Role of the Microbiome on HIV Infection, Prevention, and Treatment
Dr Klatt discusses the importance of understanding the effect of the microbiome on HIV pathogenesis, prevention, and treatment.
The understanding of the human microbiome continues to grow rapidly. Innumerable projects have been launched worldwide to understand the role that the microbiome plays and its impact on human health. However, information on the role of the microbiome on HIV infection, prevention, and treatment is still limited.
Sara Gianella Weibel, MD, on behalf of Infectious Disease Advisor, talks with Nichole Klatt, PhD, associate professor in the department of pharmaceutics at University of Washington in Seattle about the importance of the human microbiome on HIV, including the next steps in research and its relevance in clinical practice.
Infectious Disease Advisor: Dr Klatt, can you tell us about the human microbiome and why is it so important for human health in general?
Nichole Klatt, PhD: The human body harbors 10 to 100 trillion symbiotic microbial cells, with more than twice as many bacterial cells than human cells. Bacteria altogether can constitute several pounds of our body weight. These bacteria are important constituents of the human microbiome and they are an important and very active part of all mucosal tissues and body fluids (oral, gut, genital, skin, airways). In fact, the microbiome is integral in many functions and likely plays a crucial role for the immunologic, hormonal, and metabolic homeostasis of the host.
Infectious Disease Advisor: What factors affect the human microbiome? For example, do we know if there are differences by geographic location, diet, sex or sexual orientation, or other factors?
Dr Klatt: There are certainly geographic differences in microbiome composition and diversity. Recent studies have also demonstrated divergences in the microbiome structure between healthy individuals from different race and ethnicity.1 The microbiome is distinct to each body site, such as lung, oral, gut, penile, and vaginal microbiomes. There are also differences within each anatomic site, such as different parts of the gastrointestinal tract or within the female reproductive tract.2 There are also possibly differences related to sexual practices and lifestyle.3
A caveat of microbiome studies, however, is that the use of extremely varied material and methods has led to inconsistent findings, and future larger microbiome studies will need to control for all the behavioral and social factors.
Infectious Disease Advisor: Can we characterize people's microbiome, and what can this tell us about their health?
Dr Klatt: Different methods can be used to characterize the human microbiome at various mucosal sites, most frequently by sequencing 16s rRNA bacterial genes. In this regard, the American Gut Microbiome Project (which is led by Dr Rob Knight, UCSD) is the world's largest crowd-funded science project in existence. This initiative is collecting and sequencing stool samples from the entire population and enables participants to learn about their own body's microbes while also contributing to the greater scientific knowledge. The goal is to learn how the human microbiome is associated with various aspects of our health — from associations with diet to the amount of alcohol consumed to whether or not someone has autism or any other disease. Because all de-identified data are made freely available, researchers from all over the world can access the data to ask questions about the microbiome and its association with a variety of health and lifestyle factors.
Additional advances in our understanding of the microbiome will hopefully provide exciting prospects for exploiting and manipulating the microbiome to improve our health.
Infectious Disease Advisor: Regarding HIV, does the virus itself interact with the human microbiome in either direction?
Dr Klatt: HIV infection is associated with alterations in the gut microbiome, which occur early in the course of infection and are not fully restored with antiretroviral therapy. Mucosal HIV replication and consequent depletion of CD4+ T cells in the gut is associated with epithelial barrier damage (leaky gut) and increased translocation of bacterial products from the gut into systemic blood circulation (microbial translocation). In turn, microbial translocation is associated with systemic immune activation and predicts disease progression and mortality in both untreated and treated HIV-infected individuals.4,5 However, the interactions between HIV, antiretroviral therapy, human sexual behavior, and the gut microbiome are complex and sorting out these interactions will be important to design future interventions. Also, the effect of HIV on the microbiome in other mucosal sites (eg, genital tract, oral) is not as well studied.
Infectious Disease Advisor: You recently published a paper in Science demonstrating that tenofovir efficacy in women depends on the composition of the vaginal microbiome.6 Can you tell us a little more about this study?
Dr Klatt: In our paper, we used stored samples from 688 women enrolled in the CAPRISA 004 clinical trial to investigate whether the composition of the vaginal microbiome modulates the microbicide efficacy of tenofovir gel used as pre-exposure prophylaxis (PrEP) to prevent HIV infection. In this study, cervicovaginal lavages from women who were assigned to either the tenofovir or the placebo-gel arm were analyzed by protein mass spectrometry and 16s ribosomal RNA sequencing. Our data suggest that women with non-Lactobacillus-dominant vaginal flora have decreased efficacy of tenofovir-based mucosal preventions. On the other hand, bacterial communities rich in Lactobacillus may improve efficacy of topical microbicide gels. Importantly, we found that the mechanism underlying this altered efficacy is likely that dysbiotic bacteria such as Gardnerella vaginalis can directly metabolize tenofovir, likely leading to ineffective levels of tenofovir gel in women with these bacteria. Vaginal microbiota screening could be a useful tool to enhance efficacy of HIV prevention in women.