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  17th CROI
Conference on Retroviruses
and Opportunistic Infections
San Francisco CA
February 16-19, 2010
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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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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

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.

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