Over the past several years, research has uncovered just how important the microbiome is to human health. Catapulted by the Human Microbiome Project, researchers have begun to tap into a wealth of scientific knowledge showing us that the microbiome can affect and contribute to maintaining health, as well as impact the course of numerous diseases. Scientific publications on the microbiome have increased by 700% over the past six years. Several presentations at IAS 2017 focused on the microbiome.
Data continues to mount showing a complicated inter- relationship between HIV and the microbiome. Evidence has linked the microbiome to numerous aspects of HIV, including dysbiosis; inflammation; HIV- related conditions; chronic diarrhea and HIV transmission.
This research is particularly important for the developing world where treating co- morbidities may be beyond the budget of many governments and individuals as people live longer with access to ARVs. Based upon microbiome research, interventions are being developed that may lessen the development and progression of conditions such as chronic diarrhea and co-morbidities that stem, at least in part, from HIV- related inflammation.
HIV is essentially a disease of the gut where two- thirds of CD4 cells are located and where the initial onslaught to the immune system occurs following HIV infection. This infection creates a disruption of the gut microbiome, called dysbiosis, which leads to a weakening of the intestinal lining, a leakage of bacteria into the bloodstream, and an ongoing inflammatory response. This systemic inflammation is thought to contribute to numerous HIV co- morbidities.
Researchers at the University of North Carolina Chapel Hill and Guangzhou No. 8 People's Hospital in China set out to better understand the changes that occur to the gut microbiome after acute HIV infection.
Fecal transplantation was used to colonize germ- free bone marrow/liver/thymus (BLT) humanized mice with a sample of human fecal matter. The mice were then infected with HIV so that the researchers could ascertain and study the interaction between HIV and the gut microbiome.
A decrease in CD4 cells, an increase in CD8 activation and significant alterations to the gut microbiome of the mice was observed. These alterations began during acute infection and suggest that dysbiosis develops over time. The results of this study support the need for therapeutics that would help maintain a balanced microbiome during acute infection, potentially averting the development of harmful dysbiosis and inhibiting disease progression.
Such drugs are already being developed and tested for conditions such as IBS and Clostridium difficile infection. Called Ecobiotic drugs by one company developing microbiome therapies (Seres Therapeutics), these investigational drugs aim to rebuild a healthy microbiome. While traditional drugs often lead to a clinical response through a specific pathway, microbiome therapeutics have the potential to affect a multitude of pathways by the very nature of the complex ecologic network in which these microbes co-exist, interact and function.
The gut microbiome is just one of the body’s microbiomes that interact with HIV. Two new studies show that the type of bacterial strains within the vagina increase the risk of HIV acquisition.
A South African study looked at the link between cervicovaginal bacteria, inflammation and HIV transmission. Researchers analyzed bacterial strains from the cervicovaginal and gut microbiome of young HIV- negative woman (ages 18-23) and found that the bacterial communities common to South African women are connected to a higher risk of HIV acquisition.
Researchers found that women whose cervicovaginal communities were deficient in a bacterial strain called Lactobacillus had a 4-fold increased risk for acquiring HIV compared to those with Lactobacillus crispatus-dominant communities. In women with this deficiency, researchers also found a 17- fold higher number of cervical target cells which researchers assert is a biological mechanism for an increased risk of HIV. In addition, researchers also identified other bacterial strains present that were associated with increased HIV risk.
The majority of woman in South Africa are Lactobacillus deficient. Researchers concluded that cervicovaginal bacteria regulate HIV risk and that the specific bacterial communities present in South African women place them at higher risk for HIV acquisition.
In a second study related to the vaginal microbiome, researchers analyzed samples taken from the well- known CAPRISA 004 study. In the original study, a tenofovir- based microbicide was studied in African women and found to achieve only a 44% percent protection rate against HIV. In this most recent study, researchers investigated whether the vaginal microbiome influenced the low rate of protection seen in the original study.
In the samples taken from 688 CAPRISA 004 study participants (both those that seroconverted and those who did not acquire HIV), two major bacterial community state-types were identified. One of low diversity (LD) with Lactobacillus iners and L. crispatus as the most common strain and the other with high ecological diversity where Gardnerella vaginalis predominated, co-dominant with Prevotella, Mobiluncus, and other anaerobic bacteria (bacteria that do not need oxygen). A three-fold higher rate of protection against HIV was seen in woman with low diversity. Lower mucosal tenofovir was detected in the non-LD women and negatively correlated with G. vaginalis abundance. Tenofovir was found to be rapidly metabolized and depleted by 64.5% by G. vaginalis in 24 hours but not by L. iners or L. crispatus. Prevotella, Mobiluncus, and other anaerobic bacteria also significantly deplete tenofovir.
This study shows that protection against HIV when tenofovir gel is used, is linked to vaginal bacteria, as certain strains of bacteria deplete levels of tenofovir. This study offers a clearer understanding of why tenofovir gel was not effective at protecting against HIV for certain women.
Not presented at IAS 2017 but discussed in several sessions was an AIDS Clinical Trials Group study of an 8- bacterial strain probiotic studied in HIV- -positive study participants. Probiotics have been studied in small groups of HIV- positive people and have shown some benefit, but the full effect remains unknown. Previous studies include a small study of ARV- naive Nigerian women who consumed yogurt with Lactobacillus strains. In 11 of the 12 women, CD4 counts remained the same or slightly increased and incidences of diarrhea were completely abated in all of the women after 2 days of the 15-day study.
In the recent ACTG study, a probiotic mixture called Visbiome was given to participants on ARVs with long- term viral suppression to measure its effect on inflammation. Results of this trial are pending, however, previous studies of this probiotic has had interesting results. The gut microbiome is also known to help regulate neurocognitive function. In a study conducted by The University of Rome, the probiotic was shown to have positive effects on neurocognitive abilities. Improvements were seen in several tests including a verbal learning test, phonological verbal fluency and time and weight estimation tests. A separate study of the same probiotic tested in HIV- positive participants, also at the University of Rome, found a reduction in CNS inflammation in participants who had consumed Visbiome. This inflammation has been linked to a decrease in neurocognitive abilities.
The Rome studies show the potential of a probiotic in offering a simple, cost- effective intervention that could be used universally to better the cognitive abilities of people living with HIV.
Further research on the role of the microbiome in HIV disease, as well as the study of novel microbiome therapeutics, is essential to improving our understanding of the bacterial communities harbored in the body and how they affect our health and influence diseases such as HIV.
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