CD4+ T Cell Subsets and Pathways to HIV Latency

Abstract

Latent infection of CD4⁺ T cells is the main barrier to eradicating HIV-1 infection from infected patients. The cellular and molecular mechanisms involved in the establishment and maintenance of latent infection are directly linked to the transcriptional program of the different CD4⁺ T cell subsets targeted by the virus. In this review, we provide an overview of how T cell activation, T cell differentiation into functional subsets, and the mode of initial viral infection influence HIV proviral transcription and entry into latency.

Keywords: CD4 T cell differentiation; HIV latency; HIV transcription.

FIG. 1.

Overview of T cell differentiation. Upon antigen presentation, T_N are activated and differentiate in effector cells (T_E). The specific effector functions that these cells will undertake largely depend on the stimulus and the cytokine milieu during antigen presentation. A fraction of T_E cells will undergo apoptosis after resolution of the immune response while another fraction will return to a resting state to become memory cells (T_EM, T_CM, and T_EMRA). T_CM can differentiate into T_EM or T_E depending on the stimulus, whereas T_EM can typically only differentiate into T_E during subsequent stimulus. Some T_N differentiate into T_SCM after antigen presentation. These cells have self-renewal potential and can also differentiate into other memory subsets.

FIG. 2.

Cellular mechanisms for the generation of latent infection in CD4⁺ T cells. (A) Latent infection can be established during the transition of activated CD4⁺ T cells to a quiescent/resting state. When fully or intermediately activated, CD4⁺ T cells become infected with HIV, a proportion will undergo apoptosis due to the cytopathic effects of viral replication, and a proportion will survive infection and return to a resting state in which viral replication is suppressed.^, (B) Latent infection can also be established by direct infection of quiescent/resting CD4⁺ T cells with cell-free particles,^,,, or by cell-to-cell transmission from productively infected T cells (Agosto and Henderson, unpublished work), from APC,^,, and from endothelial cells. APC, antigen-presenting cells.