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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