title: Defective proviruses rapidly accumulate during acute HIV-1 infection.
abstract: Although antiretroviral therapy (ART) suppresses viral replication to clinically undetectable levels, human immunodeficiency virus type 1 (HIV-1) persists in CD4(+) T cells in a latent form that is not targeted by the immune system or by ART. This latent reservoir is a major barrier to curing individuals of HIV-1 infection. Many individuals initiate ART during chronic infection, and in this setting, most proviruses are defective. However, the dynamics of the accumulation and the persistence of defective proviruses during acute HIV-1 infection are largely unknown. Here we show that defective proviruses accumulate rapidly within the first few weeks of infection to make up over 93% of all proviruses, regardless of how early ART is initiated. By using an unbiased method to amplify near-full-length proviral genomes from HIV-1-infected adults treated at different stages of infection, we demonstrate that early initiation of ART limits the size of the reservoir but does not profoundly affect the proviral landscape. This analysis allows us to revise our understanding of the composition of proviral populations and estimate the true reservoir size in individuals who were treated early versus late in infection. Additionally, we demonstrate that common assays for measuring the reservoir do not correlate with reservoir size, as determined by the number of genetically intact proviruses. These findings reveal hurdles that must be overcome to successfully analyze future HIV-1 cure strategies.
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Katherine M
authors: KM
authors: Bruner
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Alexandra J
authors: AJ
authors: Murray
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Ross A
authors: RA
authors: Pollack
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Mary G
authors: MG
authors: Soliman
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Sarah B
authors: SB
authors: Laskey
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Baltimore, Maryland, USA.
authors: Adam A
authors: AA
authors: Capoferri
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Jun
authors: J
authors: Lai
authors: Department of Medicine, University of California, San Diego (UCSD), San Diego, California, USA.
authors: Matthew C
authors: MC
authors: Strain
authors: Veteran's Affairs (VA) San Diego Healthcare System, San Diego, California, USA.
authors: Steven M
authors: SM
authors: Lada
authors: Department of Medicine, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Rebecca
authors: R
authors: Hoh
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Ya-Chi
authors: YC
authors: Ho
authors: Department of Medicine, University of California, San Diego (UCSD), San Diego, California, USA.|Veteran's Affairs (VA) San Diego Healthcare System, San Diego, California, USA.|Department of Pathology, University of California, San Diego, San Diego, California, USA.
authors: Douglas D
authors: DD
authors: Richman
authors: Department of Medicine, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Steven G
authors: 0000-0001-6371-747X
authors: SG
authors: Deeks
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Janet D
authors: JD
authors: Siliciano
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Baltimore, Maryland, USA.
authors: Robert F
authors: RF
authors: Siliciano
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use; D001499:Bayes Theorem; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000378:metabolism*; D019562:Viral Load; D017735:Virus Latency; D014779:Virus Replication; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents