Memory CD4+ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency

Rasmussen, Thomas A; Zerbato, Jennifer M.; Rhodes, Ajantha; Tumpach, Carolin; Dantanarayana, Ashanti; McMahon, James; Lau, Jillian S.Y.; Chang, Judy; Gubser, Céline; Brown, Wendy J.; Hoh, Rebecca; Krone, Melissa; Pascoe, Rachel; Chiu, Chris; Bramhall, Michael; Lee, Hyun Jae; Haque, Ashraful; Fromentin, Rémi; Chomont, Nicolas; Milush, Jeffrey M.; Sluis, Renée M. van der; Palmer, Sarah; Deeks, Steven G.; Cameron, Paul; Evans, Vanessa A.; Lewin, Sharon R.

doi:10.1016/j.xcrm.2022.100766

Cited by 14 publications

(23 citation statements)

References 57 publications

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“…The current study therefore extends the findings of Rasmussen et al. (2022) ( 31 ) to investigate the composition of HIV-1 proviruses within a subset of these participants. Using the full-length individual proviral sequencing (FLIPS) assay, we perform an exploratory study to investigate the distribution of genetically-intact and defective HIV-1 proviruses in memory CD4 + T-cells expressing PD-1 and/or CTLA-4 from peripheral blood and paired lymph node samples from a subset of these participants, with the aim of identifying areas for further investigation.…”

Section: Introductionsupporting

confidence: 75%

“…Due to the low number of genetically-intact proviruses isolated in this study, we did not investigate whether clinical parameters correlated with the size of the genetically-intact HIV-1 reservoir in these participants. However, Rasmussen et al (2022) did perform a comparison between clinical parameters and total HIV-1 DNA content in these participants (31). Significant correlations were only observed between total HIV-1 DNA content and CD8 + T cell count and percentage, and this was observed in DN and CTLA-4 + cells only in the peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

“…Participants were recruited from a prospective observational study of HIV-1-infected individuals on ART who had blood and lymph node collected, and findings from this study were recently reported ( 31 ). In brief, a total of 16 participants treated with suppressive ART for at least 3 years were included in the current sub-study, 11 of which were enrolled at The Alfred Hospital, Melbourne, Australia, and 5 of which were enrolled at the University of California San Francisco (UCSF), California, USA.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, a study of SIV-infected macaques indicated enrichment of SIV DNA in CTLA-4 + PD-1 - CD4 + T-cells in the lymph node ( 30 ). In a recent study from our team, we demonstrated a modest enrichment of HIV-1 DNA in cells expressing both PD-1 and CTLA-4 compared to double negative cells in the peripheral blood, but that the provirus within these cells was more difficult to activate in these double positive cells compared to double negative cells ( 31 ).…”

Section: Introductionmentioning

confidence: 90%

“…Representative plots for the sorting strategy can be found in Supplementary Figure 1, and in Rasmussen et al (2022) (31). As shown in Rasmussen et al (2022), to avoid collecting cells that overlap between the four cell populations, small gaps between the individual gates for each cell population were introduced during cell sorting (31). The purity of the sorted populations was also assessed on a subset of samples.…”

Section: Sample Processing and Cell Sortingmentioning

confidence: 99%

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Unequal distribution of genetically-intact HIV-1 proviruses in cells expressing the immune checkpoint markers PD-1 and/or CTLA-4

et al. 2023

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IntroductionHIV-1 persists in resting CD4+ T-cells despite antiretroviral therapy (ART). Determining the cell surface markers that enrich for genetically-intact HIV-1 genomes is vital in developing targeted curative strategies. Previous studies have found that HIV-1 proviral DNA is enriched in CD4+ T-cells expressing the immune checkpoint markers programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocyte associated protein-4 (CTLA-4). There has also been some success in blocking these markers in an effort to reverse HIV-1 latency. However, it remains unclear whether cells expressing PD-1 and/or CTLA-4 are enriched for genetically-intact, and potentially replication-competent, HIV-1 genomes. MethodsWe obtained peripheral blood from 16 HIV-1-infected participants, and paired lymph node from four of these participants, during effective ART. Memory CD4+ T-cells from either site were sorted into four populations: PD-1-CTLA-4- (double negative, DN), PD-1+CTLA-4- (PD-1+), PD-1-CTLA-4+ (CTLA-4+) and PD-1+CTLA-4+ (double positive, DP). We performed an exploratory study using the full-length individual proviral sequencing (FLIPS) assay to identify genetically-intact and defective genomes from each subset, as well as HIV-1 genomes with specific intact open reading frames (ORFs). Results and DiscussionIn peripheral blood, we observed that proviruses found within PD-1+ cells are more likely to have intact ORFs for genes such as tat, rev and nef compared to DN, CTLA-4+ and DP cells, all of which may contribute to HIV-1 persistence. Conversely, we observed that CTLA-4 expression is a marker for cells harbouring HIV-1 provirus that is more likely to be defective, containing low levels of these intact ORFs. In the lymph node, we found evidence that CTLA-4+ cells contain lower levels of HIV-1 provirus compared to the other cell subsets. Importantly, however, we observed significant participant variation in the enrichment of HIV-1 proviruses with intact genomes or specific intact ORFs across these memory CD4+ T-cell subsets, and therefore consideration of additional cellular markers will likely be needed to consistently identify cells harbouring latent, and potentially replication-competent, HIV-1.

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Section: Introductionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Sample Processing and Cell Sortingmentioning

confidence: 99%

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