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Article: Transforming Growth Factor β Signaling Promotes HIV-1 Infection in Activated and Resting Memory CD4+ T Cells
Title | Transforming Growth Factor β Signaling Promotes HIV-1 Infection in Activated and Resting Memory CD4+ T Cells |
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Authors | |
Issue Date | 12-Apr-2023 |
Publisher | American Society for Microbiology |
Citation | Journal of Virology, 2023 How to Cite? |
Abstract | 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 in vitro 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-1JR-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 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-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. 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-β was upregulated during the acute phase of infection. Using an in vitro 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. |
Persistent Identifier | http://hdl.handle.net/10722/328552 |
ISSN | 2023 Impact Factor: 4.0 2023 SCImago Journal Rankings: 1.378 |
DC Field | Value | Language |
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dc.contributor.author | Yim, LY | - |
dc.contributor.author | Lam, KS | - |
dc.contributor.author | Luk, TY | - |
dc.contributor.author | Mo, YF | - |
dc.contributor.author | Lu, XF | - |
dc.contributor.author | Wang, JL | - |
dc.contributor.author | Cheung, KW | - |
dc.contributor.author | Lui, GCY | - |
dc.contributor.author | Chan, DPC | - |
dc.contributor.author | Wong, BCK | - |
dc.contributor.author | Lau, TTK | - |
dc.contributor.author | Ngan, CB | - |
dc.contributor.author | Zhou, DY | - |
dc.contributor.author | Wong, YC | - |
dc.contributor.author | Tan, ZW | - |
dc.contributor.author | Liu, L | - |
dc.contributor.author | Wu, H | - |
dc.contributor.author | Zhang, T | - |
dc.contributor.author | Lee, SS | - |
dc.contributor.author | Chen, ZW | - |
dc.date.accessioned | 2023-06-28T04:46:13Z | - |
dc.date.available | 2023-06-28T04:46:13Z | - |
dc.date.issued | 2023-04-12 | - |
dc.identifier.citation | Journal of Virology, 2023 | - |
dc.identifier.issn | 0022-538X | - |
dc.identifier.uri | http://hdl.handle.net/10722/328552 | - |
dc.description.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<sup>+</sup> 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<sup>+</sup> T cells via Smad3 activation. The production of live HIV-1<sub>JR-FL</sub> upon infection and reactivation was increased in TGF-β-treated resting memory CD4<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cells and lymphoid organ homing of infected central memory CD4<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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> | - |
dc.language | eng | - |
dc.publisher | American Society for Microbiology | - |
dc.relation.ispartof | Journal of Virology | - |
dc.title | Transforming Growth Factor β Signaling Promotes HIV-1 Infection in Activated and Resting Memory CD4+ T Cells | - |
dc.type | Article | - |
dc.identifier.doi | 10.1128/jvi.00270-23 | - |
dc.identifier.eissn | 1098-5514 | - |
dc.identifier.issnl | 0022-538X | - |