Archary, Derseree.

Kwon, Douglas S.

Liebenberg, Lenine Julie.

Sivro, Aida.

Editorial summary Advances in molecular tools to characterize the microbiome have led to the discovery of unique roles for microbes in human disease. Findings that the female genital microbiome can influence HIV acquisition and prevention emphasize the importance of microbiome analysis in clinical trials that assess the efficacy of HIV prevention interventions

Lenine J. P. Liebenberg

Derseree Archary

Aida Sivro

Douglas S. Kwon

Directory of Open Access Journals

Genome Medicine

Bugs, drugs, and HIV: the role of the vaginal microbiome in HIV risk and antiretroviral efficacy for HIV prevention

Liebenberg, Lenine J. P.

Archary, Derseree

Sivro, Aida

Harvard University - DASH 

ResearchSpace@UKZN

Liebenberg et al. Genome Medicine  (2017) 9:74 DOI 10.1186/s13073-017-0469-2COMMENT Open AccessBugs, drugs, and HIV: the role of thevaginal microbiome in HIV risk andantiretroviral efficacy for HIV preventionLenine J. P. Liebenberg1,2*†, Derseree Archary1,2†, Aida Sivro1† and Douglas S. Kwon3,4*†Editorial summaryAdvances in molecular tools to characterize themicrobiome have led to the discovery of unique rolesfor microbes in human disease. Findings that thefemale genital microbiome can influence HIVacquisition and prevention emphasize the importanceof microbiome analysis in clinical trials that assess theefficacy of HIV prevention interventions.Genital inflammation and HIV acquisition riskPartial HIV protection demonstrated by theCAPRISA 004 vaginal microbicideGlobally, more than 90% of HIV is transmitted followingheterosexual sex. Young women in sub-Saharan Africa rep-resent a key target population for the development of newmethods for HIV prevention, given that HIV prevalence issignificantly higher in this population compared with youngmen [1]. In the absence of a vaccine or cure for HIV, em-phasis has been placed on developing other biomedicaltools that women can use to prevent HIV infection, such asvaginal microbicides, oral pre-exposure prophylaxis (PrEP),and better treatments for sexually transmitted infections.The Centre for the AIDS Programme of Research in SouthAfrica (CAPRISA) 004 study was a double-blind, random-ized, placebo-controlled trial conducted in KwaZulu-Natal,South Africa, which demonstrated that a single vaginal ap-plication of a microbicide gel containing the antiretroviral(ARV) tenofovir within 12 h before, and then after sex, re-duced HIV acquisition by 39% overall, and by 54% inwomen with high levels of gel adherence [2]. Althoughpoor adherence diminished drug efficacy in this and later* Correspondence: lenine.liebenberg@caprisa.org; dkwon@mgh.harvard.edu†Equal contributors1Centre for the AIDS Programme of Research in South Africa (CAPRISA),University of KwaZulu-Natal, Durban, South Africa3Ragon Institute of MGH, MIT, and Harvard, Harvard Medical School,Cambridge, MA, USAFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zemicrobicide trials [1], subsequent research identified genitalinflammation [3] and the genital microbiome [4] as key bio-logical factors that contributed to the efficacy of the gel.Thus, a deeper understanding of the causes of genitalinflammation and the underlying mechanisms by whichvaginal bacteria might lead to reduced efficacy of ARV-based strategies for PrEP is needed to produce effectiveHIV prevention modalities.During sexual transmission of HIV, productive infectionis facilitated by micro-abrasions in the mucosal barrierand access to local activated CD4+ T cells (HIV targetcells). Genital cytokine biomarkers of inflammation havebeen associated with both the number of local targetcells and the potential to compromise the ability of thegenital mucosa to serve as an effective barrier to HIVinfection [5]. The combined effect of genital inflamma-tion on mucosal barrier integrity and HIV target cellnumbers likely contributes to the association of genitalinflammation and infection by less-infectious HIVvariants [6]. Recent findings have suggested that vaginalbacteria could be an important underlying contributorto baseline inflammation and HIV risk in women livingin sub-Saharan Africa.The vaginal microbiome and HIV riskIncreasing evidence suggests that microbial communitiesin the female genital tract could directly impact genitalinflammation and HIV acquisition risk. A study by Gos-mann et al. [7] showed that young South African womenwith diverse vaginal microbial communities and lowLactobacillus abundance acquired HIV at over