HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer⁺Gag-Specific CD4⁺T Cells in Chronic Clade C HIV-1 Infection

Abstract

Immune control of viral infections is heavily dependent on helper CD4 T cell function. However, the understanding of the contribution of HIV-specific CD4 T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4 T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4 T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4 T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4 T cells in HIV controllers than progressors ( = 0.0001), and these expanded Gag-specific CD4 T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control ( = -0.5, = 0.02). These data identify an association between HIV-specific CD4 T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4 T cell responses in natural infections. Increasing evidence suggests that virus-specific CD4 T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4 T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV infections worldwide. Understanding the contribution of HIV-specific CD4 T cell responses in clade C infection is particularly important for developing vaccines that would be efficacious in sub-Saharan Africa, where clade C infection is dominant. Here, we employed MHC class II tetramers designed to immunodominant Gag epitopes and used them to characterize CD4 T cell responses in HIV-1 clade C infection. Our results demonstrate an association between the frequency of HIV-specific CD4 T cell responses targeting an immunodominant DRB1*11-Gag41 complex and HIV control, highlighting the important contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infections.

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

“…Tfh). Human HLA class II diversity is a tremendous challenge in the development of broadly applicable reagents, but recent efforts to develop suites of HLA class II tetramers for chronic infections such as HIV, HCV and tuberculosis have allowed an increased understanding of human CD4 + T cell differentiation during chronic infections 82,83 . However, even tetramers can introduce a bias, given that they can only identify responses to a single epitope (Figure 2).…”

Frequencies of circulating Th1-biased T follicular helper cells in acute HIV-1 infection correlate with the development of HIV-specific antibody responses and lower set point viral load

“…Figure 5A shows representative flow plots of unstimulated controls (top panel), cytokine secreting antigen specific CD4 + cells responding to HIV peptide pools (middle panel) or SEB stimulation (bottom panel) in an ICS assay. Our group previously showed that most of the HIV-specific CD4 + T cells in chronic clade C infection target the HIV Gag protein (26). Here we found no significant differences in Gag, Nef and Env responses (Figure 5B).…”

“…Several reports have implicated bulk CD4 + T cells in immune mediated control of chronic HIV infection (25, 26, 33), but little is known about the role of HIV-specific cTfh cells in HIV control mainly because of their very low frequency in circulation and the paucity of reliable tools to study them. Even though there were few numbers of cytokine secreting cTfh cells in response to stimulation by HIV peptide as previously shown (34), our tetramer staining results provided conclusive evidence of the existence of HIV-specific cTfh cells during primary HIV infection.…”

DNA Vaccination by Electroporation Amplifies Broadly Cross-Restricted Public TCR Clonotypes Shared with HIV Controllers

“…The Gag293 peptide and its shorter variants are able to bind efficiently to an unusually large array of HLA-DR molecules, with up to 13 alleles recognized (43, 44). This promiscuous HLA II binding likely contributes the frequent detection of the Gag293-specific response, which is the most immunodominant among CD4 responses directed at the HIV proteome (11, 24, 43, 44). HLA cross-restriction also depends on TCR clonotype properties, as by definition an HLA-cross-restricted TCR can recognize multiple peptide/MHC complexes.…”

“…Importantly, the high degree of clonotype sharing observed in controller CD4+ T cells opens the possibility to search for these clonotypes in a diverse population of vaccinated volunteers. We focused the clonotypic analysis on Gag293 specific cells, as this epitope is remarkably immunodominant, independently of the MHC II background (11, 23, 24). In addition, the Gag293 epitope is located in the most conserved region of HIV-1 capsid, called the major homology region, and is thus rarely mutated, with two cases of mutational escape in minor viral variants reported so far (25, 26).…”