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Prediction of X4-tropic Human Immunodeficiency Virus from Proviral Envelope Sequence in Patients with Suppressed Viral Load on Antiretroviral Therapy (ART).
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Download the The Tree download PDF here
Reported by jules Levin
CROI Feb 16-19 2010 SF
Elizabeth White1,Maya Balamane1, Keith Henry2, David Katzenstein1 for the ACTG A5102 Team
1Division of Infectious Diseases, Stanford University, Stanford, CA, USA, 94305
2University of Minnesota
ABSTRACT
Background: The presence of X4-tropic HIV negates the antiviral response
to R5 antagonists. However, the identification of X4 tropic HIV is currently
possible only in patients with HIV viremia. We evaluated the prevalence of
X4-tropic HIV among ACTG A5102 patients who had plasma HIV RNA levels
< level of detection for > 1 year comparing tropism predicted from the HIV
proviral DNA sequence before treatment interruption to the plasma HIV
tropism after interrupting antiretroviral therapy (ART).
Methods: Envelope sequence (C2-C3) was amplified from proviral DNA
isolated from PBMCs before treatment interruption; co-receptor usage was
predicted using the PSSM program
(http://indra.mullins.microbiol.washington.edu/pssm/) for the population
sequence and 10-20 cloned env amplicons were also examined. After
antiretroviral therapy was stopped, tropism was evaluated with the Trofile
assay from Monogram Biosciences in the matched samples when the
plasma HIV RNA level was > 1000 copies/ml.
Results: Among 18 evaluable patients treated for > 1 year, median CD4 was
888/mm3 which decreased to 649 /mm3 2-8 weeks (mean 2.8 weeks) after
interruption. The median first detectable RNA > 1,000 copies/ml after
stopping therapy was 4.27 log10 c/ml. Proviral env sequences predicted X4-
tropic virus for 5/18 (28%); in 3 by consensus proviral sequence and in two
samples by cloning. For the two cloned samples, 5/20 and 2/12 clones from
proviral V3 loop DNA were predicted to be X4. Only the 3 samples with X4 in
consensus proviral sequence had dual/mixed (D/M) virus by the Trofile assay
from the corresponding plasma samples. These 3 D/M patients exhibited
trends towards a lower nadir CD4 count (p=0.076, Mann-Whitney) and less
reduction in CD4 count after interruption (p=.085, Mann-Whitney) compared
to the patients with only R5-tropic HIV.
Conclusions: Currently, R5 inhibitors are recommended only for those with
a measurable plasma HIV level and demonstration of exclusive R5 tropism.
Here we show that X4-tropic HIV can be identified and predicted from
proviral env sequences among suppressed patients with high CD4 cell
counts, providing a means to identify potential situations in fully suppressed
HIV-infected patients when R5 inhibitors could be effectively used in drug
substitution or simplification studies. Surprisingly, there was no evidence of
increased CD4 decline among those with X4 tropism.
To See The Tree download poster pdf attached above, the tree was too difficult to put in this report.
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