Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion

• DOI: 10.1038/s41467-019-08431-7
• Publication Date: 2019-02-13T11:05:13Z
• Authors: Marilia Rita Pinzone; D. Jake VanBelzen; Sam Weissman; Maria Paola Bertu...; LaMont Cannon; Emmanuele Venanzi...; Stephen Migueles; R. Brad Jones; Talia Mota; Sarah B. Joseph; Kevin Groen; Alexander O. Past...; Wei-Ting Hwang; Brad Sherman; Anastasios Vourekas; Giuseppe Nunnari; Una O’Doherty
• Keywords: Adult; Male; 0301 basic medicine; Science; Antiretroviral Therapy; HIV Infections; Antiviral Agents; Article; 03 medical and health sciences; Proviruses; Antiretroviral Therapy, Highly Active; Humans; Longitudinal Studies; Viremia; Phylogeny; Q; High-Throughput Nucleotide Sequencing; Middle Aged; Viral Load; Virus Latency; 3. Good health; Proviruses, Antiretroviral Therapy, HIV-1; Mutation; HIV-1; Female

AbstractAfter initiating antiretroviral therapy (ART), a rapid decline in HIV viral load is followed by a long period of undetectable viremia. Viral outgrowth assay suggests the reservoir continues to decline slowly. Here, we use full-length sequencing to longitudinally study the proviral landscape of four subjects on ART to investigate the selective pressures influencing the dynamics of the treatment-resistant HIV reservoir. We find intact and defective proviruses that contain genetic elements favoring efficient protein expression decrease over time. Moreover, proviruses that lack these genetic elements, yet contain strong donor splice sequences, increase relatively to other defective proviruses, especially among clones. Our work suggests that HIV expression occurs to a significant extent during ART and results in HIV clearance, but this is obscured by the expansion of proviral clones. Paradoxically, clonal expansion may also be enhanced by HIV expression that leads to splicing between HIV donor splice sites and downstream human exons.