HIV controllers exhibit enhanced frequencies of major histocompatibility complex class II tetramer⁺ Gag-specific CD4⁺ T cells in chronic clade C HIV-1 infection

TY - JOUR

T1 - HIV controllers exhibit enhanced frequencies of major histocompatibility complex class II tetramer+ Gag-specific CD4+ T cells in chronic clade C HIV-1 infection

AU - Laher, Faatima

AU - Ranasinghe, Srinika

AU - Porichis, Filippos

AU - Mewalal, Nikoshia

AU - Pretorius, Karyn

AU - Ismail, Nasreen

AU - Buus, Søren

AU - Stryhn, Anette

AU - Carrington, Mary

AU - Walker, Bruce D.

AU - Ndung'u, Thumbi

AU - Ndhlovu, Zaza M.

PY - 2017/4

Y1 - 2017/4

N2 - 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 (P = 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 (r = -0.5, P = 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.

AB - 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 (P = 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 (r = -0.5, P = 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.

KW - CD4 T helper cells

KW - HIV

KW - Human immunodeficiency virus

KW - MHC class II tetramers

U2 - 10.1128/JVI.02477-16

DO - 10.1128/JVI.02477-16

M3 - Journal article

C2 - 28077659

AN - SCOPUS:85015243444

SN - 0022-538X

VL - 91

JO - Journal of Virology

JF - Journal of Virology

IS - 7

M1 - e02477-16

ER -