four-foldhigher rates than those with L. crispatus dominance.Diverse vaginal microbial communities were closelyassociated with elevated genital inflammatory cytokinesand cervical HIV target cells, which probably contrib-uted to increased susceptibility to HIV. Furthermore,le is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.Liebenberg et al. Genome Medicine  (2017) 9:74 Page 2 of 390% of white women in developed countries haveLactobacillus-dominant vaginal communities [8], whereasthe majority of South African women were found to havelow Lactobacillus abundance without clinical indication ofbacterial vaginosis, which highlights the importance ofgeography in defining what constitutes a ‘normal’ vaginalenvironment. Furthermore, behavioral, genetic and envir-onmental factors are also likely to impact the effect of thevaginal microbiome on HIV risk. For example, the use ofvaginal products for hygiene or for dry vaginal secretions toincrease sexual pleasure has been reported to be commonin several sub-Saharan African countries. These productsmight cause changes in vaginal pH and the microbiome,lead to increased inflammation, and disrupt the vaginal–epithelial barrier, which could impact HIV risk and micro-bicide efficacy in women [9].A role for Lactobacillus dominance in improvingthe efficacy of vaginal tenofovir gelRecent findings by Klatt et al. [4] demonstrate that the va-ginal microbiome can modulate the efficacy of topicaltenofovir and suggests a novel mechanism for this rela-tionship. Klatt et al. [4] utilized a metaproteomics ap-proach to classify the host–microbial proteome ofcervicovaginal lavage specimens from CAPRISA 004 par-ticipants. The authors identified two major bacterial com-munities based on relative microbial abundance: aLactobacillus-dominant community, and a diverse, non-Lactobacillus-dominant community. Notably, the authorsdemonstrated that, in women with a Lactobacillus-dominant community, the risk of HIV acquisition was re-duced by 61% using the tenofovir gel, whereas no signifi-cant HIV protection was observed in those with a vaginalmicrobiome dominated by non-Lactobacillus species. Fur-thermore, Klatt et al. [4] observed higher levels of genitaltenofovir in women with Lactobacillus dominance thanthose who had non-Lactobacillus dominance, and attrib-uted this to metabolism of tenofovir by Gardnerella vagi-nalis present in those with non-Lactobacillus-dominantcommunities. However, these observations might applyspecifically to topical tenofovir-based microbicides, as bac-terial vaginosis-associated bacteria appear to have no im-pact on the ability of oral tenofovir to protect womenfrom HIV acquisition [10]. Future work is needed to betterunderstand the specific bacterial community functionsthat potentially enable ARV metabolism. Additionally, acloser examination of the mechanism of host sensing ofvaginal bacterial communities that lead to increased HIVacquisition risk might help identify novel targets to reducethis risk.Future considerationsResearch on the relationship between the genital micro-biome and HIV risk has raised several key considerationsfor future investigations. Klatt et al. [4] combined theuse of proteomics and genomics platforms to classify va-ginal bacterial communities in the absence of clinicalmeasures of bacterial vaginosis such as the Nugentscore. Despite good concordance between the proteomicfootprint and 16S rRNA gene sequence data for somebacterial taxa, 16S rRNA analysis revealed diversity inthe Lactobacillus-dominant group that the proteomicsdata could not resolve, which raises concerns aboutwhether these approaches are adequate at this time tofully unravel the complexities of vaginal microbial com-munities. Further annotation of proteomic databases forthe specific purposes of bacterial identification will helpimprove this approach and enable the simultaneousidentification of downstream bacterial effectors. Comple-mentary methodologies such as host single-cell tran-scriptomics, microbial metagenomics, and metabolomicswill help assess the impact of the vaginal microbiome ongenital inflammation, HIV risk, and PrEP efficacy. TheKlatt et al. study [4] identified an in vitro impact of spe-cific bacteria on drug metabolism, but the contributionin the context of a community of bacteria in the vaginais less established – as is the effect of various bacterialproducts on the mucosal environment. A further oppor-tunity for investigation is longitudinal analysis of vaginalbacterial community dynamics, particularly