Transforming Growth Factor beta Signaling Promotes HIV-1 Infection in Activated and Resting Memory CD4(+) T Cells

Understanding the facilitator of HIV-1 infection and subsequent latency establishment may aid the discovery of potential therapeutic targets. Here, we report the elevation of plasma transforming growth factor beta (TGF-beta) during acute HIV-1 infection among men who have sex with men (MSM). Using a serum-free in vitro system, we further delineated the role of TGF-beta signaling in mediating HIV-1 infection of activated and resting memory CD4(+) T cells. TGF-beta could upregulate both the frequency and expression of the HIV-1 coreceptor CCR5, thereby augmenting CCR5-tropic viral infection of resting and activated memory CD4(+) T cells via Smad3 activation. The production of live HIV-1(JR-FL) upon infection and reactivation was increased in TGF-beta-treated resting memory CD4(+) T cells without increasing CD4 expression or inducing T cell activation. The expression of CCR7, a central memory T cell marker that serves as a chemokine receptor to facilitate T cell trafficking into lymphoid organs, was also elevated on TGF-beta-treated resting and activated memory CD4(+) T cells. Moreover, the expression of CXCR3, a chemokine receptor recently reported to facilitate CCR5-tropic HIV-1 infection, was increased on resting and activated memory CD4(+) T cells upon TGF-beta treatment. These findings were coherent with the observation that ex vivo CCR5 and CXCR3 expression on total resting and resting memory CD4(+) T cells in combination antiretroviral therapy (cART)-naive and cART-treated patients were higher than in healthy individuals. Overall, the study demonstrated that TGF-beta upregulation induced by acute HIV-1 infection might promote latency reservoir establishment by increasing infected resting memory CD4(+) T cells and lymphoid organ homing of infected central memory CD4(+) T cells. Therefore, TGF-beta blockade may serve as a potential supplementary regimen for HIV-1 functional cure by reducing viral latency. IMPORTANCE Incomplete eradication of HIV-1 latency reservoirs remains the major hurdle in achieving a complete HIV/AIDS cure. Dissecting the facilitator of latency reservoir establishment may aid the discovery of druggable targets for HIV-1 cure. This study showed that the T cell immunomodulatory cytokine TGF-beta was upregulated during the acute phase of infection. Using an in vitro serum-free system, we specifically delineated that TGF-beta promoted HIV-1 infection of both resting and activated memory CD4(+) T cells via the induction of host CCR5 coreceptor. Moreover, TGF-beta-upregulated CCR7 or CXCR3 might promote HIV-1 latent infection by facilitating lymphoid homing or IP-10-mediated viral entry and DNA integration, respectively. Infected resting and central memory CD4(+) T cells are important latency reservoirs. Increased infection of these cells mediated by TGF-beta will promote latency reservoir establishment during early infection. This study, therefore, highlighted the potential use of TGF-beta blockade as a supplementary regimen with cART in acute patients to reduce viral latency.