PMID- 29142136
OWN - NLM
STAT- MEDLINE
DCOM- 20180416
LR  - 20180724
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 92
IP  - 3
DP  - 2018 Feb 1
TI  - Size, Composition, and Evolution of HIV DNA Populations during Early
      Antiretroviral Therapy and Intensification with Maraviroc.
LID - e01589-17 [pii]
LID - 10.1128/JVI.01589-17 [doi]
AB  - 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 log10
      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.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Chaillon, Antoine
AU  - Chaillon A
AUID- ORCID: 0000-0001-9490-3857
AD  - University of California San Diego, La Jolla, California, USA achaillon@ucsd.edu.
FAU - Gianella, Sara
AU  - Gianella S
AD  - University of California San Diego, La Jolla, California, USA.
FAU - Lada, Steven M
AU  - Lada SM
AD  - University of California San Diego, La Jolla, California, USA.
FAU - Perez-Santiago, Josue
AU  - Perez-Santiago J
AD  - University of California San Diego, La Jolla, California, USA.
FAU - Jordan, Parris
AU  - Jordan P
AD  - University of California San Diego, La Jolla, California, USA.
FAU - Ignacio, Caroline
AU  - Ignacio C
AD  - University of California San Diego, La Jolla, California, USA.
FAU - Karris, Maile
AU  - Karris M
AD  - University of California San Diego, La Jolla, California, USA.
FAU - Richman, Douglas D
AU  - Richman DD
AD  - University of California San Diego, La Jolla, California, USA.
AD  - Veterans Administration San Diego Healthcare System, San Diego, California, USA.
FAU - Mehta, Sanjay R
AU  - Mehta SR
AUID- ORCID: 0000-0002-2028-8158
AD  - University of California San Diego, La Jolla, California, USA.
AD  - Veterans Administration San Diego Healthcare System, San Diego, California, USA.
FAU - Little, Susan J
AU  - Little SJ
AD  - University of California San Diego, La Jolla, California, USA.
FAU - Wertheim, Joel O
AU  - Wertheim JO
AD  - University of California San Diego, La Jolla, California, USA.
FAU - Smith, Davey M
AU  - Smith DM
AD  - University of California San Diego, La Jolla, California, USA.
AD  - Veterans Administration San Diego Healthcare System, San Diego, California, USA.
LA  - eng
GR  - K24 AI100665/AI/NIAID NIH HHS/United States
GR  - R01 MH101012/MH/NIMH NIH HHS/United States
GR  - R21 HD094646/HD/NICHD NIH HHS/United States
GR  - U01 AI043638/AI/NIAID NIH HHS/United States
GR  - U01 AI068636/AI/NIAID NIH HHS/United States
GR  - T32 AI007384/AI/NIAID NIH HHS/United States
GR  - DP1 DA034978/DA/NIDA NIH HHS/United States
GR  - P30 AI027763/AI/NIAID NIH HHS/United States
GR  - P30 MH062512/MH/NIMH NIH HHS/United States
GR  - P30 AI036214/AI/NIAID NIH HHS/United States
GR  - K01 AI110181/AI/NIAID NIH HHS/United States
GR  - UL1 TR000100/TR/NCATS NIH HHS/United States
GR  - U19 AI096113/AI/NIAID NIH HHS/United States
GR  - R01 MH097520/MH/NIMH NIH HHS/United States
GR  - P01 AI074621/AI/NIAID NIH HHS/United States
GR  - P01 AI131385/AI/NIAID NIH HHS/United States
GR  - R01 MH100974/MH/NIMH NIH HHS/United States
GR  - UM1 AI068636/AI/NIAID NIH HHS/United States
GR  - R24 AI106039/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180117
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (CCR5 Receptor Antagonists)
RN  - 0 (Cyclohexanes)
RN  - 0 (DNA, Viral)
RN  - 0 (RNA, Viral)
RN  - 0 (Triazoles)
RN  - MD6P741W8A (maraviroc)
SB  - IM
MH  - Adult
MH  - Antiretroviral Therapy, Highly Active
MH  - Bayes Theorem
MH  - CCR5 Receptor Antagonists/*therapeutic use
MH  - California
MH  - Cyclohexanes/*therapeutic use
MH  - DNA, Viral/blood
MH  - Double-Blind Method
MH  - Female
MH  - HIV Infections/*drug therapy/virology
MH  - HIV-1/genetics/physiology
MH  - Humans
MH  - Male
MH  - RNA, Viral/blood
MH  - Triazoles/*therapeutic use
MH  - Viral Load
MH  - Viremia/*drug therapy
MH  - Virus Replication/*drug effects
MH  - Young Adult
PMC - PMC5774877
OTO - NOTNLM
OT  - *ART intensification
OT  - *HIV
OT  - *evolution
OT  - *maraviroc
OT  - *reservoir
EDAT- 2017/11/17 06:00
MHDA- 2018/04/17 06:00
CRDT- 2017/11/17 06:00
PHST- 2017/09/13 00:00 [received]
PHST- 2017/10/27 00:00 [accepted]
PHST- 2017/11/17 06:00 [pubmed]
PHST- 2018/04/17 06:00 [medline]
PHST- 2017/11/17 06:00 [entrez]
AID - JVI.01589-17 [pii]
AID - 10.1128/JVI.01589-17 [doi]
PST - epublish
SO  - J Virol. 2018 Jan 17;92(3). pii: JVI.01589-17. doi: 10.1128/JVI.01589-17. Print
      2018 Feb 1.