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

ABSTRACT: Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8⁺ T cells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic T cell effector functions became selectively and intrinsically impaired prior to aborted control. Longitudinal transcriptomic profiling of functionally impaired HIV-specific CD8⁺ T cells revealed altered expression of genes related to activation, cytokine-mediated signaling, and cell cycle regulation, including increased expression of the antiproliferative transcription factor KLF2 but not of genes associated with canonical exhaustion. Lymphoid HIV-specific CD8⁺ T cells also exhibited poor functionality during aborted control relative to durable control. Our results identify selective functional impairment of HIV-specific CD8⁺ T cells as prognostic of impending aborted HIV control, with implications for clinical monitoring and immunotherapeutic strategies.

SUBMITTER: Collins DR

PROVIDER: S-EPMC8516715 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Functional impairment of HIV-specific CD8<sup>+</sup> T cells precedes aborted spontaneous control of viremia.

Collins David R DR Urbach Jonathan M JM Racenet Zachary J ZJ Arshad Umar U Power Karen A KA Newman Ruchi M RM Mylvaganam Geetha H GH Ly Ngoc L NL Lian Xiaodong X Rull Anna A Rassadkina Yelizaveta Y Yanez Adrienne G AG Peluso Michael J MJ Deeks Steven G SG Vidal Francesc F Lichterfeld Mathias M Yu Xu G XG Gaiha Gaurav D GD Allen Todd M TM Walker Bruce D BD

Immunity 20210907 10

Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8<sup>+</sup> T cells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic T cell effector functions became selectively and intrinsically impaired prior to aborted ...[more]

PMID: 34496223

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Project description:UnlabelledCD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcriptional signature compared to Th1 CD4+ cells but shared similar features with HIV-specific cytolytic CD8+ T cells. Furthermore, HIV-specific cytolytic CD4+ T cells showed comparable killing activity relative to HIV-specific CD8+ T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4+ T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4+ T cells as an independent subset distinct from Th1 cells that show combined activity with CD8+ T cells in the long-term control of HIV infection.ImportanceThe ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8+ T cells to control the virus, while CD4+ T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4+ T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4+ T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8+ T cells. These findings are important for our understanding of HIV immunopathology.

Project description:CD8+ and CD4+ T cells from HIV infected patients with HIV-RNA viremia of >50 copies/ml and CD8+ and CD4+ T cells from healthy controls were isolated by negative selection (Miltenyi Biotech, Auburn, CA). Cell sorting of the CD4 and CD8 T cell subsets were performed based on surface staining of CD3+CD8+ or CD3+CD4+ and na ve CD45RA+CD27+CD127highHLA-DRlow, and CD3+CD8+ or CD3+CD4+ and memory CD45RA-CD27+CD127highHLA-DRlow. Sorted cell populations were spun down and stored as dry pellets at -80M-BM-0C. Samples analyzed by transcript levels of genes related to cytokine signaling were determined by the JAK/STAT Signaling Pathway microarray. CD8+ and CD4+ T cells from HIV infected patients with HIV-RNA viremia of >50 copies/ml and CD8+ and CD4+ T cells from healthy controls were isolated by negative selection (Miltenyi Biotech, Auburn, CA). Cell sorting of the CD4 and CD8 T cell subsets were performed based on surface staining of CD3+CD8+ or CD3+CD4+ and naM-CM-/ve CD45RA+CD27+CD127highHLA-DRlow, and CD3+CD8+ or CD3+CD4+ and memory CD45RA-CD27+CD127highHLA-DRlow. Sorted cell populations were spun down and stored as dry pellets at -80M-BM-0C. Samples analyzed by transcript levels of genes related to cytokine signaling were determined by the JAK/STAT Signaling Pathway microarray (http://www.sabiosciences.com/rt_pcr_product/HTML/PAHS-039A.html, SABiosciences Frederick, MD). Briefly, total RNA was harvested from each individual T cell subset from each patient or healthy control and contaminating DNA was digested with DNase. Messenger RNA was converted to cDNA and loaded onto PCR array plates for quantitative real-time PCR. Quantification of transcript levels was determined by normalizing to 5 housekeeping genes from each individual sample. Relative gene expression levels for each subset were averaged and compared between cell populations from the patient group and healthy controls. Because of the multiple comparisons only p values M-bM-^IM-$ 0.01 were considered significant.

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

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Functional impairment of HIV-specific CD8<sup>+</sup> T cells precedes aborted spontaneous control of viremia.

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

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Functional impairment of HIV-specific CD8&lt;sup&gt;+&lt;/sup&gt; T cells precedes aborted spontaneous control of viremia.

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

Functional impairment of HIV-specific CD8<sup>+</sup> T cells precedes aborted spontaneous control of viremia.