Longitudinal Analysis of Peripheral and Colonic CD161<sup>+</sup> CD4<sup>+</sup> T Cell Dysfunction in Acute HIV-1 Infection and Effects of Early Treatment Initiation
Kerri G. Lal,
Yuwadee Phuang-Ngern,
Suchada Suhkumvittaya,
Edwin Leeansyah,
Aljawharah Alrubayyi,
Joana Dias,
Adam Waickman,
Dohoon Kim,
Eugène Kroon,
Suteeraporn Pinyakorn,
Leigh Anne Eller,
Milton Maciel Jr.,
Rungsun Rerknimitr,
Nitiya Chomchey,
Nittaya Phanuphak,
Mark S. de Souza,
Sorachai Nitayaphan,
Julie A. Ake,
Sandhya Vasan,
Merlin L. Robb,
Jintanat Ananworanich,
Johan K. Sandberg,
Alexandra Schuetz,
Michael A. Eller,
Dominic Paquin-Proulx,
on behalf of the RV217, RV254/SEARCH010, RV304/SEARCH Study Groups
Affiliations
Kerri G. Lal
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Yuwadee Phuang-Ngern
Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand
Suchada Suhkumvittaya
Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand
Edwin Leeansyah
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 14183 Stockholm, Sweden
Aljawharah Alrubayyi
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Joana Dias
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 14183 Stockholm, Sweden
Adam Waickman
Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Dohoon Kim
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Eugène Kroon
SEARCH, Institute of HIV Research and Innovation, Bangkok 10330, Thailand
Suteeraporn Pinyakorn
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Leigh Anne Eller
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Milton Maciel Jr.
Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD 20817, USA
Rungsun Rerknimitr
Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
Nitiya Chomchey
SEARCH, Institute of HIV Research and Innovation, Bangkok 10330, Thailand
Nittaya Phanuphak
SEARCH, Institute of HIV Research and Innovation, Bangkok 10330, Thailand
Mark S. de Souza
AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-0052, Japan
Sorachai Nitayaphan
Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand
Julie A. Ake
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Sandhya Vasan
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Merlin L. Robb
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Jintanat Ananworanich
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Johan K. Sandberg
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 14183 Stockholm, Sweden
Alexandra Schuetz
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Michael A. Eller
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Dominic Paquin-Proulx
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
on behalf of the RV217, RV254/SEARCH010, RV304/SEARCH Study Groups
CD161 expression on CD4+ T cells is associated with a Th17 functional phenotype, as well as with an innate capacity to respond to interleukin (IL)-12 and IL-18 without T cell receptor (TCR) stimulation. Chronic HIV-1 infection is associated with loss of the CD161+ CD4 T cell population, and non-human primate studies suggest that their depletion is associated with disease progression. However, the dynamics of the CD161+ CD4+ T cell population during acute HIV-1 infection remains unknown. In this study, we characterize peripheral blood CD161+ CD4+ T cells in detail, and examine how they are affected during the earliest stages of HIV-1 infection. Unbiased surface proteome screening and principal component analysis indicated that CD161+ CD4+ T cells are relatively phenotypically homogeneous between donors, and are intermediates between conventional CD4 T cells and innate-like T cells. In acute untreated HIV-1 infection, the circulating CD161+ CD4+ T cell population decreased in frequency, as did absolute cell counts starting from peak viral load, with elevated levels of activation and exhaustion markers expressed throughout acute HIV-1 infection. The capacity of these cells to respond to stimulation with IL-12 and IL-18 was also reduced. Early initiation of anti-retroviral treatment (ART) during acute HIV-1 infection restored the functionality of peripheral blood CD161+ CD4+ T cells, but not their frequency. In contrast, early ART initiation prevented the decline of colonic CD161+ CD4+ T cells that otherwise started during acute infection. Furthermore, loss of peripheral and colonic CD161+ CD4+ T cells in untreated infection was associated with levels of viral load. These results suggest that acute HIV-1 infection has profound effects on the CD161+ CD4+ T cell population that could not be completely prevented by the initiation of ART.
