HIV-Specific Granzyme B-Secreting but Not Gamma Interferon-Secreting T Cells Are Associated with Reduced Viral Reservoirs in Early HIV Infection.
A major barrier to a human immunodeficiency virus type 1 (HIV-1) infection cure is the establishment of a viral reservoir in spite of combined antiretroviral therapy (cART). It is unclear how HIV-specific cytotoxic T lymphocytes (CTLs) influence the size of the reservoir in early HIV infection. Twenty-eight 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 after 48 weeks of cART. At baseline, granzyme B and gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (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 at 48 weeks and with replication-competent viral infectious units per million (IUPM) CD4+T cells 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 of HIV-specific IFN-γ responses with reservoir size at baseline or at 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 CTLs 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.IMPORTANCEA major barrier to the cure of human immunodeficiency virus type 1 (HIV-1) 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 responses 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 for cure research and HIV vaccines.
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Feng Yun
FY
Yue
Keenan Research Centre for Biomedical Science of Saint Michael's Hospital, Toronto, Ontario, Canada.
Jared C
JC
Cohen
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Mu
M
Ho
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
A K M Nur-Ur
AKMN
Rahman
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Jun
J
Liu
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Shariq
S
Mujib
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Aamir
A
Saiyed
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Sabrina
S
Hundal
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Alexandra
A
Khozin
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Phil
P
Bonner
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Daheng
D
Liu
Maple Leaf Clinic, Toronto, Ontario, Canada.
Erika
E
Benko
Maple Leaf Clinic, Toronto, Ontario, Canada.
Colin
C
Kovacs
Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada mario.ostrowski@gmail.com.|Keenan Research Centre for Biomedical Science of Saint Michael's Hospital, Toronto, Ontario, Canada.
Mario
M
Ostrowski
D000328:Adult; D000998:Antiviral Agents; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D003603:Cytotoxins / Q000378:metabolism*; D004197:Disease Reservoirs / Q000821:virology*; D053804:Granzymes / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D000998:Antiviral Agents; D003603:Cytotoxins; D007371:Interferon-gamma; D053804:Granzymes
CTL; ELISpot; HIV; IFN-γ; T cell; acute; acute HIV; cure research; cytotoxic; early; early HIV; granzyme B; human immunodeficiency virus; reservoir; viral reservoirs