EBioMedicine (Oct 2022)
Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8+ T cells
- Hiroshi Takata,
- Juyeon C. Kakazu,
- Julie L. Mitchell,
- Eugene Kroon,
- Donn J. Colby,
- Carlo Sacdalan,
- Hongjun Bai,
- Philip K. Ehrenberg,
- Aviva Geretz,
- Supranee Buranapraditkun,
- Suteeraporn Pinyakorn,
- Jintana Intasan,
- Somporn Tipsuk,
- Duanghathai Suttichom,
- Peeriya Prueksakaew,
- Thep Chalermchai,
- Nitiya Chomchey,
- Nittaya Phanuphak,
- Mark de Souza,
- Nelson L. Michael,
- Merlin L. Robb,
- Elias K. Haddad,
- Trevor A Crowell,
- Sandhya Vasan,
- Victor G. Valcour,
- Daniel C. Douek,
- Rasmi Thomas,
- Morgane Rolland,
- Nicolas Chomont,
- Jintanat Ananworanich,
- Lydie Trautmann,
- Nipat Teeratakulpisarn,
- Supanit Pattanachaiwit,
- Somchai Sriplienchan,
- Ponpen Tantivitayakul,
- Ratchapong Kanaprach,
- Kiat Ruxrungtham,
- Netsiri Dumrongpisutikul,
- Ponlapat Rojnuckarin,
- Suthat Chottanapund,
- Kultida Poltavee,
- Tassanee Luekasemsuk,
- Hathairat Savadsuk,
- Suwanna Puttamsawin,
- Khunthalee Benjapornpong,
- Nisakorn Ratnaratorn,
- Kamonkan Tangnaree,
- Chutharat Munkong,
- Rommanus Thaimanee,
- Patcharin Eamyoung,
- Sasiwimol Ubolyam,
- Sukalya Lerdlum,
- Sopark Manasnayakorn,
- Rugsun Rerknimitr,
- Sunee Sirivichayakul,
- Phandee Wattanaboonyongcharoen,
- Jessica Cowden,
- Alexandra Schuetz,
- Siriwat Akapirat,
- Nampueng Churikanont,
- Saowanit Getchalarat,
- Denise Hsu,
- Ellen Turk,
- Oratai Butterworth,
- Mark Milazzo,
- Leigh Anne Eller,
- Julie Ake,
- Leigh Anne Eller,
- Serena Spudich,
- CAPT Lawrence Fox,
- Silvia Ratto-Kim,
- Victor DeGruttola,
- Yotin Chinvarun,
- Pasiri Sithinamsuwan,
- James Fletcher,
- Bruce Shiramizu,
- Alexandra Schuetz
Affiliations
- Hiroshi Takata
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Juyeon C. Kakazu
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Julie L. Mitchell
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Eugene Kroon
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Donn J. Colby
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA; SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Carlo Sacdalan
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Hongjun Bai
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Philip K. Ehrenberg
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
- Aviva Geretz
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Supranee Buranapraditkun
- Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Suteeraporn Pinyakorn
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Jintana Intasan
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Somporn Tipsuk
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Duanghathai Suttichom
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Peeriya Prueksakaew
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Thep Chalermchai
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Nitiya Chomchey
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Nittaya Phanuphak
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Mark de Souza
- SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand
- Nelson L. Michael
- 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; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Elias K. Haddad
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University, Philadelphia, PA, USA
- Trevor A Crowell
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Sandhya Vasan
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Victor G. Valcour
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA
- Daniel C. Douek
- Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA
- Rasmi Thomas
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
- Morgane Rolland
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Nicolas Chomont
- Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC, Canada
- Jintanat Ananworanich
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA; SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand; Department of Global Health, University of Amsterdam, Amsterdam, Netherlands
- Lydie Trautmann
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA; Corresponding author: Lydie Trautmann, 505 NW 185th Ave, #1107D, Beaverton, OR 97006, USA.
- Nipat Teeratakulpisarn
- Supanit Pattanachaiwit
- Somchai Sriplienchan
- Ponpen Tantivitayakul
- Ratchapong Kanaprach
- Kiat Ruxrungtham
- Netsiri Dumrongpisutikul
- Ponlapat Rojnuckarin
- Suthat Chottanapund
- Kultida Poltavee
- Tassanee Luekasemsuk
- Hathairat Savadsuk
- Suwanna Puttamsawin
- Khunthalee Benjapornpong
- Nisakorn Ratnaratorn
- Kamonkan Tangnaree
- Chutharat Munkong
- Rommanus Thaimanee
- Patcharin Eamyoung
- Sasiwimol Ubolyam
- Sukalya Lerdlum
- Sopark Manasnayakorn
- Rugsun Rerknimitr
- Sunee Sirivichayakul
- Phandee Wattanaboonyongcharoen
- Jessica Cowden
- Alexandra Schuetz
- Siriwat Akapirat
- Nampueng Churikanont
- Saowanit Getchalarat
- Denise Hsu
- Ellen Turk
- Oratai Butterworth
- Mark Milazzo
- Leigh Anne Eller
- Julie Ake
- Leigh Anne Eller
- Serena Spudich
- CAPT Lawrence Fox
- Silvia Ratto-Kim
- Victor DeGruttola
- Yotin Chinvarun
- Pasiri Sithinamsuwan
- James Fletcher
- Bruce Shiramizu
- Alexandra Schuetz
- Journal volume & issue
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Vol. 84
p. 104253
Abstract
Summary: Background: Harnessing CD8+ T cell responses is being explored to achieve HIV remission. Although HIV-specific CD8+ T cells become dysfunctional without treatment, antiretroviral therapy (ART) partially restores their function. However, the extent of this recovery under long-term ART is less understood. Methods: We analyzed the differentiation status and function of HIV-specific CD8+ T cells after long-term ART initiated in acute or chronic HIV infection ex vivo and upon in vitro recall. Findings: ART initiation in any stage of acute HIV infection promoted the persistence of long-lived HIV-specific CD8+ T cells with high expansion (P<0·0008) and cytotoxic capacity (P=0·02) after in vitro recall, albeit at low cell number (P=0·003). This superior expansion capacity correlated with stemness (r=0·90, P=0·006), measured by TCF-1 expression, similar to functional HIV-specific CD8+ T cells found in spontaneous controllers. Importanly, TCF-1 expression in these cells was associated with longer time to viral rebound ranging from 13 to 48 days after ART interruption (r =0·71, P=0·03). In contrast, ART initiation in chronic HIV infection led to more differentiated HIV-specific CD8+ T cells lacking stemness properties and exhibiting residual dysfunction upon recall, with reduced proliferation and cytolytic activity. Interpretation: ART initiation in acute HIV infection preserves functional HIV-specific CD8+ T cells, albeit at numbers too low to control viral rebound post-ART. HIV remission strategies may need to boost HIV-specific CD8+ T cell numbers and induce stem cell-like properties to reverse the residual dysfunction persisting on ART in people treated after acute infection prior to ART release. Funding: U.S. National Institutes of Health and U.S. Department of Defense.
