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Anti-HIV-1 CAR-T cells armed with autogenic broadly neutralizing antibody and follicle-homing receptor CXCR5 ar effective against different HIV-1 clades and reduce viral reservoir in HIV-1-infected individuals

ABSTRACT: Chimeric antigen receptor T (CAR-T) cells, long proposed for HIV-1 treatment, has yet to achieve desirable therapeutic efficacy. In our study, M10 CAR-T cells were used for treating 18 HIV-1 patients via a regimen combining two M10 infusions and repeat chidamide stimulation for HIV reservoir activation. Consequently, 74.3% of M10 infusions resulted in significant suppression of viral rebound (averaging 77.4% decline), with 10 patients showing persistently reduced cell-associated HIV-1 RNA levels (averaging > 1.15 log10) over the 150-day observation period. To evaluate the genetic change, the PCR products were sequenced on a PacBio sequel platform by Genewiz (Genewiz, Suzhou, China) in 10 HIV patients treated by M10 CAR-T immunotherapy and 2 controls only applied with HAART therapy. High-throughput sequencing of partial pol gene and env gene amplified from whole blood samples at baseline or final visit.The results demonstrated that several participants showed a genetic shift in the composition of viral reservoir populations after treatment. Additionally, in some participants, the remaining proviruses showed reduced overall diversity in the virus pol gene. The results also reveal the selective pressure mainly targeted the env gene. This comprehensive survey supported the potential of M10 CAR-T cells as a new, safe, and effective therapeutic option toward HIV-1 eradication in AIDS patients.

ORGANISM(S): Human immunodeficiency virus 1

PROVIDER: GSE220111 | GEO | 2022/12/08

REPOSITORIES: GEO

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Project description:Despite the critical role antigen-specific T cells play in containing viral infections, their aggregate frequencies in peripheral blood have not correlated with clinical protection during HIV infection. However, a subset of HIV-specific T cells, which are capable of simultaneously producing multiple effector cytokines, termed polyfunctional T cells, have correlated with delayed disease progression. HIV-specific polyfunctional T cells have been enumerated and characterized using the intracellular cytokine staining (ICS) assay, which allows for simultaneous multiplexed analysis of cytokine expression at the single-cell level. In addition, using an unbiased computational analysis of ICS data generated through the RV144 HIV vaccine case-control study, we identified vaccine-induced HIV envelope (Env)-specific polyfunctional CD4 T cells as a novel correlate of reduced risk of HIV infection. However, very little is known about these cells and what differentiates them from other vaccine-elicited T cells. In addition, the use of sample fixation in the ICS assay prevents those cells from being further interrogated for transcriptional differences. Thus, we developed a novel live-cell multiplexed cytokine capture assay which allows for identification, sorting and transcriptional profiling of individual antigen-specific polyfunctional T cells by single-cell RNA-sequencing (scRNA-seq). We applied these methods to peripheral blood samples from participants who had received the RV144 vaccine regimen as part of the HVTN 097 clinical trial. Using this approach, we discovered transcriptional signatures that specifically identify the single-cell Env-specific CD4 T-cell functional profiles which had correlated with reduced risk of HIV infection in RV144. Interestingly, this signature is particularly characterized by upregulation of Th2 cytokines, supporting the hypothesis that the vaccine-induced Env-specific CD4 T cells likely contributed to the reduced risk of infection by providing T cell help to the Env-specific antibody responses. By interrogating the gene signatures that correlated with polyfunctionality, we have identified potential mechanisms of how vaccine-elicited polyfunctional T cells may contribute to reduced risk of HIV infection.

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Anti-HIV-1 CAR-T cells armed with autogenic broadly neutralizing antibody and follicle-homing receptor CXCR5 ar effective against different HIV-1 clades and reduce viral reservoir in HIV-1-infected individuals

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