HIV-specific T-cell responses reflect substantive in vivo interactions with infected cells despite long-term therapy

Stevenson, Eva M.; Ward, Adam R.; Truong, Ronald; Thomas, Abu; Huang, Szu-Han; Dilling, Thomas R.; Terry, Sandra; Bui, John; Mota, Talia M.; Danesh, Ali; Lee, Guinevere Q.; Gramatica, Andrea; Khadka, Pragya; Alberto, Winiffer D. Conce; Gandhi, Rajesh T.; McMahon, Deborah; Lalama, Christina M.; Bosch, Ronald J.; Macatangay, Bernard; Cyktor, Joshua C.; Eron, Joseph J.; Mellors, John W.; Jones, R. Brad

doi:10.1101/2020.08.28.272625

Cited by 3 publications

(3 citation statements)

References 58 publications

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“…We saw remarkably similar responses for Nef-and Gag-specific IL-2producing CD4 1 and CD8 1 T cells following combination IC blockade. These data suggest that the effects of combination IC blockade extend to T cells that target either early or late viral gene products, although the frequency of Nef-specific T cells is highly stable on ART, whereas Gag-specific cells decay over time (41). There may be several explanations for the additive and synergistic effects with these Abs.…”

Section: Discussionmentioning

confidence: 96%

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy

Chiu

Chang

Dantanarayana

et al. 2022

The Journal of Immunology

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In people with HIV (PWH) on antiretroviral therapy (ART), immune dysfunction persists, including elevated expression of immune checkpoint (IC) proteins on total and HIV-specific T cells. Reversing immune exhaustion is one strategy to enhance the elimination of HIV-infected cells that persist in PWH on ART. We aimed to evaluate whether blocking CTL-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell Ig domain and mucin domain 3 (TIM-3), T cell Ig and ITIM domain (TIGIT) and lymphocyte activation gene-3 (LAG-3) alone or in combination would enhance HIV-specific CD4 + and CD8 + T cell function ex vivo. Intracellular cytokine staining was performed using human PBMCs from PWH on ART (n = 11) and expression of CD107a, IFN-g, TNF-a, and IL-2 was quantified with HIV peptides and Abs to IC. We found the following: 1) IC blockade enhanced the induction of CD107a and IL-2 but not IFN-g and TNF-a in response to Gag and Nef peptides; 2) the induction of CD107a and IL-2 was greatest with multiple combinations of two Abs; and 3) Abs to LAG-3, CTLA-4, and TIGIT in combinations showed synergistic induction of IL-2 in HIV-specific CD8 + and CD107a and IL-2 production in HIV-specific CD4 + and CD8 + T cells. These results demonstrate that the combination of Abs to LAG-3, CTLA-4, or TIGIT can increase the frequency of cells expressing CD107a and IL-2 that associated with cytotoxicity and survival of HIV-specific CD4 + and CD8 + T cells in PWH on ART. These combinations should be further explored for an HIV cure.

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Section: Discussionmentioning

confidence: 96%

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy

Chiu

Chang

Dantanarayana

et al. 2022

The Journal of Immunology

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“…It is possible that intact genomes provide the infected cells with a selective advantage to escape immune-mediated killing during proliferation. In support of this model, it was recently shown that functional Nef plays a role in the persistence of genetically intact HIV [44] and that Nef-specific CD8+ T cells are associated with the frequencies of infected cells [75]. Alternatively, the higher clonality of the inducible viral reservoir may reflect the lower inducibility of HIV genomes in TCM cells, a subset previously shown to be more refractory to reactivation [76] and which is characterized by a greater clonotypic diversity [72].…”

Section: Discussionmentioning

confidence: 88%

Phenotypic characterization of single CD4+ T cells harboring genetically intact and inducible HIV genomes

Dufour

Richard

Pardons

et al. 2022

Preprint

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The phenotype of the rare HIV-infected cells persisting during ART remains elusive. We developed a single-cell approach that combines the phenotypic analysis of HIV-infected cells with near full-length sequencing of their associated proviruses. Individual cells carrying clonally expanded identical proviruses displayed very diverse phenotypes, indicating that cellular proliferation contributes to the phenotypic diversification of the HIV reservoir. Unlike most viral genomes persisting on ART, inducible and translation-competent proviruses rarely presented large deletions but were enriched in defects in the Ψ locus. Interestingly, the few cells harboring genetically intact and inducible viral genomes expressed higher levels of the integrin VLA-4 compared to uninfected cells or cells with defective proviruses. Viral outgrowth assay confirmed that memory CD4+ T cells expressing high levels of VLA-4 were highly enriched in replication-competent HIV (27-fold enrichment). We conclude that although clonal expansions diversify the phenotype of HIV reservoir cells, CD4+ T cells harboring replication-competent HIV retain VLA-4 expression.

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“…Conversely, Nef can induce the expression of PD-1 on the surface of CD4 + T-cells in vitro (76). Recent studies have shown that the HIV-1 Nef protein is expressed during ART and can be produced from defective proviruses (46,47,77,78). Therefore, the presence of the HIV-1 Nef protein during ART may affect PD-1 and CTLA-4 expression on infected cells, in addition to the persistence of these infected cells.…”

Section: Discussionmentioning

confidence: 99%

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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HIV-specific T-cell responses reflect substantive in vivo interactions with infected cells despite long-term therapy

Cited by 3 publications

References 58 publications

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy

Phenotypic characterization of single CD4+ T cells harboring genetically intact and inducible HIV genomes

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

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