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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