Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia

Collins, David R.; Urbach, Jonathan M.; Racenet, Zachary J.; Arshad, Umar; Power, Karen A.; Newman, Ruchi M.; Mylvaganam, Geetha; Ly, Ngoc L.; Lian, Xiaodong; Rull, Anna; Rassadkina, Yelizaveta; Yanez, Adrienne G.; Peluso, Michael J.; Deeks, Steven G.; Vidal, Francesc; Lichterfeld, Mathias; Yu, Xu G.; Gaiha, Gaurav D.; Allen, Todd M.; Walker, Bruce D.

doi:10.1016/j.immuni.2021.08.007

Cited by 31 publications

(22 citation statements)

References 87 publications

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“…KLF2 was the most important gene to separate HIV from non-HIV participants. Some previous studies showed that KLF2 is related to HIV infection [ 12 , 58 ]. This gene and some others including CD74 and CD52 were also important to separate CVD from non-CVD in HIV, and CVD+CRT+ from CVD+, suggesting that these genes may be related to HIV and CVD.…”

Section: Discussionmentioning

confidence: 99%

Combined protein and transcript single-cell RNA sequencing in human peripheral blood mononuclear cells

et al. 2022

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Background Cryopreserved peripheral blood mononuclear cells (PBMCs) are frequently collected and provide disease- and treatment-relevant data in clinical studies. Here, we developed combined protein (40 antibodies) and transcript single-cell (sc)RNA sequencing (scRNA-seq) in PBMCs. Results Among 31 participants in the Women’s Interagency HIV Study (WIHS), we sequenced 41,611 cells. Using Boolean gating followed by Seurat UMAPs (tool for visualizing high-dimensional data) and Louvain clustering, we identified 50 subsets among CD4+ T, CD8+ T, B, NK cells, and monocytes. This resolution was superior to flow cytometry, mass cytometry, or scRNA-seq without antibodies. Combined protein and transcript scRNA-seq allowed for the assessment of disease-related changes in transcriptomes and cell type proportions. As a proof-of-concept, we showed such differences between healthy and matched individuals living with HIV with and without cardiovascular disease. Conclusions In conclusion, combined protein and transcript scRNA sequencing is a suitable and powerful method for clinical investigations using PBMCs.

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Section: Discussionmentioning

confidence: 99%

Combined protein and transcript single-cell RNA sequencing in human peripheral blood mononuclear cells

et al. 2022

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“…Limitations of the present study include the low sample size from our PLWH and HIV negative cohorts matched by age and sex and the unavailability to include all participants in every individual analysis performed, and finally considering IFNγ and CD107a co-expression as a readout of polyfunctional HIV-1-specific T cells without taking into account their co-expression with TNFα, which has been associated with durable and efficient CD8 + T cell responses. 17 , 65 In addition, age was intrinsically higher in the LT-ARTp cohort due to prolonged treatment duration, leading to significant associations of multiple functional and phenotypical data with this parameter. Therefore, additional studies using a larger number of patients with similar demographic characteristics and analysing TCR specificity by tetramer staining should be conducted.…”

Section: Discussionmentioning

confidence: 99%

Antiretroviral therapy duration and immunometabolic state determine efficacy of ex vivo dendritic cell-based treatment restoring functional HIV-specific CD8+ T cells in people living with HIV

et al. 2022

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“…Another study associated the LVC to a combination of viral factors, including X4 co-receptor switching, and loss of antiviral CD8 + T-cell activity [ 27 ]. Recently, the impairment of HIV-1 proliferative and cytolytic T-cell effector functions has been observed prior LVC [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Immunoescape of HIV-1 in Env-EL9 CD8 + T cell response restricted by HLA-B*14:02 in a Non progressor who lost twenty-seven years of HIV-1 control

et al. 2022

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Background Long-Term Non-Progressors (LTNPs) are untreated Human Immunodeficiency virus type 1 (HIV-1) infected individuals able to control disease progression for prolonged periods. However, the LTNPs status is temporary, as viral load increases followed by decreases in CD4 + T-cell counts. Control of HIV-1 infection in LTNPs viremic controllers, have been associated with effective immunodominant HIV-1 Gag-CD8 + T-cell responses restricted by protective HLA-B alleles. Individuals carrying HLA-B*14:02 control HIV-1 infection is related to an immunodominant Env-CD8 + T-cell response. Limited data are available on the contribution of HLA-B*14:02 CD8 + T -cells in LTNPs. Results In this study, we performed a virological and immunological detailed analysis of an HLA-B*14:02 LNTP individual that lost viral control (LVC) 27 years after HIV-1 diagnosis. We analysed viral evolution and immune escape in HLA-B*14:02 restricted CD8 + T -cell epitopes and identified viral evolution at the Env-EL9 epitope selecting the L592R mutation. By IFN-γ ELISpot and immune phenotype, we characterized HLA- B*14:02 HIV-1 CD8 + T cell responses targeting, Gag-DA9 and Env-EL9 epitopes before and after LVC. We observed an immunodominant response against the Env-EL9 epitope and a decreased of the CD8 T + cell response over time with LVC. Loss of Env-EL9 responses was concomitant with selecting K588R + L592R mutations at Env-EL9. Finally, we evaluated the impact of Env-EL9 escape mutations on HIV-1 infectivity and Env protein structure. The K588R + L592R escape variant was directly related to HIV-1 increase replicative capacity and stability of Env at the LVC. Conclusions These findings support the contribution of immunodominant Env-EL9 CD8 + T-cell responses and the imposition of immune escape variants with higher replicative capacity associated with LVC in this LNTP. These data highlight the importance of Env-EL9 specific-CD8 + T-cell responses restricted by the HLA-B*14:02 and brings new insights into understanding long-term HIV-1 control mediated by Env mediated CD8 + T-cell responses.

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Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia

Cited by 31 publications

References 87 publications

Combined protein and transcript single-cell RNA sequencing in human peripheral blood mononuclear cells

Combined protein and transcript single-cell RNA sequencing in human peripheral blood mononuclear cells

Antiretroviral therapy duration and immunometabolic state determine efficacy of ex vivo dendritic cell-based treatment restoring functional HIV-specific CD8+ T cells in people living with HIV

Immunoescape of HIV-1 in Env-EL9 CD8 + T cell response restricted by HLA-B*14:02 in a Non progressor who lost twenty-seven years of HIV-1 control

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