HIVR4P: Bacteria that may have a big influence on HIV transmission and microbicide efficacy

A number of presentations at the 2016 HIV Research for Prevention Conference (HIVR4P) in Chicago looked at the influence vaginal bacteria have on HIV susceptibility, and one presentation found that vaginal bacteria may have profound effects on the levels of certain drugs used as microbicides – but not on others.

A poster at the conference also looked at the bacteria in the rectum in gay men and found a correlation between having had condomless anal sex and changes in the predominant bacterial species that may similarly increase susceptibility to HIV infection.

Bacterial vaginosis is a condition in which acid-loving aerobic (oxygen-using) bacteria such as Lactobacillus are largely replaced by species such as Gardnerella which are anaerobic. It has for a number of years been associated both with higher rates of HIV acquisition and transmission in women. Other studies have suggested that it is not so much that the anaerobic bacteria are inflammatory but that Lactobacillus is protective.

Irene Xie of Canada’s Public Health Agency told the conference that there was considerably more bacterial vaginosis in women in surveys from Africa than from North America. In women at low risk of HIV from the US and Canada, Lactobacillus species comprised two-thirds of vaginal flora. In surveys of women from Africa, they only comprised about one-third, with about two-thirds various anaerobic species, especially Gardnerella and Prevotella. These are average proportions; in fact, women tended to fall into two distinct categories, those without bacterial vaginosis and those with, with quite separate bacterial populations, and no in-between states.

The anaerobic and aerobic bacteria in turn stimulated quite different sets of inflammatory and skin-regeneration genes in the vaginal mucosa (lining), which in turn means that whereas Lactobacillus species actually promote wound healing, lesions heal 25% more slowly where Gardnerella is the main species. This is why bacterial vaginosis is associated with higher HIV infection and transmission rates. Interestingly, some injectable contraceptives disrupt the healing of the mucosa through a similar mechanism.

As also reported at this year’s International AIDS Conference (AIDS 2016), vaginal bacteria can also have an effect on drug concentrations when they are used in microbicides. However here it is women who do not have bacterial vaginosis who are in danger of low drug levels. The drugs tenofovir and dapivirine, used in gels and rings, are efficiently absorbed by Lactobacillus crispatus, the most common species, resulting in drug concentrations in vaginal tissues ten times lower in women where this species predominates.

Although this problem can be overcome by ensuring high enough levels in the vagina itself, it could result in loss of efficacy – and may explain some infections – in situations where microbicides are used intermittently. The prodrugs of tenofovir which are taken orally, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are not absorbed, so should maybe be considered for use in microbicides too.

If the bacterial populations in the vagina form an established though still-growing area of research, research into rectal bacteria, and whether differences in them also change inflammation and susceptibility to HIV via anal sex, is almost new territory.

One poster looked at rectal bacteria in gay men. It enrolled 41 gay men who had condomless anal sex and 21 men in a control group who had never had anal sex at all, and surveyed their rectal bacteria. In the case of the men who had anal sex, it took samples for analysis at two time points; one more than three days after the last anal sex, and then one within four hours of it.

The researchers found that men who had condomless receptive anal intercourse tended to have higher levels of one bacterium, Prevotella, that is also higher in women with bacterial vaginosis. Controls had, instead, other species such as Bacteroides.

Similarly to the picture in the vagina, Prevotella also upregulates the activity of inflammatory genes in rectal tissue. The researchers hypothesise that the alkalinity of semen and micro-trauma caused by anal sex may both increase rectal inflammation directly and also cause inflammation by the overgrowth of anaerobic species such as Prevotella. The alkalinity of sperm also tips the environment against Lactobacillus in women.

It is important to emphasise firstly that other factors may also influence the vaginal and rectal flora: for instance, a western diet high in protein tends to be associated with a higher proportion of Bacteroides in the rectum and a diet high in carbohydrates and fibre more typical of poorer countries with more Prevotella. Also, the genetic probes used to find bacteria are relatively insensitive and may miss minority species, and the correlation of genetic fingerprinting techniques with the more traditional Nugent score, which counts bacterial species on slides, is poor.

Nonetheless, research into vaginal and rectal flora is a growing area of HIV and STI prevention work, and one which may guide microbicide development and treatments in the future.

Zevin A et al (presenter Xie I). Microbiome composition and function drives wound-healing impairment in the female genital tract. HIV Research for Prevention (HIVR4P) 2016 conference, Chicago, abstract OA04.05, 2016.