HIV persists throughout deep tissues with repopulation from multiple anatomical sources
Antoine Chaillon, Sara Gianella, Simon Dellicour, Stephen A. Rawlings, Timothy E. Schlub, Michelli Faria De Oliveira, Caroline Ignacio, Magali Porrachia, Bram Vrancken, Davey M. Smith
Antoine Chaillon, Sara Gianella, Simon Dellicour, Stephen A. Rawlings, Timothy E. Schlub, Michelli Faria De Oliveira, Caroline Ignacio, Magali Porrachia, Bram Vrancken, Davey M. Smith
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Clinical Research and Public Health AIDS/HIV Infectious disease

HIV persists throughout deep tissues with repopulation from multiple anatomical sources

Abstract

BACKGROUND Understanding HIV dynamics across the human body is important for cure efforts. This goal has been hampered by technical difficulties and the challenge of obtaining fresh tissues.METHODS This observational study evaluated 6 individuals with HIV (n = 4 with viral suppression using antiretroviral [ART] therapy; n = 2 with rebound viremia after stopping ART), who provided serial blood samples before death and their bodies for rapid autopsy. HIV reservoirs were characterized by digital droplet PCR, single-genome amplification, and sequencing of full-length (FL) envelope HIV. Phylogeographic methods were used to reconstruct HIV spread, and generalized linear models were tested for viral factors associated with dispersal.RESULTS Across participants, HIV DNA levels varied from approximately 0 to 659 copies/106 cells (IQR: 22.9–126.5). A total of 605 intact FL env sequences were recovered in antemortem blood cells and across 28 tissues (IQR: 5–9). Sequence analysis showed (a) the emergence of large, identical, intact HIV RNA populations in blood after cessation of therapy, which repopulated tissues throughout the body; (b) that multiple sites acted as hubs for HIV dissemination but that blood and lymphoid tissues were the main source; (c) that viral exchanges occurred within brain areas and across the blood-brain barrier; and (d) that migration was associated with low HIV divergence between sites and greater diversity at the recipient site.CONCLUSION HIV reservoirs persisted in all deep tissues, and blood was the main source of dispersal. This may explain why eliminating HIV susceptibility in circulating T cells via bone marrow transplants allowed some individuals with HIV to experience therapy-free remission, even though deeper tissue reservoirs were not targeted.TRIAL REGISTRATION Not applicable.FUNDING NIH grants P01 AI31385, P30 AI036214, AI131971-01, AI120009AI036214, HD094646, AI027763, AI134295, and AI68636.

Authors

Antoine Chaillon, Sara Gianella, Simon Dellicour, Stephen A. Rawlings, Timothy E. Schlub, Michelli Faria De Oliveira, Caroline Ignacio, Magali Porrachia, Bram Vrancken, Davey M. Smith

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Figure 4

ML phylogenies and clonal populations (FL envelope) for 2 participants who either stopped ART or remained virally suppressed on ART.

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ML phylogenies and clonal populations (FL envelope) for 2 participants w...
IQ-TREE (97) was used to estimate phylogenies for the FL HIV env sequences obtained from premortem blood plasma and tissues and from PBMCs collected during rapid autopsy. (A) ML phylogeny for participant LG01, who stopped therapy. (B) ML phylogeny for participant LG03, who remained virally suppressed. Tips are colored by compartment as in the legend. The size and distribution of nearly identical FL env populations (99% identical, populations of at least 3 identical proviruses) for each participant are presented in the middle of each tree. Colors represent the tissues described in the key. For LG01, nearly identical FL env populations including HIV RNA viruses sampled in blood plasma during viral rebound are marked with an asterisk. See also Supplemental Figure 4 for data on the 4 remaining participants.