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

Faatima Laher; Srinika Ranasinghe; Filippos Porichis; Nikoshia Mewalal; Karyn Pretorius; Nasreen Ismail; Søren Buus; Anette Stryhn; Mary Carrington; Bruce D. Walker; Thumbi Ndung'u; Zaza M. Ndhlovu

doi:10.1128/JVI.02477-16

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

Faatima Laher, Srinika Ranasinghe, Filippos Porichis, Nikoshia Mewalal, Karyn Pretorius, Nasreen Ismail, Søren Buus, Anette Stryhn, Mary Carrington, Bruce D. Walker, Thumbi Ndung'u, Zaza M. Ndhlovu^*

^*Corresponding author for this work

9 Citations (Scopus)

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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 (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.

Original language	English
Article number	e02477-16
Journal	Journal of Virology
Volume	91
Issue number	7
Number of pages	17
ISSN	0022-538X
DOIs	https://doi.org/10.1128/JVI.02477-16
Publication status	Published - Apr 2017

Keywords

CD4 T helper cells
HIV
Human immunodeficiency virus
MHC class II tetramers

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Cite this

Laher, F., Ranasinghe, S., Porichis, F., Mewalal, N., Pretorius, K., Ismail, N., Buus, S., Stryhn, A., Carrington, M., Walker, B. D., Ndung'u, T., & Ndhlovu, Z. M. (2017). HIV controllers exhibit enhanced frequencies of major histocompatibility complex class II tetramer⁺ Gag-specific CD4⁺ T cells in chronic clade C HIV-1 infection. Journal of Virology, 91(7), Article e02477-16. https://doi.org/10.1128/JVI.02477-16

HIV controllers exhibit enhanced frequencies of major histocompatibility complex class II tetramer⁺ Gag-specific CD4⁺ T cells in chronic clade C HIV-1 infection. / Laher, Faatima; Ranasinghe, Srinika; Porichis, Filippos et al.
In: Journal of Virology, Vol. 91, No. 7, e02477-16, 04.2017.

Research output: Contribution to journal › Journal article › Research › peer-review

Laher, F, Ranasinghe, S, Porichis, F, Mewalal, N, Pretorius, K, Ismail, N, Buus, S , Stryhn, A, Carrington, M, Walker, BD, Ndung'u, T & Ndhlovu, ZM 2017, 'HIV controllers exhibit enhanced frequencies of major histocompatibility complex class II tetramer⁺ Gag-specific CD4⁺ T cells in chronic clade C HIV-1 infection', Journal of Virology, vol. 91, no. 7, e02477-16. https://doi.org/10.1128/JVI.02477-16

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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 (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.",

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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.

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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

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