Among the more consistent correlates of immunological control of HIV replication is the presence of polyfunctional HIV-specific CD4 T cells that can proliferate vigorously in response to viral antigens, particularly those from the Gag protein. Although there are examples of controllers who lack these responses, they are found in the majority of individuals studied (with a recent report indicating they are present in the rectal mucosa as well as the peripheral blood). In an attempt to shed light on how these responses are maintained in controllers, a group of scientists from the ANRS evaluated how efficiently their HIV-specific CD4 T cells recognized Gag antigens (in immunological terms, this is referred to the avidity of the response).
By using an assay in which the concentration of different Gag antigens (specifically, the epitopes Gag293, Gag263 and Gag161) could be serially reduced, it was found that CD4 T cell responses to Gag293 were significantly more sensitive and mounted robust responses even at minimal epitope concentrations. The researchers suggest that these responses may explain why many controllers are able to maintain HIV-specific CD4 T cell responses even though levels of viral load (and by inference, viral antigens) are typically extremely low. In addition, they recommend considering high avidity as a desirable property for vaccine-induced T cell responses.
PLoS Pathog. 2010 Feb 26;6(2):e1000780.
HIV Controller CD4+ T Cells Respond to Minimal Amounts of Gag Antigen Due to High TCR Avidity.
Vingert B, Perez-Patrigeon S, Jeannin P, Lambotte O, Boufassa F, Lemaître F, Kwok WW, Theodorou I, Delfraissy JF, Thèze J, Chakrabarti LA; for the ANRS EP36 HIV Controllers Study Group.
Unité d'Immunogénétique Cellulaire, Institut Pasteur, Paris, France.
HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral treatment. Emerging evidence indicates that HIV control is mediated through very active cellular immune responses, though how such responses can persist over time without immune exhaustion is not yet understood. To investigate the nature of memory CD4+ T cells responsible for long-term anti-HIV responses, we characterized the growth kinetics, Vbeta repertoire, and avidity for antigen of patient-derived primary CD4+ T cell lines. Specific cell lines were obtained at a high rate for both HIV controllers (16/17) and efficiently treated patients (19/20) in response to the immunodominant Gag293 peptide. However, lines from controllers showed faster growth kinetics than those of treated patients. After normalizing for growth rates, IFN-gamma responses directed against the immunodominant Gag293 peptide showed higher functional avidity in HIV controllers, indicating differentiation into highly efficient effector cells. In contrast, responses to Gag161, Gag263, or CMV peptides did not differ between groups. Gag293-specific CD4+ T cells were characterized by a diverse Vbeta repertoire, suggesting that multiple clones contributed to the high avidity CD4+ T cell population in controllers. The high functional avidity of the Gag293-specific response could be explained by a high avidity interaction between the TCR and the peptide-MHC complex, as demonstrated by MHC class II tetramer binding. Thus, HIV controllers harbor a pool of memory CD4+ T cells with the intrinsic ability to recognize minimal amounts of Gag antigen, which may explain how they maintain an active antiviral response in the face of very low viremia.
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