Defective proviruses rapidly accumulate during acute HIV-1 infection

• Published in: Nature medicine Vol. 22; no. 9; pp. 1043 - 1049
• Main Authors: Bruner, Katherine M, Murray, Alexandra J, Pollack, Ross A, Soliman, Mary G, Laskey, Sarah B, Capoferri, Adam A, Lai, Jun, Strain, Matthew C, Lada, Steven M, Hoh, Rebecca, Ho, Ya-Chi, Richman, Douglas D, Deeks, Steven G, Siliciano, Janet D, Siliciano, Robert F
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2016; Nature Publishing Group
• Subjects: 13/106; 45/22; 45/23; 45/77; 631/250/254; 631/250/255/1901; Acute Disease; Adult; Aged; Anti-HIV Agents - therapeutic use; Antiretroviral agents; Bayes Theorem; Biomedicine; Cancer Research; Care and treatment; CD4-Positive T-Lymphocytes - virology; Cohort Studies; Development and progression; Disease Progression; Female; Genomes; Highly active antiretroviral therapy; HIV; HIV infections; HIV Infections - drug therapy; HIV Infections - metabolism; HIV Infections - virology; HIV-1; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immune system; Infections; Infectious Diseases; Lentivirus; letter; Male; Medicine; Metabolic Diseases; Middle Aged; Molecular Medicine; Neurosciences; Observations; Patient outcomes; Polymerase Chain Reaction; Proviruses - metabolism; Retroviridae; Viral Load; Virulence (Microbiology); Virus Latency; Virus Replication; Young Adult; San Francisco California; California; United States > US; Maryland; Baltimore Maryland
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4156

Bruner
et al
. report that defective HIV-1 proviruses predominate in early infection, even when antiretroviral therapy is initiated in the first months after infection. The results highlight challenges in estimating the reservoir of intact, replication-competent virus that may influence cure strategies.
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
1
,
2
,
3
,
4
,
5
. 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
6
. 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.