Transcriptional Reprogramming during Effector-to-Memory Transition Renders CD4+ T Cells Permissive for Latent HIV-1 Infection

• Published in: Immunity (Cambridge, Mass.) Vol. 47; no. 4; pp. 766 - 775.e3
• Main Authors: Shan, Liang, Deng, Kai, Gao, Hongbo, Xing, Sifei, Capoferri, Adam A., Durand, Christine M., Rabi, S. Alireza, Laird, Gregory M., Kim, Michelle, Hosmane, Nina N., Yang, Hung-Chih, Zhang, Hao, Margolick, Joseph B., Li, Linghua, Cai, Weiping, Ke, Ruian, Flavell, Richard A., Siliciano, Janet D., Siliciano, Robert F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.10.2017; Elsevier Limited
• Subjects: CCR5 protein; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; CD8 antigen; Cells, Cultured; Cellular Reprogramming - genetics; Cellular Reprogramming - immunology; Chemokines; Cytokines - genetics; Cytokines - immunology; Effector cells; Female; Flow Cytometry; Gene expression; Gene Expression Profiling - methods; HIV; HIV-1 - immunology; HIV-1 - physiology; Host-Pathogen Interactions - immunology; Human immunodeficiency virus; Humans; Immunologic Memory - genetics; Immunologic Memory - immunology; Immunological memory; Infections; Kinases; Latency; Latent infection; Life cycle engineering; Life cycles; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Male; Memory; Memory cells; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Transcription; Transcription, Genetic; Vaccines; Virus Latency - immunology; Virus Replication - immunology; Viruses
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2017.09.014

The latent reservoir for HIV-1 in resting memory CD4+ T cells is the major barrier to curing HIV-1 infection. Studies of HIV-1 latency have focused on regulation of viral gene expression in cells in which latent infection is established. However, it remains unclear how infection initially becomes latent. Here we described a unique set of properties of CD4+ T cells undergoing effector-to-memory transition including temporary upregulation of CCR5 expression and rapid downregulation of cellular gene transcription. These cells allowed completion of steps in the HIV-1 life cycle through integration but suppressed HIV-1 gene transcription, thus allowing the establishment of latency. CD4+ T cells in this stage were substantially more permissive for HIV-1 latent infection than other CD4+ T cells. Establishment of latent HIV-1 infection in CD4+ T could be inhibited by viral-specific CD8+ T cells, a result with implications for elimination of latent HIV-1 infection by T cell-based vaccines. [Display omitted] •HIV replicates continuously, and the evolutionary basis of latency has been unclear•CD4+ T lymphoblasts transitioning to a memory state can be latently infected•Infection in a narrow time window after T cell activation leads to HIV latency•HIV-specific CTL can inhibit the establishment of latency The latent reservoir for HIV is a barrier to cure, but it is unclear why HIV establishes latency given its ability to evade immune responses through evolution. Shan et al. show that latency is an unfortunate consequence of infection of CD4+ T cells within a narrow time window after activation.