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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