Sequence Analysis of Inducible, Replication-Competent Virus Reveals No Evidence of HIV-1 Evolution During Suppressive Antiviral Therapy Indicating A Lack Of Ongoing Viral Replication
Sook-Kyung Lee, Amy Sondgeroth, Yinyan Xu, Joanna Warren, Shuntai Zhou, Maria Gilleece, Blake M Hauser, Cynthia L Gay, JoAnn D Kuruc, Nancie M Archin, Joseph J Eron, David M Margolis, Nilu Goonetilleke, Ronald Swanstrom- Infectious Diseases
- Oncology
Abstract
Background
Persistence of HIV-1 in reservoirs necessitates life-long antiretroviral therapy (ART). There are conflicting data using genetic analysis on whether persistence includes an actively replicating reservoir with strong evidence arguing against replication.
Methods
We investigated the possibility of ongoing viral evolution during suppressive therapy by comparing near full-length viral genomic sequences using phylogenetic analysis of viral RNA in plasma before therapy initiation early after infection and from virus induced to grow from the latent reservoir after a period of suppressive ART. We also focused our analysis on evidence of selective pressure by drugs in the treatment regimen and at sites of selective pressure by the adaptive immune response.
Results
Viral genomes induced to grow from the latent reservoir from 10 participants with up to 9 years on suppressive ART were highly similar to the nearly homogeneous sequences in plasma taken early after infection at ART initiation. The finding was consistent across the entire genome and when the analysis focused at sites targeted by the drug regimen and by host selective pressure of antibody and cytotoxic T cells. The lack of viral evolution away from pretherapy sequences in spite of demonstrated selective pressure is most consistent with a lack of viral replication during reservoir persistence.
Conclusion
These results do not support ongoing viral replication as a mechanism of HIV-1 persistence during suppressive ART.