HIV silencing and cell survival signatures in infected T cell reservoirs

• Published in: Nature (London) 2023-02, Vol.614 (7947), p.318-325
• Main Authors: Clark, Iain C., Mudvari, Prakriti, Thaploo, Shravan, Smith, Samuel, Abu-Laban, Mohammad, Hamouda, Mehdi, Theberge, Marc, Shah, Sakshi, Ko, Sung Hee, Pérez, Liliana, Bunis, Daniel G., Lee, James S., Kilam, Divya, Zakaria, Saami, Choi, Sally, Darko, Samuel, Henry, Amy R., Wheeler, Michael A., Hoh, Rebecca, Butrus, Salwan, Deeks, Steven G., Quintana, Francisco J., Douek, Daniel C., Abate, Adam R., Boritz, Eli A.
• Format: Article
• Language: English
• Subjects: 13/62; 38/39; 38/91; 631/250/255/1901; 631/326/421; 692/699/255/1901; Anti-Retroviral Agents - pharmacology; Anti-Retroviral Agents - therapeutic use; Antiretroviral agents; Antiretroviral therapy; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Deoxyribonucleic acid; DNA; DNA, Viral - isolation & purification; Drug therapy; Gene expression; Gene Expression Regulation, Viral - drug effects; Genes; Genetic engineering; HIV; HIV Infections - drug therapy; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - isolation & purification; HIV-1 - pathogenicity; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Immunologic Memory; Immunological memory; Lymphocytes; Lymphocytes T; Memory cells; Microfluidics; multidisciplinary; Necroptosis; Necroptosis - drug effects; RNA processing; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Signaling; Survival; Therapy; Transcriptome - drug effects; Transcriptomes; Transcriptomics; Virus Latency - drug effects; Viruses
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-022-05556-6

Rare CD4 T cells that contain HIV under antiretroviral therapy represent an important barrier to HIV cure 1 – 3 , but the infeasibility of isolating and characterizing these cells in their natural state has led to uncertainty about whether they possess distinctive attributes that HIV cure-directed therapies might exploit. Here we address this challenge using a microfluidic technology that isolates the transcriptomes of HIV-infected cells based solely on the detection of HIV DNA. HIV-DNA + memory CD4 T cells in the blood from people receiving antiretroviral therapy showed inhibition of six transcriptomic pathways, including death receptor signalling, necroptosis signalling and antiproliferative Gα12/13 signalling. Moreover, two groups of genes identified by network co-expression analysis were significantly associated with HIV-DNA + cells. These genes ( n  = 145) accounted for just 0.81% of the measured transcriptome and included negative regulators of HIV transcription that were higher in HIV-DNA + cells, positive regulators of HIV transcription that were lower in HIV-DNA + cells, and other genes involved in RNA processing, negative regulation of mRNA translation, and regulation of cell state and fate. These findings reveal that HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population with host gene expression patterns that favour HIV silencing, cell survival and cell proliferation, with important implications for the development of HIV cure strategies. HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population of cells with transcriptomic patterns that favour HIV silencing, cell survival and cell proliferation.