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Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy
Sean Philpott, … , Cheryl Brunner, Harold Burger
Sean Philpott, … , Cheryl Brunner, Harold Burger
Published February 15, 2001
Citation Information: J Clin Invest. 2001;107(4):431-438. https://doi.org/10.1172/JCI11526.
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Article

Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy

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Abstract

To initiate infection, HIV-1 requires a primary receptor, CD4, and a secondary receptor, principally the chemokine receptor CCR5 or CXCR4. Coreceptor usage plays a critical role in HIV-1 disease progression. HIV-1 transmitted in vivo generally uses CCR5 (R5), but later CXCR4 (X4) strains may emerge; this shift heralds CD4+ cell depletion and clinical deterioration. We asked whether antiretroviral therapy can shift HIV-1 populations back to R5 viruses after X4 strains have emerged, in part because treatment has been successful in slowing disease progression without uniformly suppressing plasma viremia. We analyzed the coreceptor usage of serial primary isolates from 15 women with advanced disease who demonstrated X4 viruses. Coreceptor usage was determined by using a HOS-CD4+ cell system, biological and molecular cloning, and sequencing the envelope gene V3 region. By constructing a mathematical model to measure the proportion of virus in a specimen using each coreceptor, we demonstrated that the predominant viral population shifted from X4 at baseline to R5 strains after treatment. Multivariate analyses showed that the shift was independent of changes in plasma HIV-1 RNA level and CD4+ cell count. Hence, combination therapy may lead to a change in phenotypic character as well as in the quantity of HIV-1. Shifts in coreceptor usage may thereby contribute to the clinical efficacy of anti-HIV drugs.

Authors

Sean Philpott, Barbara Weiser, Kathryn Anastos, Christina Michelle Ramirez Kitchen, Esther Robison, William A. Meyer III, Henry S. Sacks, Usha Mathur-Wagh, Cheryl Brunner, Harold Burger

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Figure 1

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The effect of combination antiretroviral therapy on HIV-1 coreceptor usa...
The effect of combination antiretroviral therapy on HIV-1 coreceptor usage over time in representative study subjects. Patients 1, 2, 6, 8, and 10 received new combination therapy and patient 13 remained untreated. Arrows note the first time during the study period that a new combination of antiretroviral drugs was initiated. Two arrows appear if a patient received a two-drug regimen first, then HAART. The duration of treatment with each agent is indicated. PT., patient; AZT, zidovudine; 3TC, lamivudine; Rit, ritonavir; Ind, indinavir; Saq, saquinavir; d4T, stavudine; Nel, nelfinavir; ddI, didanosine; ddC, zalcitabine; Nev, nevirapine.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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