A study published in the January 11th edition of AIDS has explored the evolution of HIV in women, within the blood plasma and the genital tract. While viral diversity continues to expand in the blood plasma, a limited set of viral variants was found to be selected very early after infection and to persist in the genital tract. But drug resistance patterns in genital virus were found to be very close to those in overall blood plasma in another study published in the online edition of The Journal of Infectious Diseases. These findings have implications for treatment and vaccine development.
HIV genetic diversity
Previous research into male-to-female sexual transmission of HIV has found that a subset of HIV variants from the infecting partner is selected during infection, leading to a genetically narrow range of HIV in the early stages of infection. As infection progresses, genetic evolution of the virus progresses differently in the genital tract and in the blood plasma, leading to distinct populations of virus in these two “compartments”.
To further investigate the development of viral diversity in HIV-positive women, researchers from France and the Central African Republic (CAR) conducted a prospective cohort study of 139 women in Bangui, CAR. Of these women, 101 were HIV-negative, eight were diagnosed as being in the acute/primary stage of HIV infection (less than three months), and 30 were seropositive for chronic HIV infection (all of whom were asymptomatic and not on antiretroviral treatment). The eight women with primary infection, and a randomly selected seven with chronic infection, were selected for analysis. For these 15 women, variations in the highly variable env sequences of the viral genome were analysed, both in free viral RNA and in proviral DNA, from blood samples and cervicovaginal secretions (CVS).
Overall HIV genetic diversity was significantly higher for chronically than for acutely infected women, in blood plasma (mean 1% vs. 0.25%, p=.0006) but not in CVS (1% vs. 2%, p=0.42). HIV in blood plasma was genetically very similar in all acutely-infected women, and similar to the viral strains in the genital tract “indicating that viral selection occurs during the early phase of sexual transmission”. This is consistent with the findings of numerous previous studies (although two other prior studies, in Kenya and in Rwanda, have found the opposite – that genetically varied HIV is present in the blood plasma of women with primary infection).
Viral evolution was found to proceed along distinct paths in the blood plasma and in the CVS, confirming that HIV is “compartmentalized in chronically-infected women, in agreement with previous studies”, and that this occurs “at late stages in the natural history of HIV disease”, probably due to different immune pressures in the two bodily areas.
A unique finding of this study was that, in the CVS, viral RNA and DNA sequences were dissimilar, suggesting that certain viral variants “are archived as cell-associated DNA in the genital tract early during primary infection…" Thus, the female genital environment may act as a ‘viral filter’ ” by selecting variants best able to replicate in both the genital tract and the blood plasma. The investigators believe that these findings provide “new perspectives for the development of effective preventive HIV vaccines.”
HIV drug resistance
In another, similar study, a group of American researchers looked at blood and CVS samples from 14 women enrolled at the New York City site of the Women’s Interagency Study (WIHS), a multicentre, longitudinal study of HIV in women. The objective was to investigate whether drug-resistant variants were also compartmentalized between the blood plasma and the genital tract, “an issue that has not been studied in detail”. The women in the study had detectable blood plasma RNA despite antiretroviral treatment (ART): eleven were receiving antiretroviral therapy at the time of the study and three had been treated previously.
HIV RNA sequences were obtained for 280 unique viral variants isolated; genotypic resistance profiles (from the April 2006 version of the Stanford HIV drug resistance database) and predicted phenotypic profiles (using Virtual Phenotype, vircoTYPE HIV-1 assay, version 3.7.01) were derived and compared. The researchers found that resistance patterns varied greatly between women, but were “highly concordant between viruses in the plasma and genital tract for 13 of the 14 patients.” Three distinct patterns were identified in these 13 – six women who displayed no drug resistance, five who had resistance mutations in all variants isolated from them, and two with mixed resistant and susceptible virus. A single participant showed drug-resistant virus in plasma but none in the genital tract.
The researchers stated that “[t]hese data suggest that, for the majority of women … HIV-1 drug resistance in the plasma will approximate the drug-resistance pattern in the genital tract” – a finding they believe has clinical implications for female-to-male and mother-to-child transmission. They were also able to identify “minority species bearing distinctive linked mutations, which may serve as a source of novel resistance genotypes.”
Chomont N et al. Early archives of genetically-restricted proviral DNA in the female genital tract after heterosexual transmission of HIV-1. AIDS. 21: 153-162, 2007.
Kemal KS et al. HIV-1 drug resistance in variants from the female genital tract and plasma. J Infect Dis. 195 (online edition), 2007.