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The vaginal microbiota and susceptibility to HIV

Buvé, Annea,*; Jespers, Vickya; Crucitti, Taniab; Fichorova, Raina N.c,*

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doi: 10.1097/QAD.0000000000000432
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Differences in the epidemic spread of HIV between populations where the predominant mode of transmission is sexual intercourse can be ascribed to diversity in sexual behaviour patterns and to variations in biological and behavioural co-factors that enhance the HIV transmission probability per sexual act [1,2]. Co-factors that have been implicated in HIV transmission include the following: the stage of disease in the HIV-infected partner and his/her treatment with antiretroviral drugs; the presence of another sexually transmitted infection (STI) and bacterial vaginosis; condom use and anal intercourse; male circumcision and hormonal contraception. A commonly used estimate of the HIV transmission probability per heterosexual act, in the absence of co-factors, is 0.001. This estimate was derived from studies on HIV-discordant heterosexual couples in high-income countries. Recent meta-analyses found that the risk of HIV infection per heterosexual act is higher in low-income countries than in high-income countries, and it is not clear whether these discrepancies can be explained by variations in the prevalence of known co-factors [3,4]. The authors of the meta-analyses concluded that more research is needed to explain these divergences.

We hypothesize that variations in the composition of the vaginal microbiota may be at least partially responsible for population differences in HIV transmission probability. Here we discuss data that are in support of this hypothesis.

The vaginal microbiota: what is healthy and what is not healthy?

Until about a decade ago, studies of the vaginal microbiota relied on culture techniques. Lactobacillus species were found to be the dominant bacterial species in the healthy vaginal microbiota, ‘healthy’ being defined as the absence of vaginal discharge or other symptoms of vaginitis and a low pH. The development of molecular techniques and especially pyrosequencing has increased our understanding of the complexity of the vaginal microbiota. It appears that there is no single ‘healthy’ vaginal microbiota formula, but that a variety of compositions of the vaginal microbiota can be found in healthy, asymptomatic women of reproductive age. According to two studies, a sizeable proportion of healthy women (20–27%) have a vaginal microbiota that is not dominated by lactobacilli [5,6]. Furthermore, those studies found that vaginal microbial communities that are not dominated by lactobacilli were more frequently found in African-American and Hispanic women than in Caucasian and Asian women [5,6]. Important variations also exist in the vaginal microbiota that are dominated by Lactobacillus spp. Ravel et al.[5] distinguished five community groups, four of which were dominated by Lactobacillus spp., including L. crispatus (group I), L. gasseri (group II), L. iners (group III) and L. jensenii (group V).

Prospective studies of women who frequently took a vaginal swab found more or less large variations in the composition of the vaginal microbiota over the course of the menstrual cycle [7–9]. During menses, the concentration of Gardnerella vaginalis appears to increase, whereas the concentration of L. crispatus decreases, suggesting that during menses, women are especially vulnerable to disturbances of the vaginal microbiota. A possible explanation would be that oestrogen levels and glycogen production are at their lowest during menses, which would hamper the growth of the lactobacilli, whereas the iron in the menstrual blood stimulates the growth of G. vaginalis[7]. Likewise, changes in the oestrogen levels and related vaginal mucosal changes may be responsible for variations in the vaginal microbiota over the lifetime of women. Pre-pubertal girls and post-menopausal women have a vaginal microbiota that is characterized by less lactobacilli as compared with women of reproductive age [10].

