Hormonal contraceptives are associated with altered cervical immunity, dependent on the presence of genital tract infections

Past studies have shown an association between hormonal contraceptives and risk of HIV-1 infection, as well as between genital tract infection and acquisition of HIV-1. The types of hormonal contraceptives that have been associated with increased risk of HIV include progestin injectable depot medroxyprogesterone acetate (DMPA) and combined estrogen-progestin oral contraceptives (COC). Untreated cervical pathogens such as Trichomonas vaginalis, Neisseria gonorrhoeae, Chlyamydia trachomatis, Candida albicans, and genital herpesvirus 2 also contribute to increased risk of HIV. In a study recently published in mBio by the American Society for Microbiology, researchers investigated the combined effects of hormonal contraceptives and genital tract infections on risk level of HIV.

The participants of this study were 633 HIV-negative women and 199 HIV-positive women, all of whom live in Uganda or Zimbabwe. It was found that more than half the study participants were positive for herpes. Cases of herpes were evenly distributed among women with chlamydia, candidiasis, and bacterial vaginosis. However, herpes was significantly more common among women positive for T. vaginalis or gonorrhea. As for contraceptives, women with asymptomatic infections were mainly COC users (65%) followed by DMPA users (60%). Symptomatic infections were most common in the group that did not use hormonal contraceptives.  

To test for risk factors of HIV, the researchers looked at certain immune system response components. It was found that HIV was associated with higher levels of two immune components known as RANTES and BD2. RANTES was seen to be increased among combined estrogen-progestin oral contraceptive users whom were also associated with herpes and abnormal vaginal microbiota. BD2 was seen increased among COC and non-HC users by T. vaginalis infection and among DMPA users by herpes, candidiasis, and bacterial vaginosis.

As is common in all processes of life, there seem to be many factors that contribute to HIV infection. Changes in the immune system caused by hormones, like contraceptive hormones, and genital bacteria composition may combine to influence vulnerability to HIV infection. This study is important, because the more knowledge scientists have about women’s reproductive health, the greater the possibility that we can develop treatment and prevention plans for infections.

HIV vaccine failed because of interaction with microbiome

Scanning electron micrograph of HIV-1, colored green, on a lymphocyte.

From 2009 to 2013, scientists at Duke University and the National Institute of Allergy and Infectious Diseases had been working on what looked like a promising cure to HIV. The study was terminated in 2013 because it was clear that the vaccine was not effective in protecting against HIV infection. An article recently published by Science Magazine gave insight into why the HIV vaccine unfortunately failed. Hint: it has something to do with the microbiome.

The vaccine was administered in the study to adult males in the form of an initial vaccine as well as a second booster vaccine. The HIV vaccine looked promising because it stimulated the body’s immune system to produce antibodies that recognize HIV. The unexpected result, however, was that these antibodies also recognized bacteria like Escherichia coli, a very important bacteria that lives in the human gut. It should be easy to see why this is a bad thing for the microbiome. Destroying important gut bacteria is very detrimental to humans, which we see over and over again here on the blog. Additionally, because the antibodies were reactive to bacteria as well as the HIV virus, it took away from the effectiveness of fighting HIV.

This study is very important in the search towards finding a cure to HIV, because it presented an unexpected obstacle that a lot can be learned from. Moving forward, questions are already being raised by the scientists such as, would this vaccine work for children if immunization was given to pregnant mothers? Perhaps the still-developing immune system would better be able to work with the vaccine. Only more research can prove whether the HIV vaccine is indeed still promising.  In addition, this may provide insights into the efficacy of vaccines for other diseases.  Perhaps the microbiome plays a large role in their effectiveness.  Vaccine research going forward should begin to take the microbiome into account.

Sometimes-pathogenic Neisseria are constantly invoking immune response in humans

Fluorescent antibody stain of Neisseria gonorrhoeae.

Bacteria from the genus Neisseria exist as normal commensals in greater than 95% of adults.  That being said, two strains, Neisseria meningitides (a cause of bacterial meningitis) and Neisseria gonorrhoeae (the cause of gonorrhea),are known pathogens, although these too can often asymptomatic.  A new study published last week in Science suggests that although asymptomatic, Neisseria may always be inducing an autoimmune response, via a metabolite they are constantly producing and releasing into the environment. 

Using genetic approaches, scientists from the University of Toronto identified the inflammation-inducing metabolite as heptose-1,7-bisphosphate (HBP), which prior to the study had not been implicated as causing an immune response.  To prove its effect, the researchers injected the metabolite into mice and showed that these mice displayed inflammation almost immediately.  The scientists recognized that this metabolite is actually produced by many bacteria, and wondered if these others were causing harm as well.  Using mouse studies though, they demonstrated that other bacteria do not release it from their cells into the environment, so these bacteria only induce a response when they are lysed.  Thus far only Neisseria have been shown to produce and release this metabolite, which is important because it means as long as they are growing they are constantly producing an immune response. 

The scientists also discovered the immune pathway by which HMP triggers a response: the TRAF-interacting protein with forkhead-associated domain (TIFA).  Interestingly, it has been known for many years that infection with N. meningitidis or N. gonorrhoeae increases HIV shedding and transmission, but the reason was still a mystery.  The scientists figured out this connection when they recognized that HIV actually use the TIFA pathway to reproduce.  They observed that these bacteria invoke the TIFA response via HBP, which gives the HIV the proper cells it needs to replicate.

Given what we know about the effects of chronic inflammation and its effects on many diseases these findings could be very important.  Perhaps there is no such thing as a nonpathogenic Neisseria, and its existence in ‘healthy’ guts may not be so healthy after all.

New research helps determine what is healthy and unhealthy in the vaginal microbiome

Editor’s note: This blog about the vaginal microbiome is a good primer for this coming Monday’s Microbiome Podcast with Jacques Ravel, where we will discuss the vaginal microbiome and women’s health at length.  There will also be a special announcement during this podcast, so anyone interested should be sure to download it Monday, June 1.

The typical ‘healthy’ vaginal microbiome is dominated by a Lactobacillus.  However many women, especially those of African descent, are not dominated by this genus, and instead have a high diversity of bacteria in their vaginal tract.  This low lactobacilli, high diversity phenotype has been associated with many disease states, such as bacterial vaginosis (BV), preterm birth, and higher rates of sexually transmitted disease (STD) transmission.  (We have written about some of these diseases before, and encourage any interested reader to click the ‘vaginal microbiome’ below this story to learn more.)  Vaginal microbiome research is still in its early days though, and it is not clear why vaginal microbiome not dominated by Lactobacillus should lead to these diseases, and if this phenotype, if asymptomatic, should even be considered unhealthy.  New research though, out of Harvard University, shows that this phenotype does lead to inflammation, and that these inflammatory response can affect reproductive health and STD transmission.  They published their study in the journal Immunity last week.

The scientists studied the vaginal microbiomes of a cohort of 146 HIV negative, asymptomatic, black, South African women.  They discovered that 63% of them were not dominated by Lactobacillus, an extremely high percentage, especially compared to their counterparts in developed countries (38% of black women and 10% of white women).  Nearly half of those women were dominated by Gardneralla vaginalis, which is most commonly associated with BV, and a large percentage of the other half were diagnosed with BV after investigation.  This is especially interesting because, as stated before, all of the women in the cohort claimed to be asymptomatic, but as we are learning, many women are unaware that there is anything wrong.  Overall, the women were able to be grouped into 4 specific phenotypes, those dominated by Lactobacillus iners, those dominated by other Lactobacillus crispatus, those dominated by Gardnerella vaginalis, and those with a high diversity including Gardnerella vaginalis, Fusobacterium gonidiaformans, Prevotella bivia, and Atopobium vaginae (note the lack of Lacotbacillus in this high diversity group). 

The scientists discovered that there were no associations between each vaginal microbiome group and the rate of STDs, contraceptive use, or sexual behavior.  This is important in showing that, at least on first pass, these bacterial communities were not the result of these exogenous factors (nor did they cause them, for that matter).  They also discovered that there was only a loose association between inflammatory cells in the vaginas of these women, and whether or not they had an STD.  The loose association was only observed in women with Chlamydia, and the women with the highest levels of inflammation had no apparent STDs.

The fact that STDs were not strongly associated with inflammation led the researchers to hypothesize that the vaginal microbiome community, rather than STDs, were responsible for vaginal inflammation.  Indeed, when they compared the amount of inflammatory cells in each vagina with the different microbiome groups described earlier, they found a strong association between inflammation and the highly diverse microbiome group.   Moreover, when they tracked individual women over time, those women whose vaginal microbiomes shifted to the high diversity group also increased inflammatory responses.  The researchers then took this work a step further, and identified specific bacteria that were associated with the inflammatory response:  Prevotella amnii, Mobiluncus mulieris, Sneathia amnii, and Sneathia sanguinegens.

Finally, the researchers measured genes for specific receptors in the vagina that are known to trigger an immune response.  They discovered that those women with the high diversity vaginal microbiomes upregulated genes for these receptors, which are known to be activated by bacteria.  Making matters worse, specific immune cells that are triggered by these receptors, which are thought to be critically important to HIV transmission, were found in higher abundances in women in the high diversity vaginal microbiome group.

This paper did a really great job showing that a vaginal microbiome that lacks Lactobacillus is indeed an unhealthy state, because it creates a highly inflammatory vaginal microbiome which likely causes or contributes to many other ailments, beyond just the higher rates of HIV transmission that was demonstrated.  Unfortunately, at the moment, there are no easy ways for women to check which vaginal microbiome they have, but that should be changing soon, and we recommend that all of our readers tune into the Microbiome Podcast this coming Monday to hear a big announcement in this area.