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Soghoian, Damien

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Soghoian

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Damien

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Soghoian, Damien

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2013 - 20152

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Author's Publications: search.filters.isAuthorOfPublication.5f57e550-281b-41d8-8728-26618b5b1d25

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    Association of HLA-DRB1-restricted CD4+ T cell responses with HIV immune control
    (2013) Ranasinghe, Srinika; Cutler, Sam; Davis, Isaiah; Lu, Richard; Soghoian, Damien; Qi, Ying; Sidney, John; Kranias, Gregory; Flanders, Michael; Lindqvist, Madelene; Kuhl, Bjorn; Alter, Galit; Deeks, Steven G.; Walker, Bruce; Gao, Xiaojiang; Sette, Alessandro; Carrington, Mary; Streeck, Hendrik
    The contribution of HLA class II-restricted CD4+ T cell responses to HIV immune control is poorly defined. Here, we delineated novel peptide-DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors (n=1085). We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with DRB1*15:02 significantly associated with low viremia (P=0.003, q=0.04) and DRB1*03:01 significantly associated with high viremia (P=0.004, q=0.04). Interestingly, a sub-group of HLA-DRB1 alleles linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 alleles linked with high viremia (p=0.018). Our data provide systematic evidence that HLA-DRB1 allele expression significantly impacts the durable control of HIV replication, an effect that appears to be mediated primarily by the protein-specificity of HIV-specific CD4+ T cell responses to Gag and Nef.
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    HIV-Specific CD4 T Cells and Viral Control
    (2015-01-15) Soghoian, Damien; Pillai, Shiv; Kaur, Miti; Luban, Jeremy
    CD4 T cells play an important and central role in the immune system, coordinating the arms of the adaptive immune system to shape an effective response while simultaneously regulating non-essential or deleterious activities. Their critical necessity is demonstrated most strikingly during acquired immunodeficiency syndrome (AIDS), when depletion of CD4 T cells by human immunodeficiency virus (HIV) type 1 ultimately results in a host of immune dysfunctions and susceptibility to opportunistic pathogens. Although virus-specific CD4 T cell responses are generally vital for the control of viral infections, HIV-specific CD4 T cells have long been recognized to be preferentially targeted and depleted by the virus—raising questions about their utility as immune effectors both during HIV-1 infection and in the context of a prospective HIV-1 vaccine. However, more recent research has challenged the notion that HIV-specific CD4 T cells are only relevant as targets. There is a growing appreciation for the crucial role that these cells may play in mediating anti-HIV immunity through a diverse array of effector functions—including direct anti-viral cytotoxicity. Here we show that HIV-specific CD4 T cell responses are evident throughout the course of HIV disease, including acute infection. In particular, an expansion of HIV-specific CD4 T cells with cytolytic potential early after acute HIV infection is associated with lower viral set point and better clinical progression. This expansion is evident both as an increase in HIV-specific CD4 T cells able to degranulate upon antigen recognition and as cells with a unique granzyme and perforin expression pattern. Further, HIV-specific cytolytic CD4 T cell responses are functionally enhanced in the setting of durable HIV control during chronic infection, where they exhibit a profile reminiscent of HIV-specific CD8 T cells and are associated with T-bet and Eomesodermin expression. We also show that in HIV controllers, the function of HIV-specific CD4 T cells is very tightly correlated with clinical status. Together these results strongly support the concept that CD4 T cells are critical players in the cellular immune response to HIV, and point to specific CD4 T cell functions—including direct cytolysis—which may be most important for anti-HIV immunity.