Size, Composition, and Evolution of HIV DNA Populations during Early Antiretroviral Therapy and Intensification with Maraviroc
| Autor: | Davey M. Smith, Susan J. Little, Douglas D. Richman, Sara Gianella, Josué Pérez-Santiago, Antoine Chaillon, Parris Jordan, Joel O. Wertheim, Caroline Ignacio, Steven M. Lada, Maile Y. Karris, Sanjay Mehta |
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| Přispěvatelé: | Silvestri, Guido |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Adult Antiretroviral Therapy Highly Active Bayes Theorem CCR5 Receptor Antagonists/*therapeutic use California Cyclohexanes/*therapeutic use DNA Viral/blood Double-Blind Method Female HIV Infections/*drug therapy/virology HIV-1/genetics/physiology Humans Male Maraviroc RNA Viral/blood Triazoles/*therapeutic use Viral Load Viremia/*drug therapy Virus Replication/*drug effects Young Adult *ART intensification *Hiv *evolution *maraviroc *reservoir maraviroc HIV Infections Virus Replication Medical and Health Sciences California Maraviroc ART intensification chemistry.chemical_compound Interquartile range Antiretroviral Therapy Highly Active Viral Viral/blood Double-Blind Method Female HIV Infections/*drug therapy/virology HIV-1/genetics/physiology Humans Male Maraviroc RNA Viral Load Biological Sciences Infectious Diseases Viral evolution 6.1 Pharmaceuticals CCR5 Receptor Antagonists RNA Viral HIV/AIDS Female Infection Viral load medicine.drug Adult reservoir Immunology Clinical Trials and Supportive Activities Antiretroviral Therapy Viremia Biology Microbiology Deep sequencing 03 medical and health sciences Young Adult Double-Blind Method Cyclohexanes Clinical Research Virology evolution medicine Humans Highly Active Agricultural and Veterinary Sciences Evaluation of treatments and therapeutic interventions HIV Bayes Theorem DNA Triazoles medicine.disease Entry inhibitor 030104 developmental biology Good Health and Well Being Genetic Diversity and Evolution Viral replication chemistry Viral/blood Triazoles/*therapeutic use Viral Load Viremia/*drug therapy Virus Replication/*drug effects Young Adult *ART intensification *Hiv *evolution *maraviroc *reservoir Insect Science DNA Viral HIV-1 RNA Adult Antiretroviral Therapy Highly Active Bayes Theorem CCR5 Receptor Antagonists/*therapeutic use California Cyclohexanes/*therapeutic use DNA |
| Zdroj: | Journal of virology, vol 92, iss 3 Chaillon, Antoine; Gianella, Sara; Lada, Steven M; Perez-Santiago, Josué; Jordan, Parris; Ignacio, Caroline; et al.(2018). Size, Composition, and Evolution of HIV DNA Populations during Early Antiretroviral Therapy and Intensification with Maraviroc.. Journal of virology, 92(3). doi: 10.1128/JVI.01589-17. UC Office of the President: Research Grants Program Office (RGPO). Retrieved from: http://www.escholarship.org/uc/item/2dz5q4q8 |
| DOI: | 10.1128/JVI.01589-17. |
| Popis: | Residual viremia is common during antiretroviral therapy (ART) and could be caused by ongoing low-level virus replication or by release of viral particles from infected cells. ART intensification should impact ongoing viral propagation but not virion release. Eighteen acutely infected men were enrolled in a randomized controlled trial and monitored for a median of 107 weeks. Participants started ART with ( n = 9) or without ( n = 9) intensification with maraviroc (MVC) within 90 days of infection. Levels of HIV DNA and cell-free RNA were quantified by droplet digital PCR. Deep sequencing of C2-V3 env , gag , and pol (454 Roche) was performed on longitudinally collected plasma and peripheral blood mononuclear cell (PBMC) samples while on ART. Sequence data were analyzed for evidence of evolution by (i) molecular diversity analysis, (ii) nonparametric test for panmixia, and (iii) tip date randomization within a Bayesian framework. There was a longitudinal decay of HIV DNA after initiation of ART with no difference between MVC intensification groups (−0.08 ± 0.01 versus −0.09 ± 0.01 log 10 copies/week in MVC + versus MVC − groups; P = 0.62). All participants had low-level residual viremia (median, 2.8 RNA copies/ml). Across participants, medians of 56 (interquartile range [IQR], 36 to 74), 29 (IQR, 25 to 35), and 40 (IQR, 31 to 54) haplotypes were generated for env , gag , and pol regions, respectively. There was no clear evidence of viral evolution during ART and no difference in viral diversity or population structure from individuals with or without MVC intensification. Further efforts focusing on elucidating the mechanism(s) of viral persistence in various compartments using recent sequencing technologies are still needed, and potential low-level viral replication should always be considered in cure strategies. IMPORTANCE Residual viremia is common among HIV-infected people on ART. It remains controversial if this viremia is a consequence of propagating infection. We hypothesized that molecular evolution would be detectable during viral propagation and that therapy intensified with the entry inhibitor maraviroc would demonstrate less evolution. We performed a randomized double-blinded treatment trial with 18 acutely infected men (standard ART versus standard ART plus maraviroc). From longitudinally collected blood plasma and cells, levels of HIV DNA and cell-free HIV RNA were quantified by droplet digital PCR, and HIV DNA ( env , gag , and pol coding regions) was deep sequenced (454 Roche). Investigating people who started ART during the earliest stages of their HIV infection, when viral diversity is low, provides an opportunity to detect evidence of viral evolution. Despite using a battery of analytical techniques, no clear and consistent evidence of viral propagation for over 90 weeks of observation could be discerned. |
| Databáze: | OpenAIRE |
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