Maintenance of Large Numbers of Virus-Specific CD8+ T Cells in HIV-Infected Progressors and Long-Term Nonprogressors

Abstract

The virus-specific CD8+ T cell responses of 21 HIV-infected patients were studied including a unique cohort of long-term nonprogressors with low levels of plasma viral RNA and strong proliferative responses to HIV Ags. HIV-specific CD8+ T cell responses were studied by a combination of standard cytotoxic T cell (CTL) assays, MHC tetramers, and TCR repertoire analysis. The frequencies of CD8+ T cells specific to the majority of HIV gene products were measured by flow cytometric detection of intracellular IFN-γ in response to HIV-vaccinia recombinant-infected autologous B cells. Very high frequencies (0.8–18.0%) of circulating CD8+ T cells were found to be HIV specific. High frequencies of HIV-specific CD8+ T cells were not limited to long-tern nonprogressors with restriction of plasma virus. No correlation was found between the frequency of HIV-specific CD8+ T cells and levels of plasma viremia. In each case, the vast majority of cells (up to 17.2%) responded to gag-pol. Repertoire analysis showed these large numbers of Ag-specific cells were scattered throughout the repertoire and in the majority of cases not contained within large monoclonal expansions. These data demonstrate that high numbers of HIV-specific CD8+ T cells exist even in patients with high-level viremia and progressive disease. Further, they suggest that other qualitative parameters of the CD8+ T cell response may differentiate some patients with very low levels of plasma virus and nonprogressive disease.

The phenotype of hepatitis B virus–specific T cells differ in the liver and blood in chronic hepatitis B virus infection

“…This is lower than typically observed in other chronic viral infections such as in HIV-1, where the magnitude of HIV-1-specific IFN-␥ ϩ CD8 ϩ T cells ranges from 0.8% to 18.0%. 12,17 The magnitude of intrahepatic cytokine ϩ HBV-specific T cells was similar to that seen in cultured PBMC (0.0%-1.80%). The low magnitude of HBV-specific T cells found in blood was therefore not explained by sequestration of HBV-specific T cells to the liver, which has been previously shown to be true in both HBV and HCV infections when using virus-specific tetramer ϩ T cells.…”

Phenotypic and Functional Analysis of Immune CD8+ T Cell Responses Induced by a Single Injection of a HIV DNA Vaccine in Mice

“…Interestingly, this sequential type of response has been reported during natural HIV infection with early strong responses often seen toward Nef and Env epitopes (29,30). Later, most HIV-infected patients, particularly LTNP patients, develop and maintain a broad response directed to multiple HIV Ags with a vast majority of cells responding to Gag and Pol (30,31). Our results with ⌬4SHIV KU2 DNA vaccine in mice demonstrated that an anti-HIV CD8 ϩ T cell response expanded the magnitude and breadth of T cell epitopes in a manner similar to natural HIV infection.…”

Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection

“…In the absence of treatment, different levels of viremia establish which probably represent different levels of antigenic stimulation on one hand, whereas increased frequencies of effective HIV-specific CD8 ϩ T cells may control viral replication on the other hand. These complex interactions between VL and CTL frequencies might preclude the detection of straightforward correlations (14,32,33). Third, it is likely that the amount of viral replication is controlled by the synergistic action of multiple immunological effector arms, including CD8 ϩ T cells (by means of cytolytic and noncytolytic mechanisms), CD4 ϩ T cells, antiviral neutralizing antibodies, and natural killer cells.…”