Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4^sup +^ T cells

• Published in: The Journal of clinical investigation 2017-07, Vol.127 (7), p.2689
• Main Authors: Lee, Guinevere Q, Orlova-Fink, Nina, Einkauf, Kevin, Chowdhury, Fatema Z, Sun, Xiaoming, Harrington, Sean, Kuo, Hsiao-Hsuan, Hua, Stephane, Chen, Hsiao-Rong, Ouyang, Zhengyu, Reddy, Kavidha, Dong, Krista, Ndung'u, Thumbi, Walker, Bruce D, Rosenberg, Eric S, Yu, Xu G, Lichterfeld, Mathias
• Format: Article
• Language: English
• Subjects: Antiretroviral therapy; Bioinformatics; Biomedical research; CD4 antigen; Cell proliferation; Cytokines; Deoxyribonucleic acid; DNA; DNA sequencing; Drug therapy; Gene expression; Genomes; HIV; Human immunodeficiency virus; Immunological memory; Infections; Latent infection; Leukocytes (mononuclear); Lymphocytes; Lymphocytes T; Memory cells; Nucleotide sequence; Peripheral blood mononuclear cells; Replication
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI93289

HIV-1 causes a chronic, incurable disease due to its persistence in CD4· T cells that contain replication-competent provirus, but exhibit little or no active viral gene expression and effectively resist combination antiretroviral therapy (cART). These latently infected T cells represent an extremely small proportion of all circulating CD4· T cells but possess a remarkable long-term stability and typically persist throughout life, for reasons that are not fully understood. Here we performed massive single-genome, near-full-length next-generation sequencing of HIV-1 DNA derived from unfractionated peripheral blood mononuclear cells, ex vivo-isolated CD4· T cells, and subsets of functionally polarized memory CD4· T cells. This approach identified multiple sets of independent, near-full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4· T cells harboring intact HIV-1. Intact, near-full-genome HIV-1 DNA sequences that were derived from such clonally expanded CD4· T cells constituted 62% of all analyzed genomeintact sequences in memory CD4 T cells, were preferentially observed in Th1-polarized cells, were longitudinally detected over a duration of up to 5 years, and were fully replication- and infection-competent. Together, these data suggest that clonal proliferation of Th1-polarized CD4· T cells encoding for intact HIV-1 represents a driving force for stabilizing the pool of latently infected CD4· T cells.