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Initial productive and latent HIV infections originate in vivo by infection of resting T cells
Stephen W. Wietgrefe, … , Ashley T. Haase, on behalf of the RV254/SEARCH 010 Study Team
Stephen W. Wietgrefe, … , Ashley T. Haase, on behalf of the RV254/SEARCH 010 Study Team
Published September 21, 2023
Citation Information: J Clin Invest. 2023;133(22):e171501. https://doi.org/10.1172/JCI171501.
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Research Article AIDS/HIV Article has an altmetric score of 4

Initial productive and latent HIV infections originate in vivo by infection of resting T cells

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Abstract

Productively infected cells are generally thought to arise from HIV infection of activated CD4+ T cells, and these infected activated cells are thought to be a recurring source of latently infected cells when a portion of the population transitions to a resting state. We discovered and report here that productively and latently infected cells can instead originate from direct infection of resting CD4+ T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting CD4+ T cells was correlated with the availability of susceptible target cells in lymphoid tissues largely restricted to resting CD4+ T cells in which expression of pTEFb enabled productive infection, and we documented persistence of HIV-producing resting T cells during antiretroviral therapy (ART). Thus, we provide evidence of a mechanism by which direct infection of resting T cells in lymphoid tissues to generate productively and latently infected cells creates a mechanism by which the productively infected cells can replenish both populations and maintain two sources of virus from which HIV infection can rebound, even if ART is instituted at the earliest stage of detectable infection.

Authors

Stephen W. Wietgrefe, Jodi Anderson, Lijie Duan, Peter J. Southern, Paul Zuck, Guoxin Wu, Bonnie J. Howell, Cavan Reilly, Eugène Kroon, Suthat Chottanapund, Supranee Buranapraditkun, Carlo Sacdalan, Nicha Tulmethakaan, Donn J. Colby, Nitiya Chomchey, Peeriya Prueksakaew, Suteeraporn Pinyakorn, Rapee Trichavaroj, Julie L. Mitchell, Lydie Trautmann, Denise Hsu, Sandhya Vasan, Sopark Manasnayakorn, Mark de Souza, Sodsai Tovanabutra, Alexandra Schuetz, Merlin L. Robb, Nittaya Phanuphak, Jintanat Ananworanich, Timothy W. Schacker, Ashley T. Haase, on behalf of the RV254/SEARCH 010 Study Team

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Figure 2

In vitro expression of pTEFb components CDK9 and cyclin T in PBMCs before and after stimulation.

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In vitro expression of pTEFb components CDK9 and cyclin T in PBMCs befor...
PBMCs from a person without HIV infection were cultured and (A and B) not stimulated or (C and D) stimulated with CD3/CD28 activator beads and stained with antibodies against CDK9 (left) or cyclin T1 (right). Nuclei were counterstained blue with DAPI. Without stimulation, CDK9 and cyclin T1 were not detectable in the nuclei. Cell stimulation induced expression of both CDK9 and cyclin T1 in a speckled pattern in the nuclei of stimulated cells. Scale bar: 20 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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