Long-term persistence of distinct mutations in genital tract

Two studies, one using isolates from women and one using isolates from men, show viral mutations in genital tracts that are different to those in blood plasma, and which persisted sometimes for years even without selective pressure of treatment.

Grisselle Tirado and colleagues at the Ponce School of Medicine in Puerto Rico, analysed 45 paired blood and vaginal samples from HIV-1-positive women. Their cross-sectional study suggests that local selective forces allow distinct viral lineages to emerge and evolve independently in the plasma and the vaginal compartment. [1]

They report that delayed clearance of drug resistance mutants was observed in the vaginal compartment and these viruses remained macrophage-tropic despite presence of T cell tropism in plasma and advanced HIV-1 disease “thus suggesting the vaginal tract could serve as a reservoir for M-tropic drug resistant mutants and perhaps contribute to the transmission of drug resistance”.

Two patients maintained T215Y in vaginal HIV two and four years after stopping AZT, and a third maintained 184V four years after discontinuing 3TC.

Population sequencing identified a mixture of 215F/L in the source partner (together with high level resistance to NNRTIs and nelfinavir) and length polymorphism analysis of all samples revealed multiple HIV quasispecies but that the blood and plasma samples of the index patient were more similar to the semen rather than plasma sample of the source partner.

They write: “Since antiretrovirals differentially penetrate the blood and male genital compartments, it may facilitate the production and/or selective retention of revertants. This has significant public health implications, as these revertants represent highly fit viruses that can become resistant to zidovudine more readily than wild-type virus.”

Comment

The presence of resistant virus in the genital tract whilst that in the plasma remains wild type has great implications for the sexual transmission of drug resistant HIV, especially when it remains M tropic.

The fact that 3TC resistance persisted in the female genital tract for more than two years in the absence of therapy is quite remarkable and is not something commonly seen in plasma. Similar findings were reported by Taylor et al in ARHR 2003; 19:353-61.

References are to the XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, 10-14 June 2003; published as part of Antiviral Therapy Volume 8 Issue 3.