α4β7+ 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 alpha(4)beta(+)(7) gut-homing CCR7(-) CD4(+) effector/effector memory T cells (T-EM) and results in massive depletion of these cells and other subsets of T-EM in gut-associated lymphoid tissues. However, besides being eliminated by HIV-1, the role of T-EM during the early stage of infection remains in-conclusive. Here, using in vitro-induced alpha(4)beta(+)(7) gut-homing T-EM (alpha(4)beta(+)(7) T-EM), we found that alpha(4)beta(+)(7) T-EM differentiated into CCR7(+) CD4(+) central memory T cells (T-CM). This differentiation was HIV-1 independent but was inhibited by SB431542, a specific transforming growth factor beta (TGF-beta) receptor I kinase inhibitor. Consistently, T-EM-toT(CM) differentiation was observed in alpha(4)beta(+)(7) T-EM stimulated with TGF-beta 1 (TGF-beta). The T-CM properties of the TGF-beta-induced T-EM-derived T-CM (alpha(4)beta(+)(7) T-CM) were confirmed by their enhanced CCL19 chemotaxis and the downregulation of surface CCR7 upon T cell activation in vitro. Importantly, the effect of TGF-beta on T-CM differentiation also held in T-EM directly isolated from peripheral blood. To investigate the significance of the TGF-beta-dependent T-EM-to-T-CM differentiation in HIV/AIDS pathogenesis, we observed that both productively and latently infected alpha(4)beta(+)(7) T-CM could differentiate from alpha(4)beta(+)(7) T-EM in the presence of TGF-beta during HIV-1 infection. Collectively, this study not only provides a new insight for the plasticity of T-EM but also suggests that the TGF-beta-dependent T-EM-to-T-CM differentiation is a previously unrecognized mechanism for the formation of latently infected T-CM after HIV-1 infection. IMPORTANCE 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-EM), 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-EM after infection. Our findings suggest previously unrecognized roles of CD4 T-EM in HIV-1 pathogenesis.