ARTICLE

Inflammation, which is known to be associated with HIV; vaginal microbial dysbiosis is also associated with inflammation.

is known to be associated with HIV; vaginal microbial dysbiosis is also associated with inflammation. Reduced epithelial barrier integrity because of dysbiotic vaginal bacteria

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Over 1 million women are infected with HIV on an annual basis. To reduce this number, more understanding is needed. Even after decades of research, not much is known about the biological mechanisms that lead to HIV acquisition in this population.This lack of knowledge was addressed in the Tuesday Plenary Lecture of the 25th Conference on Retroviruses and Opportunistic Infections (CROI), during which Nichole Klatt, PhD, from the University of Washington, provided an overview of what is known about vaginal microbial dysbiosis and its association with HIV infection as well as how vaginal bacteria may influence transmission in women.“Over 50% of new infections occur in women,” Dr. Klatt stressed. “Every minute, 2 women are infected with HIV worldwide, which means that during my 25-minute talk, 50 women might be infected with HIV.”Women face several challenges in the fight against HIV. First, they tend to get infected at younger ages; women aged 15 to 24 living in sub-Saharan Africa are 2 times more likely to get infected with the virus compared with their male counterparts. Women also have to worry about mother-to-child transmission of the virus. Those living in developing countries are faced with even more obstacles when it comes to prevention, as they lack sexual protection rights in an environment rife with sexual violence. However, the particular challenge that Dr. Klatt chose to address was a lack of understanding of how biological mechanisms influence transmission for the female reproductive tract.Other factors typically associated with HIV transmission have already been studied, including the role of a damaged epithelial barrier (associated with inflammation), neutrophil infiltration, and, the focus of Dr. Klatt’s presentation, an altered microbiome.“The microbiome is the microorganisms in an environment. There are 10 trillion to 100 trillion microorganisms in each person, and a good anecdote that I like to give is that every adult has approximately 5 to 10 pounds of bacteria in the gastrointestinal tract,” Dr. Klatt explained. “However, while we think of the microbiome as bacteria, it’s not just bacteria, as it also includes things like viruses, fungi, protists, and archaea. Also, when we talk about the microbiome, it’s not just the actual microorganisms; it’s the genes that they have, the metabolites they make, and the other by-products that they may have made.”Although the most well-known microbiome is arguably the gut microbiome, Dr. Klatt zeroed in on the vaginal microbiome and how dysbiosis, which is highly associated with disease, could affect HIV transmission.“A good microbiome, or a healthy microbiome, per se, would be Lactobacillus dominant. When we [look at] the single [bacterium] Lactobacillus, it’s a very low pH, and it seems to be very protective,” explained Dr. Klatt. “However, when we see this dysbiosis, we see a dominance of polymicrobial, mostly anaerobic bacteria; this is associated with increased pH, inflammation, and barrier damage, and it has been associated with transmission of several sexually transmitted infections.” Essentially, the more diverse the microbiome is, the more anaerobes there are, and thus, the more dysbiotic it is.The clinical diagnosis for microbiome dysbiosis is bacterial vaginosis (BV), which is detected by 1 of 2 tests: the Nugent score and Amsel criteria. Dr. Klatt stressed that “having a clinical diagnosis of BV does not necessarily mean that there is microbial dysbiosis, and having a microbial dysbiosis does not necessarily mean that that woman is clinically BV-positive.”The vaginal microbiome also varies across ethnicities. One study Dr. Klatt highlighted indicated that more Lactobacillus bacteria in the microbiome have been found in white women, whereas women of other ethnicities, such as black and Hispanic, have proved to have much more diverse dysbiotic communities. “This is why I hesitate, and I kind of use quotes when I say ‘healthy’ or ‘good’ [microbiome] because we don’t really know,” she admitted. “Many women around the world have dysbiosis or these highly diverse communities, and so it may not necessarily be a bad thing; however, for HIV transmission it does seem to play a role.”Past research has shown that increased vaginal dysbiosis is highly prevalent in areas where rates of HIV infection in women are high. Dr. Klatt highlighted the differences seen in women’s microbiomes between sub-Saharan Africa and North America to illustrate this point. In sub-Saharan Africa, where HIV prevalence is especially high, much fewer Lactobacillus bacteria are seen in the microbiome than with dysbiosis, whereas in North America it is the exact opposite.