Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion
Open Access
- 12 February 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 10 (1), 1-12
- https://doi.org/10.1038/s41467-019-08431-7
Abstract
After 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.Keywords
This publication has 84 references indexed in Scilit:
- Differences in HIV Burden and Immune Activation within the Gut of HIV‐Positive Patients Receiving Suppressive Antiretroviral TherapyThe Journal of Infectious Diseases, 2010
- The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled TrialPLoS Medicine, 2010
- Nuclear RNA Export and Packaging Functions of HIV-1 Rev RevisitedJournal of Virology, 2010
- New Algorithms and Methods to Estimate Maximum-Likelihood Phylogenies: Assessing the Performance of PhyML 3.0Systematic Biology, 2010
- Cellular Levels of HIV Unspliced RNA from Patients on Combination Antiretroviral Therapy with Undetectable Plasma Viremia Predict the Therapy OutcomePLOS ONE, 2009
- Analysis of Human Immunodeficiency Virus Type 1 Viremia and Provirus in Resting CD4 + T Cells Reveals a Novel Source of Residual Viremia in Patients on Antiretroviral TherapyJournal of Virology, 2009
- Human Immunodeficiency Virus Type 1-Specific CD8+T-Cell Responses during Primary Infection Are Major Determinants of the Viral Set Point and Loss of CD4+T CellsJournal of Virology, 2009
- HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferationNature Medicine, 2009
- Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapyProceedings of the National Academy of Sciences of the United States of America, 2009
- Residual Human Immunodeficiency Virus Type 1 Viremia in Some Patients on Antiretroviral Therapy Is Dominated by a Small Number of Invariant Clones Rarely Found in Circulating CD4 + T CellsJournal of Virology, 2006