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

ABSTRACT: Productively infected cells are generally thought to arise by HIV infection of activated CD4+ T cells, and these infected activated cells are also 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 by 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 restricted to resting CD4+ T cells and expression of pTEFb in these resting cells to enable productive infection, and we documented persistence of HIV producing resting T cells during ART. We thus provide evidence of a mechanism by which direct infection of resting T cell populations in lymphoid tissues to generate productively and latently infected cells could continually 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.

SUBMITTER: Wietgrefe SW

PROVIDER: S-EPMC10645380 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Wietgrefe Stephen W SW Anderson Jodi J Duan Lijie L Southern Peter J PJ Zuck Paul P Wu Guoxin G Howell Bonnie J BJ Reilly Cavan C Kroon Eugène E Chottanapund Suthat S Buranapraditkun Supranee S Sacdalan Carlo C Tulmethakaan Nicha N Colby Donn J DJ Chomchey Nitiya N Prueksakaew Peeriya P Pinyakorn Suteeraporn S Trichavaroj Rapee R Mitchell Julie L JL Trautmann Lydie L Hsu Denise D Vasan Sandhya S Manasnayakorn Sopark S de Souza Mark M Tovanabutra Sodsai S Schuetz Alexandra A Robb Merlin L ML Phanuphak Nittaya N Ananworanich Jintanat J Schacker Timothy W TW Haase Ashley T AT

The Journal of clinical investigation 20231115 22

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 infect ...[more]

PMID: 37733443

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Project description:BackgroundHIV-infected cell lines are widely used to study latent HIV infection, which is considered the main barrier to HIV cure. We hypothesized that these cell lines differ from each other and from cells from HIV-infected individuals in the mechanisms underlying latency.ResultsTo quantify the degree to which HIV expression is inhibited by blocks at different stages of HIV transcription, we employed a recently-described panel of RT-ddPCR assays to measure levels of 7 HIV transcripts ("read-through," initiated, 5' elongated, mid-transcribed/unspliced [Pol], distal-transcribed [Nef], polyadenylated, and multiply-sliced [Tat-Rev]) in bulk populations of latently-infected (U1, ACH-2, J-Lat) and productively-infected (8E5, activated J-Lat) cell lines. To assess single-cell variation and investigate cellular genes associated with HIV transcriptional blocks, we developed a novel multiplex qPCR panel and quantified single cell levels of 7 HIV targets and 89 cellular transcripts in latently- and productively-infected cell lines. The bulk cell HIV transcription profile differed dramatically between cell lines and cells from ART-suppressed individuals. Compared to cells from ART-suppressed individuals, latent cell lines showed lower levels of HIV transcriptional initiation and higher levels of polyadenylation and splicing. ACH-2 and J-Lat cells showed different forms of transcriptional interference, while U1 cells showed a block to elongation. Single-cell studies revealed marked variation between/within cell lines in expression of HIV transcripts, T cell phenotypic markers, antiviral factors, and genes implicated in latency. Expression of multiply-spliced HIV Tat-Rev was associated with expression of cellular genes involved in activation, tissue retention, T cell transcription, and apoptosis/survival.ConclusionsHIV-infected cell lines differ from each other and from cells from ART-treated individuals in the mechanisms governing latent HIV infection. These differences in viral and cellular gene expression must be considered when gauging the suitability of a given cell line for future research on HIV. At the same time, some features were shared across cell lines, such as low expression of antiviral defense genes and a relationship between productive infection and genes involved in survival. These features may contribute to HIV latency or persistence in vivo, and deserve further study using novel single cell assays such as those described in this manuscript.

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

Publications

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

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