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We previously described a bispecific CAR-T cell targeting two highly conserved gp120 epitopes (duoCAR-T cell) with potent anti-HIV-1 activity that is currently in clinical trials. However, elevated levels of transforming growth factor \u03b2 (TGF-\u03b2) present in many PLWH may hinder the activity of both infused HIV-1-specific CAR-T cells, such as duoCAR-T cells and endogenous HIV-1-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, thereby limiting their effectiveness to achieve a functional HIV-1 cure. We hypothesized that HCW9218, a novel bifunctional immunomodulatory protein composed of TGF-\u03b2RII and IL-15\/IL-15R\u03b1, would enhance anti-HIV-1 immunity by TGF-\u03b2RII binding and neutralizing TGF-\u03b2, while IL-15\/IL-15R\u03b1 would stimulate effector cells and reactivate latent HIV-1-infected cells. We used duoCAR-T cells generated from CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from people without HIV (PWoH) and PLWH donors to demonstrate the\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      capacity of HCW9218 to block TGF-\u03b2 activity, and enhance duoCAR-T cell proliferation, cytotoxicity, and anti-HIV-1 activity. HCW9218 also functioned as a latency-reversing agent, stimulating HIV-1 production by CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells from ART-suppressed PLWH. Production of HIV-1 by HCW9218-treated CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells from ART-suppressed PLWH donors was suppressed by co-culture with autologous duoCAR-T cells. Together, these findings highlight the potential of HCW9218 to augment T cell and CAR-T-based therapies and contribute to strategies aimed at achieving a functional cure for HIV-1.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The persistence of HIV-1 reservoirs remains the primary barrier to an HIV-1 cure because antiretroviral therapy (ART) suppresses viral replication but does not eliminate latent HIV-1-infected cells. Treatment with anti-HIV-1 duoCAR-T cells is a potential strategy to target and eliminate HIV-1-infected cells, but their activity may be impaired by the immunosuppressive environment in lymphoid tissues of people living with HIV (PLWH). Transforming growth factor \u03b2 (TGF-\u03b2), a pleiotropic cytokine elevated in PLWH, is a key mediator of this immunosuppression. Here, we show that HCW9218, a bifunctional fusion protein with TGF-\u03b2-neutralizing activity and IL-15 superagonist activity, preserves duoCAR-T cell function in the presence of TGF-\u03b2 and reactivates HIV-1 production by latent HIV-1-infected cells in ART-suppressed CD4\n                        <jats:sup>+<\/jats:sup>\n                        T cells from PLWH. These findings highlight HCW9218 as a unique dual-function immunotherapy that may enhance the efficacy of duoCAR-T cells while facilitating clearance of the HIV reservoir.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00051-26","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T13:00:37Z","timestamp":1786712437000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing HIV-1-specific CAR-T cell functional activity by treatment with a novel cytokine-based scaffold with IL-15 superagonist and TGF-\u03b2-neutralizing 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