A new study from Mark Connors research group at NIAID offers a detailed description of the functionality of HIV-specific CD8 T cell responses in people whose viral load is suppressed by antiretroviral therapy (ART). Many previous studies have looked at the function of HIV-specific CD8 T cells among individuals with progressive HIV infection compared to long-term non-progressors (LTNP), and Connors group has highlighted two key differences:
- The ability of HIV-specific CD8 T cells to proliferate (copy themselves) in response to HIV antigens.
- The ability of HIV-specific CD8 T cells to kill HIV-infected CD4 T cells (cytotoxicity).
Other researchers have also described differences in the capacity of HIV-specific CD8 T cells to perform multiple functions (termed “polyfunctionality”), such as the release of several different cytokines/chemokines and expression of particular markers of cytotoxicity.
The new paper investigates these parameters and compares results between people with viral suppression resulting from ART and LTNP with undetectable viral loads in the absence of treatment. Significant differences are reported for:
- HIV-specific CD8 T cell proliferation in response to HIV-infected CD4 T cells. A median of 10.9% of CD8 T cells showed evidence of proliferation among individuals on ART versus 41.9% among LTNP. Further analyses revealed that these differences in proliferation related to the number of HIV-specific CD8 T cells that were capable of proliferating (as opposed to the same number of cells proliferating more); the median fraction of cells that proliferated in LTNP was 31.3% compared to 14.5% in study participants on ART. The same did not hold true for CMV-specific CD8 T cell responses; the median proportion of these cells that proliferated in the two groups was 23.9% versus 21.2%, respectively.
- HIV-infected CD4+ T cell elimination (ICE). This assay was developed to measure the ability of HIV-specific CD8 T cells to kill HIV-infected CD4 T cells, and the responses measured by ICE were significantly different between LTNP and the group on ART with medians of 25.6% versus 10.7%, respectively.
- HIV-specific CD8 T cell polyfunctionality. The fraction of HIV-specific CD8 T cells from LTNP capable of exerting more than one function was significantly higher on average than those of people on ART, but there was considerable overlap between the two groups.
The researchers conclude: “these data suggest that there are selective qualitative abnormalities within the HIV-specific CD8 T-cell compartment that persist under conditions of low levels of antigen.” Although many parameters of immune function improve dramatically as a result of ART-mediated viral suppression, these improvements aren’t associated with the development of a full spectrum of functions by HIV-specific CD8 T-cells, suggesting a persistent defect tracing back to when the responses were initially primed. These findings support the continuation of efforts to create more functional HIV-specific CD8 T-cell responses in people on ART, either by inducing new responses or restoring function to extant HIV-specific CD8 T-cells.
Another implication of the results is that HIV-specific CD8 T cell responses induced by vaccines – such as the DNA/Ad5 regimen designed by the Vaccine Research Center that is now being evaluated in the HVTN 505 trial – should be evaluated for their ability to kill HIV-infected CD4 T cell targets and capacity to proliferate. This type of data could have been obtained prior to the initiation of HVTN 505, but wasn’t.
JVI Accepts, published online ahead of print on 2 September 2009
J. Virol. doi:10.1128/JVI.01153-09
Stephen A. Migueles, Kristin A. Weeks, Eric Nou, Amy M. Berkley, Julia E. Rood, Christine M. Osborne, Claire W. Hallahan, Nancy A. Cogliano-Shutta, Julia A. Metcalf, Mary McLaughlin, Richard Kwan, JoAnn M. Mican, Richard T. Davey Jr., and Mark Connors
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Abstract
Identifying the functions of HIV-specific CD8+ T-cells that are not merely modulated by the level of virus, but clearly distinguish patients with immune control from those without such control is of paramount importance. Features of the HIV-specific CD8+ T-cell response were comprehensively examined in antiretroviral-treated (Rx<50) and untreated (long-term nonprogressors [LTNP]) patient groups matched for very low HIV RNA levels. The proliferative capacity of HIV-specific CD8+ T-cells was not restored in Rx<50 to the level observed in LTNP, even though HIV-specific CD4+ T-cell proliferation was comparable between the patient groups. This diminished HIV-specific CD8+ T-cell proliferation in Rx<50 was primarily due to a smaller fraction of antigen-specific cells recruited to divide, and not the numbers of divisions proliferating cells had undergone. Exogenous IL-2 induced proliferating cells to divide further, but did not rescue the majority of antigen-specific cells with defective proliferation. In addition, differences in HIV-specific CD8+ T-cell proliferation could not be attributed to differences in cellular subsets bearing a memory phenotype, IL-2 production, or PD-1 expression. Although polyfunctionality of HIV-specific CD8+ T-cells in Rx<50 was not restored to the levels observed in LTNP despite prolonged suppression of HIV RNA levels, per-cell cytotoxic capacity was the functional feature that most clearly distinguished the cells of LTNP from those of Rx<50. Taken together, these data suggest that there are selective qualitative abnormalities within the HIV-specific CD8+ T-cell compartment that persist under conditions of low levels of antigen.
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