Format

Send to

Choose Destination
See comment in PubMed Commons below
J Infect Dis. 2014 Sep 1;210(5):728-35. doi: 10.1093/infdis/jiu155. Epub 2014 Mar 11.

HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat.

Author information

1
Department of Medicine, University of North Carolina at Chapel Hill.
2
HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
3
HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland Departments of Genetics and Molecular Biology, Tufts University School of Medicine, School of Public Health, Boston, Massachusetts.
4
Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System, La Jolla.
5
Department of Biostatistics, School of Public Health, Boston, Massachusetts.
6
Merck Research Laboratories, White Horse Junction, Pennsylvania.

Abstract

BACKGROUND:

A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge.

METHODS:

Five participants in whom resting CD4(+) T-cell-associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4(+) T cells were assayed.

RESULTS:

VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged.

CONCLUSIONS:

Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥ 24 hours. The optimal schedule for VOR administration is still to be defined.

KEYWORDS:

HDAC inhibitor; HIV; acetylation; histone; latency; vorinostat

PMID:
24620025
PMCID:
PMC4148603
DOI:
10.1093/infdis/jiu155
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Silverchair Information Systems Icon for PubMed Central
    Loading ...
    Support Center