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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 1

HIV-producing cells in Fiebig I are CD4+CD25–.

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HIV-producing cells in Fiebig I are CD4+CD25–.
ISH with ELF97 substrate ...
ISH with ELF97 substrate identifies HIV-producing cells as cells with green virions visible against diffusely stained HIV intracellular RNA. Nuclei were counterstained blue with DAPI. (A) Example of a single productively infected cell. Arrow points to visible HIV virions. (B) Arrow points to visible virions shared by 2 cells, consistent with cell-to-cell spread. (C and D) HIV-producing cells are CD4+. Virions and intracellular RNA, green; CD4, red. (C) HIV-producing CD4+ cell with red/yellow CD4 staining visible at the cell’s margins. (D) Double-labeled red/yellow HIV-producing cell. (E) HIV-producing cells are CD25–. Virions and intracellular RNA, green; CD25, red; DAPI counterstain. Two HIV-producing (arrows) cell-CD25– conjugates with visible HIV virions shared by the 2 cells (arrows) in a field with a CD25+ HIV– cell. Scale bar: 10 mm. (F) Whisker plot of data in Table 5 from 5 participants, with percentages of HIV virus+ producing CD25– cells (red; average 99.9%, range 99.4%–100%) and virus-uninfected CD25– cells (green; average 98.3%, range 97.5%–100%). Scale bar: 10 µm.

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

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