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- Title
HIV proviral genetic diversity, compartmentalization and inferred dynamics in lung and blood during long-term suppressive antiretroviral therapy.
- Authors
Shahid, Aniqa; Jones, Bradley R.; Yang, Julia S. W.; Dong, Winnie; Shaipanich, Tawimas; Donohoe, Kathryn; Brumme, Chanson J.; Joy, Jeffrey B.; Leung, Janice M.; Brumme, Zabrina L.
- Abstract
The lung is an understudied site of HIV persistence. We isolated 898 subgenomic proviral sequences (nef) by single-genome approaches from blood and lung from nine individuals on long-term suppressive antiretroviral therapy (ART), and characterized genetic diversity and compartmentalization using formal tests. Consistent with clonal expansion as a driver of HIV persistence, identical sequences comprised between 8% to 86% of within-host datasets, though their location (blood vs. lung) followed no consistent pattern. The majority (77%) of participants harboured at least one sequence shared across blood and lung, supporting the migration of clonally-expanded cells between sites. The extent of blood proviral diversity on ART was also a strong indicator of diversity in lung (Spearman's ρ = 0.98, p<0.0001). For three participants, insufficient lung sequences were recovered to reliably investigate genetic compartmentalization. Of the remainder, only two participants showed statistically significant support for compartmentalization when analysis was restricted to distinct proviruses per site, and the extent of compartmentalization was modest in both cases. When all within-host sequences (including duplicates) were considered, the number of compartmentalized datasets increased to four. Thus, while a subset of individuals harbour somewhat distinctive proviral populations in blood and lung, this can simply be due to unequal distributions of clonally-expanded sequences. For two participants, on-ART proviruses were also phylogenetically analyzed in context of plasma HIV RNA populations sampled up to 18 years prior, including pre-ART and during previous treatment interruptions. In both participants, on-ART proviruses represented the most ancestral sequences sampled within-host, confirming that HIV sequences can persist in the body for decades. This analysis also revealed evidence of re-seeding of the reservoir during treatment interruptions. Results highlight the genetic complexity of proviruses persisting in lung and blood during ART, and the uniqueness of each individual's proviral composition. Personalized HIV remission and cure strategies may be needed to overcome these challenges. Author summary: HIV persists in the body despite long-term antiretroviral therapy (ART). Much of our knowledge about the HIV reservoir comes from studying blood proviruses on ART, but a fundamental question is whether these are distinct from those in tissue. The lung could theoretically engender genetically distinctive HIV populations, but this remains understudied. Our analysis of nearly 900 subgenomic proviral sequences from blood and lung of individuals receiving long-term HIV therapy revealed substantial within-host heterogeneity, yet some common patterns. Identical sequences (consistent with clonal expansion of infected cells) were observed in everyone, though at varying (8–86%) frequencies. The same sequence was often recovered from both blood and lung (77% of participants). Only a subset of individuals exhibited blood-lung genetic compartmentalization, and only modestly so, where this compartmentalization was sometimes due to differential frequencies of identical sequences, not the presence of truly genetically distinctive populations, across sites. Blood proviral diversity mirrored that in lung, indicating that strategies to limit the former (e.g. early ART) should also limit the latter. Results also revealed evidence that blood and lung proviruses can persist for >20 years within-host, and that viruses emerging in blood during treatment interruptions can re-seed both lung and blood reservoirs.
- Subjects
LUNGS; ANTIRETROVIRAL agents; GENETIC variation; CELL migration
- Publication
PLoS Pathogens, 2022, Vol 18, Issue 11, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1010613