Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones

Collora, Jack A.; Liu, Runxia; Pinto-Santini, Delia; Ravindra, Neal G.; Ganoza, Carmela; Lama, Javier R.; Alfaro, Ricardo; Chiarella, Jennifer; Spudich, Serena; Mounzer, Karam; Tebas, Pablo; Montaner, Luis J.; Dijk, David van; Duerr, Ann; Ho, Ya-Chi

doi:10.1016/j.immuni.2022.03.004

Cited by 69 publications

(74 citation statements)

References 88 publications

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“…The fact that HIV preferentially infects cells belonging to large clones ( 44 ) that recirculate between blood and tissues is consistent with the preferential infection of effector memory CD4+ T cells during acute infection, as we previously reported ( 8, 45 ). Indeed, when compared to less differentiated central memory cells, effector memory cells are known to display restricted TCR repertoire as a result of their expansions ( 46, 47 ), to contain clones shared between anatomical sites ( 48 ), and to express higher levels of CCR5.…”

Section: Discussionsupporting

confidence: 90%

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections

Gantner

Buranapraditkun

Pagliuzza

et al. 2022

Preprint

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Upon infection, HIV disseminates throughout the human body within 1-2 weeks. However, its early cellular targets remain poorly characterized. We analyzed productively and latently infected cells in blood and lymphoid tissue from individuals in acute infection. The phenotype of productively infected cells rapidly evolved with time and differed between blood and lymph nodes. The TCR repertoire of productively infected cells was heavily biased, with preferential infection of previously expanded/disseminated cells, but composed almost exclusively of unique clonotypes, indicating that they were the product of independent infection events. Latent genetically intact proviruses were already archived early in infection. Hence, productive infection is initially established in a pool of phenotypically and clonotypically distinct T cells in blood and lymph nodes and latently infected cells are generated simultaneously.One-Sentence SummaryHIV initially infects phenotypically and clonotypically distinct T cells and establishes a latent reservoir concomitantly.

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Section: Discussionsupporting

confidence: 90%

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections

Gantner

Buranapraditkun

Pagliuzza

et al. 2022

Preprint

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“…This explains why some authors conclude that CD4 CTL are derived from Th1 ( 40 ) and others that CD4 CTL can arise from different lineages ( 42 ). The unprecedented potential of single cell analysis techniques to detect rare cell populations will undoubtedly lead to discovery of CD4 CTL in other pathologies, as was recently demonstrated for COVID-19 ( 78 ), HIV ( 79 ), Parkinson’s disease ( 80 ), Sjögren’s disease ( 81 ), colitis ( 82 ), colorectal cancer ( 83 ), and cutaneous T cell lymphoma ( 84 ). Further mechanistic studies based on these findings will also lead to more insight in the cell lineage(s) that CD4 CTL develop from.…”

Section: Discussionmentioning

confidence: 99%

When Helpers Go Above and Beyond: Development and Characterization of Cytotoxic CD4+ T Cells

et al. 2022

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Once regarded as an experimental artefact, cytotoxic CD4+ T cells (CD4 CTL) are presently recognized as a biologically relevant T cell subset with important functions in anti-viral, anti-tumor, and autoimmune responses. Despite the potentially large impact on their micro-environment, the absolute cell counts of CD4 CTL within the peripheral circulation are relatively low. With the rise of single cell analysis techniques, detection of these cells is greatly facilitated. This led to a renewed appraisal of CD4 CTL and an increased insight into their heterogeneous nature and ontogeny. In this review, we summarize the developmental path from naïve CD4+ T cells to terminally differentiated CD4 CTL, and present markers that can be used to detect or isolate CD4 CTL and their precursors. Subsets of CD4 CTL and their divergent functionalities are discussed. Finally, the importance of local cues as triggers for CD4 CTL differentiation is debated, posing the question whether CD4 CTL develop in the periphery and migrate to site of inflammation when called for, or that circulating CD4 CTL reflect cells that returned to the circulation following differentiation at the local inflammatory site they previously migrated to. Even though much remains to be learned about this intriguing T cell subset, it is clear that CD4 CTL represent interesting therapeutic targets for several pathologies.

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“…CD4 + T cell containing integrated proviruses in individuals on suppressive ART can express HIV-1 RNA, but the majority of these cells harbor defective proviruses 7, 8, 10, 15, 17, 29, 33, 34, 79–82 . When examined based on HIV-1 RNA expression alone, irrespective of whether the provirus is intact, CD4+ T cells containing integrated proviruses are enriched in Granzyme B expression, suggestive of residence in the CD4 cytotoxic T cell compartment 83 . Although we find a fraction of latent cells containing intact proviruses in the cytotoxic CD4+ T cell compartment, this is a minority in 5 out of 6 individuals.…”

Section: Discussionmentioning

confidence: 99%

“…When examined based on HIV-1 RNA expression alone, irrespective of whether the provirus is intact, CD4+ T cells containing integrated proviruses are enriched in Granzyme B expression, suggestive of residence in the CD4 cytotoxic T cell compartment 83 . Although we find a fraction of latent cells containing intact proviruses in the cytotoxic CD4+ T cell compartment, this is a minority in 5 out of 6 individuals.…”

Section: Discussionmentioning

confidence: 99%

Distinct gene expression by expanded clones of quiescent memory CD4⁺ T cells harboring intact latent HIV-1 proviruses

Weymar

Bar-On

Oliveira

et al. 2022

Preprint

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Antiretroviral therapy controls but does not cure HIV-1 infection due to a reservoir of rare CD4+ T cells harboring latent proviruses. To date little is known about the transcriptional program of latent cells. Here we report on a novel strategy to enrich clones of latent cells carrying intact HIV-1 proviruses directly from blood based on their expression of unique T cell receptors. This enabled single cell transcriptomic analysis of 1,050 CD4+ T cells belonging to expanded clones that harbor intact HIV-1 proviruses from 6 different individuals. The analysis revealed that most of these cells share transcriptional signatures with cytotoxic CD4+ T cells, but do not express granzymes B and H, perforin 1, NKG7, and granulysin that are required for cytotoxicity. We conclude that clones of latent cells carrying intact HIV-1 proviruses persist preferentially in a distinct CD4+ T cell population opening new possibilities for eradication.

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Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones

Cited by 69 publications

References 88 publications

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections

When Helpers Go Above and Beyond: Development and Characterization of Cytotoxic CD4+ T Cells

Distinct gene expression by expanded clones of quiescent memory CD4⁺ T cells harboring intact latent HIV-1 proviruses

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Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones

Cited by 69 publications

References 88 publications

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections

When Helpers Go Above and Beyond: Development and Characterization of Cytotoxic CD4+ T Cells

Distinct gene expression by expanded clones of quiescent memory CD4+ T cells harboring intact latent HIV-1 proviruses

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Product

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Distinct gene expression by expanded clones of quiescent memory CD4⁺ T cells harboring intact latent HIV-1 proviruses