αβ CD4 Effector/Effector Memory T Cells Differentiate into Productively and Latently Infected Central Memory T Cells by Transforming Growth Factor β1 during HIV-1 Infection.

HIV-1 transmission occurs mainly through mucosal tissues. During mucosal transmission, HIV-1 preferentially infects αβ gut-homing CCR7 CD4 effector/effector memory T cells (T) and results in massive depletion of these cells and other subsets of T in gut-associated lymphoid tissues. However, besides being eliminated by HIV-1, the role of T during the early stage of infection remains inconclusive. Here, using -induced αβ gut-homing T (αβ T), we found that αβ T differentiated into CCR7 CD4 central memory T cells (T). This differentiation was HIV-1 independent but was inhibited by SB431542, a specific transforming growth factor β (TGF-β) receptor I kinase inhibitor. Consistently, T-to-T differentiation was observed in αβ T stimulated with TGF-β1 (TGF-β). The T properties of the TGF-β-induced T-derived T (αβ T) were confirmed by their enhanced CCL19 chemotaxis and the downregulation of surface CCR7 upon T cell activation Importantly, the effect of TGF-β on T differentiation also held in T directly isolated from peripheral blood. To investigate the significance of the TGF-β-dependent T-to-T differentiation in HIV/AIDS pathogenesis, we observed that both productively and latently infected αβ T could differentiate from αβ T in the presence of TGF-β during HIV-1 infection. Collectively, this study not only provides a new insight for the plasticity of T but also suggests that the TGF-β-dependent T-to-T differentiation is a previously unrecognized mechanism for the formation of latently infected T after HIV-1 infection. HIV-1 is the causative agent of HIV/AIDS, which has led to millions of deaths in the past 30 years. Although the implementation of highly active antiretroviral therapy has remarkably reduced the HIV-1-related morbidity and mortality, HIV-1 is not eradicated in treated patients due to the presence of latent reservoirs. Besides, the pathogenesis in CD4 T cells early after infection still remains elusive. Immediately after HIV-1 mucosal infection, CD4 T cells are preferentially infected and depleted. However, in addition to being depleted, the other roles of the CD4 T cells, especially the effector/effector memory T cells (T), in disease progression are not completely understood. The significance of this study is in revealing a novel mechanism for the formation of latently HIV-1-infected central memory CD4 T cells, a major latent reservoir from CD4 T after infection. Our findings suggest previously unrecognized roles of CD4 T in HIV-1 pathogenesis.