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

Abstract

<p>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 β (TGF-β) during acute HIV-1 infection among men who have sex with men (MSM). Using a serum-free <em>in vitro</em> system, we further delineated the role of TGF-β signaling in mediating HIV-1 infection of activated and resting memory CD4⁺ T cells. TGF-β 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-β-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-β-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-β treatment. These findings were coherent with the observation that <em>ex vivo</em> 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-β 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-β blockade may serve as a potential supplementary regimen for HIV-1 functional cure by reducing viral latency.</p><p><strong>IMPORTANCE</strong> 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-β was upregulated during the acute phase of infection. Using an <em>in vitro</em> serum-free system, we specifically delineated that TGF-β promoted HIV-1 infection of both resting and activated memory CD4⁺ T cells via the induction of host CCR5 coreceptor. Moreover, TGF-β-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-β will promote latency reservoir establishment during early infection. This study, therefore, highlighted the potential use of TGF-β blockade as a supplementary regimen with cART in acute patients to reduce viral latency.</p>