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

To initiate infection, HIV-1 requires a primary receptor, CD4, and a second ary 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 as ked whether antiretroviral therapy can shift HIV-1 populations back to R5 v iruses after X4 strains have emerged, in part because treatment has been su ccessful in slowing disease progression without uniformly suppressing plasm a viremia, We analyzed the corecepcor usage of serial primary isolates from 15 women with advanced disease who demonstrated X4 viruses. Coreceptor usa ge was determined by using a HOSCD4(+) cell system, biological and molecula r cloning, and sequencing the envelope gene V3 region. By constructing a ma thematical model to measure the proportion of virus in a specimen using eac h coreceptor, we demonstrated that the predominant viral population shifted from X4 at baseline to R5 strains after treatment. Multivariate analyses s howed that the shift was independent of changes in plasma HIV-1 RNA level a nd CD4(+) cell count. Hence, combination therapy may lead to a change in ph enotypic character as well as in the quantity of HIV-1, Shifts in corecepto r usage may thereby contribute to the clinical efficacy of anti-HIV drugs.