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HIV-Resistant and HIV-Specific CAR-Modified CD4⁺ T Cells Mitigate HIV Disease Progression and Confer CD4⁺ T Cell Help In Vivo.

ABSTRACT: HIV infection preferentially depletes HIV-specific CD4⁺ T cells, thereby impairing antiviral immunity. In this study, we explored the therapeutic utility of adoptively transferred CD4⁺ T cells expressing an HIV-specific chimeric antigen receptor (CAR₄) to restore CD4⁺ T cell function to the global HIV-specific immune response. We demonstrated that CAR₄ T cells directly suppressed in vitro HIV replication and eliminated virus-infected cells. Notably, CAR₄ T cells containing intracellular domains (ICDs) derived from the CD28 receptor family (ICOS and CD28) exhibited superior effector functions compared to the tumor necrosis factor receptor (TNFR) family ICDs (CD27, OX40, and 4-1BB). However, despite demonstrating limited in vitro efficacy, only HIV-resistant CAR₄ T cells expressing the 4-1BBζ ICD exhibited profound expansion, concomitant with reduced rebound viremia after antiretroviral therapy (ART) cessation and protection of CD4⁺ T cells (CAR^-) from HIV-induced depletion in humanized mice. Moreover, CAR₄ T cells enhanced the in vivo persistence and efficacy of HIV-specific CAR-modified CD8⁺ T cells expressing the CD28ζ ICD, which alone exhibited poor survival. Collectively, these studies demonstrate that HIV-resistant CAR₄ T cells can directly control HIV replication and augment the virus-specific CD8⁺ T cell response, highlighting the therapeutic potential of engineered CD4⁺ T cells to engender a functional HIV cure.

SUBMITTER: Maldini CR

PROVIDER: S-EPMC7335752 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Increasing data suggest that NK cells can mediate antiviral activity in HIV-1-infected humans, and as such, novel approaches harnessing the anti-HIV-1 function of both T cells and NK cells represent attractive options to improve future HIV-1 immunotherapies. Chronic progressive HIV-1 infection has been associated with a loss of CD4(+) T helper cell function and with the accumulation of anergic NK cells. As several studies have suggested that cytokines produced by CD4(+) T cells are required to enhance NK cell function in various infection models, we hypothesized that reconstitution of HIV-1-specific CD4(+) T-cell responses by therapeutic immunization would restore NK cell activity in infected individuals. Using flow cytometry, we examined the function of CD4(+) T cells and NK cells in response to HIV-1 in subjects with treated chronic HIV-1 infection before and after immunization with an adjuvanted HIV-1 Gp120/NefTat subunit protein vaccine candidate provided by GlaxoSmithKline. Vaccination induced an increased expression of interleukin-2 (IL-2) by Gp120-specific CD4(+) T cells in response to HIV-1 peptides ex vivo, which was associated with enhanced production of gamma interferon (IFN-?) by NK cells. Our data show that reconstitution of HIV-1-specific CD4(+) T-cell function by therapeutic immunization can enhance NK cell activity in HIV-1-infected individuals.NK cells are effector cells of the innate immune system and are important in the control of viral infection. Recent studies have demonstrated the crucial role played by NK cells in controlling and/or limiting acquisition of HIV-1 infection. However, NK cell function is impaired during progressive HIV-1 infection. We recently showed that therapeutic immunization of treated HIV-1-infected individuals reconstituted strong T-cell responses, measured notably by their production of IL-2, a cytokine that can activate NK cells. The current study suggests that reconstitution of T-cell function by therapeutic vaccination can enhance NK cell activity in individuals with chronic HIV-1 infection. Our findings provide new insights into the interplay between adaptive and innate immune mechanisms involved in HIV-1 immunity and unveil opportunities to harness NK cell function in future therapeutic vaccine strategies to target HIV-1.

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HIV-Resistant and HIV-Specific CAR-Modified CD4⁺ T Cells Mitigate HIV Disease Progression and Confer CD4⁺ T Cell Help In Vivo.

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HIV-Resistant and HIV-Specific CAR-Modified CD4+ T Cells Mitigate HIV Disease Progression and Confer CD4+ T Cell Help In Vivo.

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OmicsDI is part of the ELIXIR infrastructure

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HIV-Resistant and HIV-Specific CAR-Modified CD4⁺ T Cells Mitigate HIV Disease Progression and Confer CD4⁺ T Cell Help In Vivo.