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HIV-specific granzyme B, but not interferon-γ secreting T Cells are associated with reduced viral reservoirs in early HIV infection.

HIV-specific granzyme B, but not interferon-γ secreting T Cells are associated with reduced viral reservoirs in early HIV infection.
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Yue FY, Cohen JC, Ho M, Rahman AK, Liu J, Mujib S, Saiyed A, Hundal S, Khozin A, Bonner P, Liu D, Benko E, Kovacs C, Ostrowski M,


Yue FY, Cohen JC, Ho M, Rahman AK, Liu J, Mujib S, Saiyed A, Hundal S, Khozin A, Bonner P, Liu D, Benko E, Kovacs C, Ostrowski M, (click to view)

Yue FY, Cohen JC, Ho M, Rahman AK, Liu J, Mujib S, Saiyed A, Hundal S, Khozin A, Bonner P, Liu D, Benko E, Kovacs C, Ostrowski M,

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Journal of virology 2017 02 08() pii 10.1128/JVI.02233-16

Abstract

A major barrier to an Human Immunodeficiency Virus Type 1 (HIV) infection cure is the establishment of a viral reservoir despite cART. It is unclear how HIV-specific CTLs influence the size of the reservoir in early HIV infection. 28 subjects with early HIV infection were recruited to receive cART and followed for 48 weeks. HIV reservoirs in peripheral CD4+ T cells measured by cell associated proviral DNA and viral outgrowth cultures were determined at baseline and 48 weeks of cART. At baseline, Granzyme B and IFN-γ ELISpot assays were performed with peptides spanning the HIV proteome. All subjects had detectable HIV-specific granzyme B and IFN-γ responses at baseline. The quantity and specificity of granzyme B responses did not correlate with IFN-γ responses. For Granzyme B, Tat/Rev was the most dominant whereas for IFN-γ, Gag predominated. HIV-specific granzyme B T cell responses negatively correlated with HIV proviral loads at baseline and 48 weeks, and with replication competent viral IUPM at baseline but not significantly at 48 weeks. Tat/Rev-, Env-, Gag- and Vif-specific granzyme B responses correlated most strongly with reservoir control. There was no correlation with HIV-specific IFN-γ responses with reservoir size at baseline or 48 weeks. The majority of granzyme B responses were contributed by CD8(+) T cells. Thus, our findings suggest that the induction of potent granzyme B producing CTL to Tat, Rev, Env, Gag and Vif during early infection may be able to prevent the establishment of a large viral reservoir, thereby facilitating a reduced HIV burden.IMPORTANCE A major barrier to the cure of Human Immunodeficiency Virus Type 1 (HIV) infection is the establishment of a viral reservoir that must be significantly reduced or eradicated entirely to enable a cure. Combined antiretroviral therapy (cART) alone is unable to clear this viral reservoir. It has been shown that CD8(+) cytotoxic T lymphocytes (CTLs) are important in controlling early HIV infection by reducing plasma viremia. However, it is not known if these HIV-specific CTLs influence the establishment of the viral reservoir in early HIV infection. We show that HIV-specific granzyme B targeting HIV Tat/rev, Env, Gag and Vif, but not IFN-γ responses are associated with reduced virus reservoirs at baseline and at 48 weeks of cART. These findings shed light on the nature of the effector CTL response that might limit reservoir size with implications on cure research and HIV vaccines.

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