Clinical criteria are used to distinguish between healthy vaginal microbiota and disturbed vaginal microbiota. Bacterial vaginosis, worldwide the most common cause of vaginal symptoms, is usually diagnosed in clinical settings using Amsel's clinical criteria [11]. In research settings, the scoring system developed by Nugent et al.[12] is considered the gold standard for the diagnosis of bacterial vaginosis. It consists of semi-quantifying the lactobacilli and bacterial vaginosis-related bacterial morphotypes in a Gram-stained smear of the vaginal fluid. Each morphotype is scored according to the number observed per field. The sum of the different scores is interpreted according to a scale ranging from normal (score = 0–3) through intermediate (score = 4–6) to bacterial vaginosis (score = 7–10). The ‘intermediate vaginal microbiota’ is characterized by a decreasing number of lactobacilli and an increasing number of anaerobes. This condition is transient and can revert back to a normal microbiota dominated by lactobacilli, or evolve to bacterial vaginosis with disappearance of the lactobacilli and replacement by anaerobic bacteria [13]. Using molecular techniques, a wide range of microorganisms have been detected that are associated with disturbances of the vaginal microbiota, in particular bacterial vaginosis. In fact, bacterial vaginosis is also known as polybacterial dysbiosis because of the higher bacterial diversity associated with a higher Nugent score [5,14,15]. The microorganisms found to be associated with bacterial vaginosis include G. vaginalis, Atopobium vaginae, Prevotella spp., Leptotrichia spp., Megasphaera spp., Eggerthella spp., Dialister spp., Bifidobacterium spp., Slackia spp. and bacteria of the Clostridium phylum (BVAB1, BVAB2, BVAB3) [16–19]. Of these microorganisms, G. vaginalis has been proposed as sexually transmitted, causative agent of bacterial vaginosis [20]. This seems to contradict studies that have found G. vaginalis to be present in women without bacterial vaginosis as assessed by the Nugent score [5,9,21] unless one accepts that there are differences in virulence between different strains of G. vaginalis[22].

In conclusion, we do not yet have clear criteria to determine what is a healthy vaginal microbiota. Ma et al.[23] propose to further characterize the function of the vaginal ecosystem and to define disturbances or ‘unhealthy’ vaginal microbiota on the basis of functional criteria.

The protective role of the normal vaginal microbiota

The healthy vaginal microbiota plays an essential role in the natural defence system against HIV and other STIs. Several mechanisms have been identified or postulated, including antagonisms between microbiota constituents, direct microbicidal action of bacteria-derived substances, and bacterial-host cross-talk leading to changes in the host immune function.

Cumulative clinical and experimental evidence suggests that a group of vaginotropic Lactobacillus species hamper bacterial colonization and survival of urogenital pathogens, for example, Escherichia coli, Candida albicans, Staphylococcus aureus, group B streptococci and Neisseria gonorrhoeae, by producing synergistic microbicide factors such as H2O2, bacteriocins and lactic acid, and likely more mediators yet to be identified [24–28]. The lack of H2O2-producing lactobacilli associated with bacterial vaginosis has been regarded as a particular risk of HIV acquisition and transmission given the fact that H2O2, especially in combination with host-derived peroxidases and halides, is virucidal to HIV in vitro[29]. However, the powerful microbicidal properties of H2O2 and its efficiency in suppressing the growth of bacterial vaginosis bacteria are reduced in the context of human vaginal fluid and semen, possibly due to naturally occurring antioxidants [30,31]. In contrast, the lactic acid has powerful microbicidal properties against HIV and bacterial vaginosis bacteria that are maintained in the context of the vaginal fluid as long as the pH is acidic [30,32,33].

In addition to their direct microbicidal properties, some of these Lactobacillus-produced factors stimulate signalling and immune responses by the cervical and vaginal epithelial cells. For example, the L-isomer of lactic acid, produced by a number of vaginal bacteria and the human vaginal epithelial cells, correlates with metalloproteinase levels in the vaginal secretions in vivo[34]. In vitro, it stimulates the IL23/IL17 lymphocyte pathway in the presence of lipopolysaccharide and acidic pH [35], and also enhances immune responses to viral RNA by the vaginal epithelial cells [36]. Lactobacilli also have been shown to suppress various checkpoints of pro-inflammatory signalling by intestinal epithelial cells by cross-talk mediators yet to be defined [37–39].

The microbiota that is classified as bacterial vaginosis and intermediate flora by Nugent scoring has been associated with a myriad of disturbances of the vaginal innate immunity [40–42]. In experimental models, in contrast to dominant vaginal lactobacilli, bacterial vaginosis-associated bacteria G. vaginalis, A. vaginae and Prevotella bivia trigger pro-inflammatory cascades including nuclear factor–kappa B (NF-kB) and differential downstream up-regulation of cytokines and chemokines by human vaginal and cervical epithelial cells [43–47]. Importantly, P. bivia has immunosuppressive effects, reducing levels of immunoregulatory chemokines, whereas A. vaginae and G. vaginalis amplify inflammatory chemokine responses to other STI pathogens, for example, Trichomonas vaginalis and its endosymbiont viruses [45]. These pro-inflammatory and immunosuppressive effects of the bacterial vaginosis-associated bacteria could enhance the risk of HIV transmission per sexual act by recruitment and activation of CD4+-positive HIV host cells at the mucosal interface and by direct up-regulation of the HIV replication cycle [48–50].

