Gut and blood differ in constitutive blocks to HIV transcription, suggesting tissue-specific differences in the mechanisms that govern HIV latency
Year: 2018
Type: article
Study design: Observational Study
Abstract: Latently-infected CD4+ T cells are widely considered to be the major barrier to a cure for HIV. Much of our understanding of HIV latency comes from latency models and blood cells, but most HIV-infected cells reside in lymphoid tissues such as the gut. We hypothesized that tissue-specific environments may impact the mechanisms that govern HIV expression. To assess the degree to which different mechanisms inhibit HIV transcription in the gut and blood, we quantified HIV transcripts suggestive of transcriptional interference (U3-U5; "Read-through"), initiation (TAR), 5' elongation (R-U5-pre-Gag; "Long LTR"), distal transcription (Nef), completion (U3-polyA; "PolyA"), and multiple splicing (Tat-Rev) in matched peripheral blood mononuclear cells (PBMCs) and rectal biopsies, and matched FACS-sorted CD4+ T cells from blood and rectum, from two cohorts of ART-suppressed individuals. Like the PBMCs, rectal biopsies showed low levels of read-through transcripts (median = 23 copies/106 cells) and a gradient of total (679)>elongated(75)>Nef(16)>polyadenylated (11)>multiply-spliced HIV RNAs(<1) [p<0.05 for all], demonstrating blocks to HIV transcriptional elongation, completion, and splicing. Rectal CD4+ T cells showed a similar gradient of total>polyadenylated>multiply-spliced transcripts, but the ratio of total to elongated transcripts was 6-fold lower than in blood CD4+ T cells (P = 0.016), suggesting less of a block to HIV transcriptional elongation in rectal CD4+ T cells. Levels of total transcripts per provirus were significantly lower in rectal biopsies compared to PBMCs (median 3.5 vs. 15.4; P = 0.008) and in sorted CD4+ T cells from rectum compared to blood (median 2.7 vs. 31.8; P = 0.016). The lower levels of HIV transcriptional initiation and of most HIV transcripts per provirus in the rectum suggest that this site may be enriched for latently-infected cells, cells in which latency is maintained by different mechanisms, or cells in a "deeper" state of latency. These are important considerations for designing therapies that aim to disrupt HIV latency in all tissue compartments.
Source: PLoS Pathogens
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: National Science Foundation, U.S. Department of Veterans Affairs, amfAR, The Foundation for AIDS Research, Delaney AIDS Research Enterprise, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institutes of Health, University of California, San Francisco, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G109341090, G150015232, Tissue Reservoirs of HIV in Victims of Sudden Death, G2047159353, G2180026884, G2428225874, G2839755957, G3181090803, DARE: Delaney AIDS Research Enterprise to find a cure., G3423487890, Traffic to and from the ERGIC, Role of Gut Associated Lymphoid Tissue in HIV Persistence, G433490187, G4713330150, G5028974557, G5148168042, G5397375411, G5509916647, Novel and efficient techniques to assess the latent HIV-1 reservoir using sensitive PCR-based measures of viral transcription, virion release and autologous infection, G6212232794, G6446673651, G6759634997, G7052378927, G864826021, G9000066077, G9000078127, G9000100957, G9000106854, G9000274586, G959250803, G97119092
OpenAlex ID: W2900495690