Infectious Disease Advisor: Do you think that the gut microbiome could have a similar effect on oral antiretroviral therapies?
Dr Klatt: That is a good question and we currently don’t know. Further studies are ongoing to investigate the role of the gut microbiome composition in pharmacokinetics of oral antiretroviral drugs.
It is important to note that one recent study among African women with a high prevalence of bacterial vaginosis found similar efficacy of daily oral PrEP for HIV prevention among women with abnormal vs healthy vaginal microbiota as defined by Nugent score,7 suggesting that the vaginal microbiome is not negatively affecting oral PrEP. However, this needs to be further studied, considering that bacterial vaginosis testing does not accurately measure vaginal microbial dysbiosis, and this should be more carefully evaluated using 16S rRNA sequencing of the microbiome of these women.
Infectious Disease Advisor: Are there any other research questions related to the microbiome and HIV that should be considered?
Dr Klatt: For the future, we need to understand the potential role of other (less well studied) microbiomes, including both non-enteric microbial communities (different body sites) as well as other domains of life beyond bacteria. For example, fungal and viral microbiomes are critical to study. We do know that there is an expansion of the enteric virome during HIV infection, but the exact meaning of this finding is not known.8 For example, certain viruses such as bacteriophage are critical for bacterial regulation, but further studies to understand their exact function and interactions are needed. The fungal microbiome is even less well known. It is clear that fungal species are important in health and there is evidence of increased fungal products in the bloodstream of HIV-infected people, which also correlate with end-organ complications.9,10 However, measurements of these are still underway and critical to better understand the exact interplay of bacteria, viruses, and fungi within the human microbiome at each mucosal site.
The role of non-enteric microbiome is important, too. For example, one recent study found that uncircumcised men who became infected by HIV during the study period had higher levels of penile anaerobes compared with uncircumcised men who remained HIV negative. The authors also reported that having higher levels of penile anaerobes was associated with higher production of certain cytokines that can recruit HIV target cells to the foreskin, suggesting that anaerobes may modify HIV risk by triggering inflammation. These anaerobes can also be shared through heterosexual contacts. Modifying the penile microbiome could potentially reduce HIV acquisition in both men and women.11
Even more important than its composition is to understand the exact function of the microbiome. Many questions remain open and we (and other groups) are working hard to understand. For example what do bacteria, fungal, or viral species regulate and how? What bacterial products do bacteria make and how are those relevant for the human host? How do they regulate immunity and epithelial barrier function? How do different bacteria affect drug disposition? Currently, many of these questions do not have clear answers, and many studies are underway and still needed to better understand these questions.
Infectious Disease Advisor: Is there anything we can do (or not do) to maintain a healthy microbiome? Can we correct the microbiome in HIV-infected people using some medications or transplant the “good germs?”
Dr Klatt: The microbiome is very difficult to manipulate. Antibiotics can briefly alter the microbiome, typically with negative consequences for the immune system, and can lead to complications such as Clostridium difficile infection. Once the microbiome is dysbiotic (perturbation of the microbiome, for example in the setting of HIV infection), it is very difficult to revert. Probiotics have demonstrated some encouraging results; however, there is a great variability in different probiotics and how beneficial they are. To date, the best clinical data has come from use of VisbiomeÒ, currently used in an AIDS Clinical Trial Group trial (ClinicalTrials.gov identifier: NCT02706717) to decrease inflammation in HIV-infected individuals. Over-the-counter products such as CulturelleÒ may also have benefits, however, these have not been proven clinically and it is likely that daily dosing is needed to be effective. Alternatives include fecal transplants, but these are quite invasive and have only shown some efficacy in the case of single organism diseases such as C difficile or vancomycin-resistant enterococci infections. The results of fecal transplant in the setting of HIV infection have been variable and are probably not the best approach currently. Early initiation of antiretroviral therapy can partially prevent mucosal damage, although there is evidence that this happens very early during the course of infection.12
We critically need better approaches to enhance the microbiome to improve health in patients with HIV.
- Gupta VK, Paul S, Dutta, C. Geography, ethnicity or subsistence-specific variations in human microbiome composition and diversity. Front Microbiol. 2017;8:1162.
- Chen C, Song X, Wei W, et al. The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat Commun. 2017;8:875.
- Noguera-Julian M, Rocafort M, Guillén Y, et al. Gut microbiota linked to sexual preference and HIV infection. EBioMedicine. 2016;5:135-146.
- Mudd JC, Brenchley JM. Gut mucosal barrier dysfunction, microbial dysbiosis, and their role in HIV-1 disease progression. J Infect Dis. 2016;214 Suppl 2:S58-66.
- Zevin AS, McKinnon L, Burgener A, Klatt NR. Microbial translocation and microbiome dysbiosis in HIV-associated immune activation. Curr Opin HIV AIDS. 2016;11:182-190.
- Klatt NR, Cheu R, Birse K, et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science. 2017;356:938-945.
- Heffron R, McClelland RS, Balkus JE, et al; Partners PrEP Study Team. Efficacy of oral pre-exposure prophylaxis (PrEP) for HIV among women with abnormal vaginal microbiota: a post-hoc analysis of the randomised, placebo-controlled Partners PrEP Study. Lancet HIV. 2017;4:e449-e456.
- Monaco CL, Gootenberg DB, Zhao G, et al. Altered virome and bacterial microbiome in human immunodeficiency virus-associated acquired immunodeficiency syndrome. Cell Host Microbe. 2016;19:311-322.
- Hoenigl M, de Oliveira MF, Pérez-Santiago J, et al. (1→3)-β-d-glucan levels correlate with neurocognitive functioning in HIV-infected persons on suppressive antiretroviral therapy: a cohort study. Medicine (Baltimore). 2016;95:e3162.
- Hoenigl M, Pérez-Santiago J, Nakazawa M, et al. (1→3)-β-d-glucan: a biomarker for microbial translocation in individuals with acute or early HIV infection? Front Immunol. 2016;7:404.
- Liu CM, Prodger JL, Tobian AAR, et al. Penile anaerobic dysbiosis as a risk factor for HIV infection. MBio. 2017;8 pii: 00996-17.
- Ericsen AJ, Lauck M, Mohns MS, et al. Microbial translocation and inflammation occur in hyperacute immunodeficiency virus infection and compromise host control of virus replication. PLoS Pathog. 2016;12:e1006048.