Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy
Year: 2019
Type: article
Abstract: Chromosomal integration of genome-intact HIV-1 sequences into the host genome creates a reservoir of virally infected cells that persists throughout life, necessitating indefinite antiretroviral suppression therapy. During effective antiviral treatment, the majority of these proviruses remain transcriptionally silent, but mechanisms responsible for viral latency are insufficiently clear. Here, we used matched integration site and proviral sequencing (MIP-Seq), an experimental approach involving multiple displacement amplification of individual proviral species, followed by near-full-length HIV-1 next-generation sequencing and corresponding chromosomal integration site analysis to selectively map the chromosomal positions of intact and defective proviruses in 3 HIV-1-infected individuals undergoing long-term antiretroviral therapy. Simultaneously, chromatin accessibility and gene expression in autologous CD4+ T cells were analyzed by assays for transposase-accessible chromatin using sequencing (ATAC-Seq) and RNA-Seq. We observed that in comparison to proviruses with defective sequences, intact HIV-1 proviruses were enriched for non-genic chromosomal positions and more frequently showed an opposite orientation relative to host genes. In addition, intact HIV-1 proviruses were preferentially integrated in either relative proximity to or increased distance from active transcriptional start sites and to accessible chromatin regions. These studies strongly suggest selection of intact proviruses with features of deeper viral latency during prolonged antiretroviral therapy, and may be informative for targeting the genome-intact viral reservoir.
DOI: 10.1172/jci124291
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Funders: Harvard University, Harvard University Center for AIDS Research, Harvard T.H. Chan School of Public Health, National Institutes of Health, Center for AIDS Research, University of Washington, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Complementary and Alternative Medicine, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: A Pilot Clinical Trial for HIV-1 Eradication, Targeting HIV-1 persistence with Interferon-a, G1338316517, G1446940221, Molecular profile of proviral reservoirs in HIV-infected drug users, G1668541246, G1788762906, Proteomics and phosphoproteomics analysis in HIV-1 infection, Targeting HIV-1 persistence with Interferon-a, BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy, Early Infant Treatment, G3501070057, G4166928756, Viral and Immune Determinants of HIV Rebound, G5286342089, G5438087974, G5693802254, Preclinical Development of Ingenol and HDACi Toward HIV Eradication, PrimeFlow RNA for detection of latently-infected CD4+ T cells, G7785852513, Preclinical Development of Ingenol and HDACi Toward HIV Eradication, G8259407239, G8360733645, Immunoregulatory Function of Myelomonocytic Receptors in HIV-1 Infection, Novel single genome approaches to determine the mechanisms of HIV latent infection in blood, gut, and lymph nodes, G853329036, Quantification of the HIV-1 Reservoir by Immuno-PCR, A systems biology approach to fingerprint HIV immune defense in Elite Controllers, Inhibitors of host kinases as molecular targets for immune defense against HIV-1, G9000005415, G9000129761, G9000208279, Harvard University Center for AIDS Research, G955699890
OpenAlex ID: W2912935425