical for the development of prophylactic vaccines and therapeutics designed to support T-cell-mediated immunity. However, defining the potential correlates of effective CD8 ؉ T-cell immunity has proven difficult; notably, comprehensive analyses have demonstrated that the size and shape of the CD8 ؉ T-cell response are not necessarily indicative of efficacy determined by measures of plasma viral load. Here, we conducted a detailed quantitative and qualitative analysis of CD8؉ T-cell responses to autologous virus in a cohort of six HIV-infected individuals with a history of structured interruption of antiretroviral therapy (ART) (SIT). The magnitude and breadth of the HIV-specific response did not, by themselves, explain the changes observed in plasma virus levels after the cessation of ART. Furthermore, mutational escape from targeted epitopes could not account for the differential virological outcomes in this cohort. However, the functionality of HIV-specific CD8 ؉ T-cell populations upon antigen encounter, determined by the simultaneous and independent measurement of five CD8 ؉ T-cell functions (degranulation and gamma interferon, macrophage inflammatory protein 1␤, tumor necrosis factor alpha, and interleukin-2 levels) reflected the emergent level of plasma virus, with multiple functions being elicited in those individuals with lower levels of viremia after SIT. These data show that the quality of the HIV-specific CD8 ؉ T-cell response, rather than the quantity, is associated with the dynamics of viral replication in the absence of ART and suggest that the effects of SIT can be assessed by measuring the functional profile of HIV-specific CD8 ؉ T cells.

T cells develop into two major populations distinguished by their T cell receptor (TCR) chains. Cells with the α β TCR generally express CD4 or CD8 lineage markers and mostly fall into helper or cytotoxic/effector subsets. Cells expressing the alternate γ δ TCR in humans generally do not express lineage markers, do not require MHC for antigen presentation, and recognize nonpeptidic antigens. We are interested in the dominant Vγ2Vδ2+ T cell subset in human peripheral blood and the control of effector function in this population. We review the literature on γ δ T cell generation and repertoire selection, along with recent work on CD56 expression and defining a cytotoxic/effector lineage within the phosphoantigen-reactive Vγ2Vδ2 cells. A unique mechanism for MHC-independent repertoire selection is linked to the control of effector function that is vital to the role for γ δ T cells in tumor surveillance. Better understanding of these mechanisms will improve our ability to exploit this population for tumor immunotherapy.

Background: In lymphocyte subsets, expression of CD56 (neural cell adhesion molecule-1) correlates with cytotoxic effector activity. For cells bearing the Vγ2Vδ2 T cell receptor, isoprenoid pyrophosphate stimulation leads to uniform activation and proliferation, but only a fraction of cells express CD56 and display potent cytotoxic activity against tumor cells. Our goal was to show whether CD56 expression was regulated stochastically, similar to conventional activation antigens, or whether CD56 defined a lineage of cells committed to the cytotoxic phenotype.

Most human immunodeficiency virus (HIV)–infected individuals experience increases in peripheral CD4+ T cell counts with suppressive antiretroviral therapy (ART) that achieves plasma HIV RNA levels that are less than the limit of detection. However, some individuals experience decreasing CD4+ T cell counts despite suppression of plasma viremia. We evaluated 4 patients with a history of CD4+ T cell decline despite successfully suppressive ART, from a median of 719 cells/mm3 (range, 360–1141 cells/mm3) to 227 cells/mm3 (range, 174–311 cells/mm3) over a period of 18–24 months; 3 of the patients were receiving tenofovir and didanosine, which may have contributed to this decrease. There was no evidence of HIV replication, nor of antiretroviral drug resistance in the blood or lymphoid tissue, or increased proliferation or decreased thymic production of naive CD4+ T cells. All 4 patients had significant fibrosis of the T cell zone of lymphoid tissue, which appeared to be an important factor in the failure to reconstitute T cells.