A new study from Barbara Shacklett’s research group investigates
the contribution of mucosal HIV-specific CD4 T cell responses to immune control
of viral replication. To the best of my knowledge, it is only the second study to measure HIV-specific CD4 T cells in the gut (a prior paper by Satya Dandekar’s group reported that the presence of these
responses was associated with better gut CD4 T cell reconstitution on ART). The
researchers find a significant association between the numbers of polyfunctional
HIV-specific CD4 T cells in the gut and virological control in the absence of
ART. Individuals with certain class II HLA genes mount particularly strong
responses, and a correlation between the magnitude of the gut HIV-specific CD4
T cell response and HIV-specific CD8 T cell response is documented. The authors
suggest that strategies to induce polyfunctional HIV-specific CD4 T cells in
the gut might offer benefit in both the preventive and therapeutic vaccine
context.
J. Virol. doi:10.1128/JVI.00980-10
April L. Ferre, Peter W. Hunt, Delandy H. McConnell, Megan
M. Morris, Juan C. Garcia, Richard B. Pollard, Hal F. Yee Jr, Jeffrey N.
Martin, Steven G. Deeks, and Barbara L. Shacklett
Department of Medical Microbiology and Immunology; Division
of Gastroenterology; Division of Infectious Diseases, School of Medicine,
University of California, Davis, CA; Positive Health Program, Department of
Medicine; Division of Gastroenterology; Department of Epidemiology and
Biostatistics San Francisco General Hospital, University of California, San
Francisco, CA
Abstract
A small percentage of HIV-infected individuals, termed elite
controllers, are able to spontaneously control HIV replication in blood. As the
gastrointestinal mucosa is an important site of HIV transmission and
replication, as well as CD4+ T-cell depletion, it is important to understand the
nature of the immune responses occurring in this compartment. Although the role
of the HIV-specific CD8+ T-cell responses in mucosal tissues has been
described, few studies have investigated the role of mucosal HIV-specific CD4+
T-cells. In this study, we assessed HIV-specific CD4+ T-cell responses in the
rectal mucosa of 28 "controllers" (VL<2,000 copies/mL), 14
"non-controllers" (VL<10,000 copies/mL), and 10 individuals on
HAART (VL<50 copies/mL). Controllers had higher magnitude Gag-specific
mucosal CD4+ T-cell responses than individuals on HAART (p<0.05), as
measured by their ability to produce IFN, IL-2, TNF, and MIP-1. The frequency
of polyfunctional mucosal CD4+ T-cells was also higher in controllers compared
to non-controllers or individuals on HAART (p<0.05). Controllers with the
strongest HIV-specific CD4+ T-cell responses possessed class II HLA alleles,
HLA-DR*13 and/or HLA-DQ*06, previously associated with a non-progression
phenotype. Strikingly, individuals with both HLA-DR*13 and HLA-DQ*06 had highly
polyfunctional mucosal CD4+ T-cells compared to individuals with HLA-DQ*06
alone or other class II alleles. The frequency of polyfunctional CD4+ T-cells
in rectal mucosa positively correlated with the magnitude of the mucosal CD8+
T-cell response (Spearman r=0.43, p=0.005), suggesting that increased CD4+
T-cell "help" may be important in maintaining strong CD8+ T-cell
responses in the gut of HIV controllers.
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