“This becomes very important, as vaginal dysbiosis and BV status can increase HIV infection risk,” Dr. Klatt stressed. She highlighted one study that found that in a group in which healthy Lactobacillus bacteria were present, there was no HIV infection risk, but as microbiome diversity increased, HIV risk also went up. Furthermore, the results of the study showed an increase in HIV infections in women with BV. “It’s not just that women who have BV are at higher risk of HIV infection, but also, a man sleeping with a woman who has BV has a higher risk of HIV infection,” she said. “There’s also a higher risk of mother-to-child transmission with a woman who has BV, and so it’s an important problem, and it’s something that we have to understand better.”Therefore, investigators are working to identify the mechanisms by which vaginal microbial dysbiosis increases HIV transmission. Some of these might include:Dr. Klatt encouraged investigators to take this understanding a step further to answer the question, Why might the vaginal microbiome affect the effectiveness of different clinical trials, such as those focusing on pre-exposure prophylaxis (PrEP)?Although PrEP has proved to be about 80% to 90% effective in men, the range of effectiveness is much broader in women, anywhere from 50% to 75% effective. Although many of the variations noted in trials have been associated with adherence, Dr. Klatt suggested that biological factors may be influencing the effectiveness as well.To study the influence of biological factors, Dr. Klatt and her team reviewed the results of the CAPRISA 004 trial, which studied the influence of a topical microbicide on tenofovir gel PrEP. The investigators found that the gel was 39% effective in reducing HIV infection in women. When looking at microbiome data, splitting the women into 2 groups (one dysbiotic with Gardnerella dominance and the other with Lactobacillus dominance), the effectiveness of the PrEP changed between the groups.“What was really striking was that if you split these women up into Lactobacillus dominant versus non-Lactobacillus groups, suddenly the efficacy changed. Women with Lactobacillus in the vagina had an efficacy of 61% instead of 39%, and so the efficacy goes up,” Dr. Klatt explained. “However, if you do not have Lactobacillus dominance of the vagina, your efficacy for tenofovir gel actually goes down to 18%, and so this was quite striking. We wanted to understand why the microbiome could be affecting the actual efficacy of the drug like this.”To study this, the team created an assay, which after some alterations found a direct correlation between infection rates in cells and the rate of degradation. “This indicates that the Gardnerella dysbiotic bacteria infection actually enhanced HIV infection, probably by metabolizing the tenofovir before it could actually affect the target cell,” Dr. Klatt explained. Subsequent research looked at other PrEP drugs such as dapivirine and next-generation tenofovir alafenamide (TAF). For dapivirine, they found “a significant negative association between how much Lactobacillus is in each sample and the rate of degradation of dapivirine,” which could “potentially explain some of the differences of efficacy in women [who] were in the dapivirine trials.”No differences in diversity were found with TAF, and there was no TAF degradation.“Dysbiosis of vaginal bacteria is a key factor in vaginal inflammation, epithelial barrier integrity, and HIV acquisition. Dysbiotic bacteria can metabolize the PrEP drugs tenofovir and dapivirine and potentially contribute to decreased PrEP efficacy in vivo,” Dr. Klatt concluded. “Importantly, TAF is not degraded by vaginal bacteria, and so this needs to be taken into consideration for more efficacious PrEP. We are also trying to assess other drugs and determine which drugs are the least metabolizable for the bacteria.”Her research underscores the need to better understand the role of the vaginal microbiome in HIV and highlights the need to find a way to increase Lactobacillus communities to prevent BV as well as dysbiosis recurrence; this is crucial for improving drug efficacy. Feature Picture Source : CDC / PHIL / Dr. S Kraus. Feature Picture Description: This photograph depicted a single Gardnerella vaginalis, formerly Haemophilus vaginalis, or Corynebacterium vaginalis, bacterial colony. The vagina is normally colonized by Lactobacillus spp., which help to regulate the region’s pH, maintaining it in the low range, thereby, inhibiting the growth of potentially-pathogenic organisms. The Gram-positive Gardnerellavaginalis bacterium is one such organism, and is a common cause for bacterial vaginosis (BV).