given the in-fluence of the menstrual cycle, endogenous hormones,hormonal contraceptives, and vaginal insertive practices.Recent studies on the vaginal microbiome highlightthe complexities of host–microbial interactions in the fe-male genital tract and underscore the need for a deeperunderstanding of the interplay between the microbiome,host immune responses and bacterial metabolic func-tion, and its impact on HIV acquisition risk. It will beimportant to understand whether the vaginal micro-biome can be used to identify individuals at high risk ofHIV acquisition or PrEP failure so that more-intensivemeasures to reduce risk can be taken. Ultimately, adeeper understanding of the vaginal microbiome mightprovide an opportunity to manipulate these communi-ties to create durable alterations that decrease HIVacquisition risk, particularly in vulnerable women livingin sub-Saharan Africa.AbbreviationsARV: Antiretroviral; CAPRISA: Centre for the AIDS Programme of Research inSouth Africa; PrEP: Pre-exposure prophylaxisAuthors’ contributionsAll authors read and approved the final manuscript.FundingThe following establishments provided research and salary support: theDST-NRF Centre of Excellence in HIV Prevention (LJPL, DA, AS), the NationalResearch Foundation of South Africa (LJPL, DA), the Poliomyelitis ResearchFoundation (DA), the Burroughs Wellcome Fund (DSK), and NIAID (DSK).Liebenberg et al. Genome Medicine  (2017) 9:74 Page 3 of 3Competing interestsNone of the authors were involved in the work in reference [4], although LL,DA and AS work at CAPRISA. The authors declare that they have nocompeting interests.Author details1Centre for the AIDS Programme of Research in South Africa (CAPRISA),University of KwaZulu-Natal, Durban, South Africa. 2Department of MedicalMicrobiology, University of KwaZulu-Natal, Durban, South Africa. 3RagonInstitute of MGH, MIT, and Harvard, Harvard Medical School, Cambridge, MA,USA. 4Division of Infectious Diseases, Massachusetts General Hospital, Boston,MA, USA.References1. Kharsany AB, Karim QA. HIV infection and AIDS in Sub-Saharan Africa:Current status, challenges and opportunities. Open AIDS J. 2016;10:34–48.2. Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C,Mansoor LE, et al. Effectiveness and safety of tenofovir gel, an antiretroviralmicrobicide, for the prevention of HIV infection in women. Science.2010;329(5996):1168–74.3. Masson L, Passmore JA, Liebenberg LJ, Werner L, Baxter C, Arnold KB, et al.Genital inflammation and the risk of HIV acquisition in women. Clin InfectDis. 2015;61(2):260–9.4. Klatt NR, Cheu R, Birse K, Zevin AS, Perner M, Noël-Romas L, et al. Vaginalbacteria modify HIV tenofovir microbicide efficacy in African women.Science. 2017;356(6341):938–45.5. Arnold KB, Burgener A, Birse K, Romas L, Dunphy LJ, Shahabi K, et al.Increased levels of inflammatory cytokines in the female reproductive tractare associated with altered expression of proteases, mucosal barrierproteins, and an influx of HIV-susceptible target cells. Mucosal Immunol.2016;9(1):194–205.6. Selhorst P, Masson L, Ismail SD, Samsunder N, Garrett N, Mansoor LE, et al.Cervicovaginal inflammation facilitates acquisition of less infectious HIVvariants. Clin Infect Dis. 2017;64(1):79–82.7. Gosmann C, Anahtar MN, Handley SA, Farcasanu M, Abu-Ali G, Bowman BA,et al. Lactobacillus-deficient cervicovaginal bacterial communities areassociated with increased HIV acquisition in young South African women.Immunity. 2017;46(1):29–37.8. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, et al. Vaginalmicrobiome of reproductive-age women. Proc Natl Acad Sci U S A.2011;108 Suppl 1:4680–7.9. Myer L, Kuhn L, Stein ZA, Wright Jr TC, Denny L. Intravaginal practices,bacterial vaginosis, and women's susceptibility to HIV infection:epidemiological evidence and biological mechanisms. Lancet Infect Dis.2005;5(12):786–94.10. Heffron R, McClelland RS, Balkus JE, Celum C, Cohen CR, Mugo N, et al.Efficacy of oral pre-exposure prophylaxis (PrEP) for HIV among women withabnormal vaginal microbiota: a post-hoc analysis of the randomised,placebo-controlled Partners PrEP Study. Lancet HIV. 2017. doi:10.1016/S2352-3018(17)30110-8.

Bugs, drugs, and HIV : the role of the vaginal microbiome in HIV risk and antiretroviral efficacy for HIV prevention.

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Bugs, drugs, and HIV : the role of the vaginal microbiome in HIV risk and antiretroviral efficacy for HIV prevention.

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