The experimental evidence of immune modulation by vaginal bacteria is supported by growing clinical evidence. In addition to the increased levels of cytokines that can promote HIV replication, for example, IL-1β, bacterial vaginosis has been associated with increased vaginal levels of heat shock protein (hsp)70 and correlating increased levels of nitric oxide, known to be stimulated by hsp70 [51]. Nitric oxide is a double-sword immune factor with protective wide-range microbicidal activity, and also with unwanted tissue damaging, pro-inflammatory and immunosuppressive effects [52].

Among the most concerning effects of bacterial vaginosis is the suppression of protective innate immunity effectors and, in particular, the secretory leukocyte protease inhibitor (SLPI) [40,53]. SLPI has direct HIV inhibitory properties in vitro[54]. Vaginal SLPI levels are reduced in women with STIs [40,55,56] and reduced levels of SLPI are associated with higher probability of HIV acquisition [57]. Thus, apart from directly suppressing SLPI, by increasing the risk of STIs, bacterial vaginosis has an additional indirect negative effect on SLPI and the associated risk of HIV acquisition.

Disturbances of the vaginal microbiome and transmission of HIV and other sexually transmitted infections

Since the 1990s, numerous epidemiological studies have explored the association between bacterial vaginosis and HIV infection. In 2008, a meta-analysis was published which included 23 papers up to the end of 2005 [58]. Three of these papers reported on longitudinal studies that could establish the temporal relationship between bacterial vaginosis and HIV acquisition. The summary relative risk of incident HIV infection associated with bacterial vaginosis was estimated at 1.6 [95% confidence interval (CI) 1.2–2.1]. Using the same key words as Atashili et al. we searched the PubMed and retrieved another five papers that were published after 2005 and that reported on longitudinal studies (Table 1). One of these publications was a meta-analysis of data from 13 prospective studies [59]. All studies found a statistically significant association between incident HIV infection and bacterial vaginosis at baseline or a visit close to the HIV-seroconversion visit. The adjusted hazard ratios ranged from 1.5 to 2.1 [59–62]. Three of the studies also considered intermediate flora, defined as a Nugent score of 4–6 on a Gram-stained vaginal smear, and in two of these studies acquisition of HIV infection was significantly associated with intermediate flora with adjusted hazard ratios of 1.4 and 2.0 [59,61,62].

Table 1:
Effect of bacterial vaginosis/intermediate flora on the risk of HIV acquisition.

There is also growing evidence from epidemiological studies for an association between bacterial vaginosis and acquisition of other STIs, in particular, herpes simplex virus 2 (HSV-2) infection, T. vaginalis and, more recently, human papilloma virus (HPV) infection. The hazard ratios for incident HSV-2 infection associated with bacterial vaginosis ranged from 1.6 to 2.4 [63–65]. Rathod et al. found bacterial vaginosis to be associated with a nine-fold increased risk of acquiring T. vaginalis infection, whereas other studies found a hazard ratio around 2 [66–68]. Brotman et al.[67] in their longitudinal study of more than 3000 women in Alabama also found an increased risk of gonorrhoea and of chlamydial infection associated with bacterial vaginosis. Two longitudinal studies that explored the association between bacterial vaginosis and incident HPV infection found odds ratios (ORs) of 1.2 and 1.4 [69,70]. Furthermore, King et al.[70] found bacterial vaginosis to be associated with delayed clearance of HPV.

It is well established that HSV-2 infection, gonorrhoea, chlamydial infection and trichomoniasis increase the risk of HIV acquisition. As bacterial vaginosis increases the risk of these infections, the association between bacterial vaginosis and incident HIV infection might be confounded (and overestimated) by the association between bacterial vaginosis and other STIs, especially HSV-2, which is a strong co-factor in the transmission of HIV [71]. More recent studies, however, adjusted for potential confounding by HSV-2 and found adjusted hazard ratios for incident HIV infection associated with bacterial vaginosis, in the range of 1.5–2.1 (Table 1). The trial by Reid et al.[62] was conducted among female sex workers who were all HSV-2-infected, and also this prospective study found an increased risk of HIV infection associated with bacterial vaginosis, independent of HSV-2 infection. One can thus conclude that bacterial vaginosis has a direct effect on HIV acquisition and an indirect effect through its association with other STIs.

