HIV Controller CD4+ T Cells Respond to Minimal Amounts of Gag Antigen Due to High TCR Avidity

Abstract

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, Vβ 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-γ 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 Vβ 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.

Functional Exhaustion of CD4+ T Lymphocytes during Primary Cytomegalovirus Infection

“…The structural characteristics of the TCR could also play an important role as lowaffinity interactions with the cognate MHC-peptide complexes would result in low functional avidity and low-intensity signaling. CD4 + T cells from HIV controllers were recently shown to express higher affinity TCRs than viremic or treated patients, suggesting that immune control of HIV replication may be favored by highaffinity CD4 + T cells (49). Further studies are needed to characterize the role of nonstructural and TCR-related mechanisms in the functional exhaustion of CD4 + T lymphocytes during primary CMV infection.…”

Comparative Analysis of the Capacity of Elite Suppressor CD4 + and CD8 + T Cells To Inhibit HIV-1 Replication in Monocyte-Derived Macrophages

“…Many studies have shown that CD8 ϩ T cells from ESs are more effective at inhibiting viral replication in CD4 ϩ T cells than CD8 ϩ T cells from chronic progressors (CPs) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Furthermore, HIV-1-specific CD4 ϩ T cells from ESs have high-avidity T cell receptors and are more likely to maintain responses that are either proliferative, polyfunctional, or cytotoxic than effector CD4 ϩ T cells from CPs (12)(13)(14)(15)(16)(17)(18)(19). While HIV-1 also infects macrophages, these target cells are rarely examined in the context of immunologic control.…”

Hierarchy of CD4 T Cell Epitopes of the ANRS Lipo5 Synthetic Vaccine Relies on the Frequencies of Pre-Existing Peptide-Specific T Cells in Healthy Donors

“…Other vaccines do not induce appropriate cellular responses specific for HIV (5), although a large body of evidence suggests that HIV-specific cellular responses contribute to control HIV viremia (6)(7)(8). In elite controllers, both CD4 and CD8 T lymphocytes react very efficiently with HIV Ags and exhibit a polyfunctional profile (9)(10)(11)(12)(13). Association of resistance to HIV infection with HLA class I (11,14,15) and class II (13,16,17) molecules also confirms the key role of the cellular response in immunity to HIV.…”