Many lines of evidence indicate that CD8 T cells targeting
HIV play a key role in suppressing viral replication in individuals who
maintain persistently low viral loads in the absence of treatment (typically
dubbed “elite controllers” if the viral load is <50 copies/mL and “viremic
controllers” if the viral load is <2,000 copies/mL). The main mechanism by
which CD8 T cells kill virus-infected cells involves release of specialized
cell-destroying substances, one of which is called perforin (named after its
ability to perforate the membrane of cells). Until quite recently it was
thought that CD8 T cells carried a stash of perforin that had to be replenished by cell proliferation after it was unleashed, but it is now appreciated that CD8 T cells can rapidly
manufacture new supplies of perforin which allows serial killing of multiple infected targets.
This revelation resulted from the discovery that the antibody normally used to detect perforin within
cells was unable to detect the rapidly synthesized form. The researchers
responsible for this advance – a group led by Michael Betts at the University
of Pennsylvania – have now applied their method for detecting perforin expression to HIV-specific CD8 T cells from elite controllers.
The study found that elite controllers consistently displayed
a higher proportion of HIV-specific CD8 T cells expressing perforin compared to
individuals with progressive infection. This finding held true for a broad
array of HIV antigens. The HIV-specific CD8 T cells of elite controllers also
made a greater amount of perforin compared to both viremic controllers and
progressors. The researchers documented a significant inverse correlation
between the average HIV-specific CD8 T cell perforin expression within each
study participant and their viral load. The correlation was still seen if CD8 T
cells to each HIV antigen were considered separately, and if the analysis was
restricted to only those individuals with detectable viral loads. Suppression
of viral load by antiretroviral therapy was not able to significantly enhance
perforin expression by HIV-specific CD8 T cells in progressors, leading the researchers
to conclude: “Further studies are necessary to identify the mechanism(s)
underlying the relative absence of perforin upregulation in progressive HIV
infection, and, if possible, to discover a means by which this critical
function can be regained or elicited through therapeutic intervention.”
PLoS Pathog 6(5): e1000917. doi:10.1371/journal.ppat.1000917
Perforin Expression Directly Ex Vivo by HIV-Specific CD8+
T-Cells Is a Correlate of HIV Elite Control
Adam R. Hersperger1, Florencia Pereyra2, Martha Nason3,
Korey Demers1, Prameet Sheth4, Lucy Y. Shin4, Colin M. Kovacs5, Benigno
Rodriguez6, Scott F. Sieg6, Leia Teixeira-Johnson7, Debbie Gudonis8, Paul A.
Goepfert9, Michael M. Lederman6, Ian Frank8, George Makedonas1, Rupert Kaul4,
Bruce D. Walker2,10, Michael R. Betts1
1 Department of Microbiology, University of Pennsylvania,
Philadelphia, Pennsylvania, United States of America, 2 Ragon Institute of MGH,
MIT, and Harvard, Boston, Massachusetts, United States of America, 3
Biostatistics Research Branch, National Institutes of Health, Bethesda,
Maryland, United States of America, 4 Department of Medicine, University of
Toronto, Toronto, Ontario, Canada, 5 Canadian Immunodeficiency Research
Collaborative, Toronto, Ontario, Canada, 6 Case Western Reserve University and
University Hospitals of Cleveland, Cleveland, Ohio, United States of America, 7
Department of Infectious Diseases, Cleveland Clinic, Cleveland, Ohio, United
States of America, 8 Division of Infectious Diseases, Department of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, United States of
America, 9 Department of Medicine, University of Alabama at Birmingham,
Birmingham, Alabama, United States of America, 10 Howard Hughes Medical
Institute, Chevy Chase, Maryland, United States of America
Many immune correlates of CD8+ T-cell-mediated control of
HIV replication, including polyfunctionality, proliferative ability, and
inhibitory receptor expression, have been discovered. However, no functional
correlates using ex vivo cells have been identified with the known ability to
cause the direct elimination of HIV-infected cells. We have recently discovered
the ability of human CD8+ T-cells to rapidly upregulate perforin—an essential
molecule for cell-mediated cytotoxicity—following antigen-specific stimulation.
Here, we examined perforin expression capability in a large cross-sectional
cohort of chronically HIV-infected individuals with varying levels of viral
load: elite controllers (n = 35), viremic controllers (n = 29), chronic
progressors (n = 27), and viremic nonprogressors (n = 6). Using polychromatic
flow cytometry and standard intracellular cytokine staining assays, we measured
perforin upregulation, cytokine production, and degranulation following
stimulation with overlapping peptide pools encompassing all proteins of HIV. We
observed that HIV-specific CD8+ T-cells from elite controllers consistently
display an enhanced ability to express perforin directly ex vivo compared to
all other groups. This ability is not restricted to protective HLA-B
haplotypes, does not require proliferation or the addition of exogenous
factors, is not restored by HAART, and primarily originates from effector CD8+
T-cells with otherwise limited functional capability. Notably, we found an
inverse relationship between HIV-specific perforin expression and viral load.
Thus, the capability of HIV-specific CD8+ T-cells to rapidly express perforin
defines a novel correlate of control in HIV infection.
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