Comparisons of CD8⁺T Cells Specific for Human Immunodeficiency Virus, Hepatitis C Virus, and Cytomegalovirus Reveal Differences in Frequency, Immunodominance, Phenotype, and Interleukin-2 Responsiveness

Abstract

To better understand the components of an effective immune response to human immunodeficiency virus (HIV), the CD8؉ T-cell responses to HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) were compared with regard to frequency, immunodominance, phenotype, and interleukin-2 (IL-2) responsiveness. Responses were examined in rare patients exhibiting durable immune-mediated control over HIV, termed long-term nonprogressors (LTNP) or elite controllers, and patients with progressive HIV infection (progressors). The magnitude of the virus-specific CD8 ؉ T-cell response targeting HIV, CMV, and HCV was not significantly different between LTNP and progressors, even though their capacity to proliferate to HIV antigens was preserved only in LTNP. In contrast to HIV-specific CD8 ؉ T-cell responses of LTNP, HLA B5701-restricted responses within CMV pp65 were rare and did not dominate the total CMV-specific response. Virus-specific CD8 ؉ T cells were predominantly CD27 ؉ 45RO ؉ for HIV and CD27 ؊ 45RA ؉ for CMV; however, these phenotypes were highly variable and heavily influenced by the degree of viremia. Although IL-2 induced significant expansions of CMV-specific CD8 ؉ T cells in LTNP and progressors by increasing both the numbers of cells entering the proliferating pool and the number of divisions, the proliferative capacity of a significant proportion of HIV-specific CD8 ؉ T cells was not restored with exogenous IL-2. These results suggest that immunodominance by HLA B5701-restricted cells is specific to HIV infection in LTNP and is not a feature of responses to other chronic viral infections. They also suggest that poor responsiveness to IL-2 is a property of HIV-specific CD8 ؉ T cells of progressors that is not shared with responses to other viruses over which immunologic control is maintained.

Defective Human Immunodeficiency Virus-Specific CD8 + T-Cell Polyfunctionality, Proliferation, and Cytotoxicity Are Not Restored by Antiretroviral Therapy

“…ϩ T cells were similar in Rx Ͻ50 and LTNP (medians of 0.94% and 1.03%, respectively; P Ͼ 0.5), whereas the frequencies of HIV tetramer-positive CD8 ϩ T cells were significantly lower in the Rx Ͻ50 group than in LTNP prior to stimulation (medians of 0.45% and 1.05%, respectively; P ϭ 0.01) (data not shown), as reported previously (19,29,39). Such differences should not influence the interpretation of our more detailed analysis, since the indices generated by the proliferation software are independent of the starting frequencies of virus-specific CD8 ϩ T cells.…”

“…Data were analyzed using FlowJo software (TreeStar, San Carlos, CA). The FlowJo Proliferation Platform was used to obtain detailed information about the division characteristics of gated tetramer-positive CD8 ϩ T cells as described previously (19 Statistical analysis. The Wilcoxon signed rank test was used to compare paired data.…”

Expansion of CD8+ T cells lacking Sema4D/CD100 during HIV-1 infection identifies a subset of T cells with decreased functional capacity

“…This is an interesting observation as CMV-specific CD8 ϩ T cells typically remain at high numbers and functional throughout HIV-1 infection. 40,41 CD57 and PD-1 expression on HIV-1-specific T cells are reported to be associated with HIV-1-related immune dysfunction and thus are proposed to contribute to lack of viral control. 29,30 These data would therefore suggest that monitoring the coexpression of CD100, CD57, and PD-1 on HIV-1-specific T cells may be a better measure of the functionality of these cells than using any of these markers alone.…”

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

“…As the proliferative potential of antigen-specific T cells is considered to be a key factor in maintaining or restoring effective antiviral immunity, 16,17,28 it was of special interest to simultaneously evaluate the functional profile and the proliferative potential of Nef-specific CD4 and CD8 T cells during the course of the study. Thawed PBMCs were stained with CFSE, incubated with peptide pools for 5 days and, after restimulation, samples were stained according to our standard protocol, with the exception that the fluorescein isothiocyanate-conjugated (FITC) CD154 antibody was omitted so as not to interfere with the detection of CFSE.…”

“…8,12 Along with the functional profile, the proliferative potential of antigen-specific T cells is believed to be a key factor in maintaining or restoring effective antiviral immunity. 16,17 Applying polychromatic flow cytometry, we performed a reevaluation on the samples collected during the MVA-nef vaccination trial to further investigate the T-cell responses elicited by the vaccine. We evaluated Nefspecific CD8 and CD4 T-cell responses at selected time points by polychromatic ICS assay and polychromatic CFSE-based proliferation assay.…”