Differences in HIV-1 pol sequences from female genital tract and blood during antiretroviral therapy

Objective: To determine whether HIV-1 replicates locally in the female genital tract during therapy, and to study whether endocervix is the dominant source of virus in cervicovaginal lavage fluid. Design: Sequence analyses of HIV-1 pol were performed from cervicovaginal secretions and blood plasma of HIV-infected women failing antiretroviral therapy with detectable viral load in both compartments, as well as from drug-naive subjects. Methods: Viral RNA was extracted from cervicovaginal lavage fluid, endocervical secretions collected by Sno-strips, and blood plasma. Population sequencing of HIV-1 pol was performed using cycle sequencing. Drug resistance mutations were analyzed. Phylogenies were constructed based on synonymous positions in the sequences. Results: Resistant virus was detected concordantly in blood and genital tract specimens, consistent with drug selection pressure in both compartments. However, drug-selected mutations often differed in each compartment, and phylogenetic analysis showed differences in virus lineage in these compartments, consistent with local replication in female genital tract. Viruses in cervicovaginal lavage and endocervical secretions were genetically distinguishable, suggesting that endocervix is not the only source of virus found in cervicovaginal lavage. Conclusion: These data support the hypothesis that HIV replication is compartmentalized within the female genital tract during antiretroviral therapy, which has implications for pathogenesis and for epidemiologic surveillance of drug-resistant virus.