Lastly, there is growing evidence that bacterial vaginosis enhances onward transmission of HIV from women to their male partners. A longitudinal study among HIV-discordant couples found an increased risk of female-to-male transmission if the female partner had bacterial vaginosis [72]. Indirect evidence of increased female-to-male transmission associated with bacterial vaginosis is provided by a study of HIV genital shedding among women in Burkina Faso who were on antiretroviral treatment [73].

Prevalence of bacterial vaginosis in different populations across the world

In 2013, a review was published of data on the prevalence of bacterial vaginosis in different countries across the world [74]. We used this review as a basis to try and compare the prevalence of bacterial vaginosis in different parts of the world and discern a pattern. We completed the review by Kenyon et al. by searching the PubMed for additional papers. In order to minimize bias in the selection of the study participants, we only considered population-based studies that included women who were not at particular risk of STIs, and studies among pregnant women. We excluded studies among women who were symptomatic and/or were HIV-infected. Inequalities in the performance of techniques to assess bacterial vaginosis can make comparison of prevalence data difficult and therefore we only considered studies that used the Nugent score. However, we made an exception for China as large-scale population-based studies have been reported from this country.

Table 2 gives an overview of the prevalence of bacterial vaginosis in different parts of the world. The lowest prevalence rates were found in Western Europe with the exception of the population of Greenland, which also has a high prevalence of other STIs. Most studies from Asia found prevalence rates that were somewhat higher than in Europe – between 10 and 20%. Several large-scale studies have been reported from China, but they used Amsel's criteria to diagnose bacterial vaginosis. A study among more than 53 000 women in rural China found a prevalence of bacterial vaginosis of 12% [113], which is probably an underestimate as the sensitivity of the Amsel's criteria to detect bacterial vaginosis is lower than the Nugent score. The prevalence rates in the Americas varied widely from 5.8% in pregnant women in Philadelphia in the United States to 40.8% among women from communities in the jungle of Peru and 49.1% in Jamaica. Overall, a high prevalence of bacterial vaginosis was found in sub-Saharan Africa, especially South and Eastern Africa. Among pregnant women in Jamaica, the prevalence of bacterial vaginosis was similar to the prevalence among pregnant women in South Africa and in Uganda. Likewise, a high prevalence was found in African-American women in the general population in the United States – 51.4 versus 31.9% in Hispanic women and 23.2% in non-Hispanic white women [75]. Among pregnant women in London, the overall prevalence of bacterial vaginosis was 14.5%, but it was 33.6% among Afro-Caribbean and African women [101].

Table 2:
Prevalence of bacterial vaginosis among women from the general population and among pregnant women in different parts of the world.

In conclusion, there seems to be an association between bacterial vaginosis and ethnic background, with the highest prevalence rates of bacterial vaginosis found in black populations that are in general heavily affected by the HIV epidemic. In addition, isolated communities of low socio-economic status, such as the communities in the studies from Peru and from Greenland, also appear to be more affected by bacterial vaginosis.

What are the risk factors for bacterial vaginosis and can they explain the variations in prevalence between different populations?

Whether bacterial vaginosis is an STI on its own is a matter of debate [114,115]. Several risk factors related to sexual behaviour have been identified that are consistent with bacterial vaginosis being an STI. Bacterial vaginosis has been found to be associated with acquisition of a new sex partner and number of sex partners, male or female, whereas condom use has been found to be protective [114]. Other arguments in favour of bacterial vaginosis being an STI are the concordance of the vaginal microbiota in couples of women who have sex with women [116] and the protective effect of male circumcision against bacterial vaginosis in their female partners [117]. Furthermore, bacteria that have recently been found to be associated with bacterial vaginosis in women including BVAB2, BVAB3, Megasphaera and Leptotrichia/Sneathia spp., have been detected in male urine and were associated with urethritis [118].

There is some evidence that suggests that other STIs, in particular, HSV-2 infection enhance the risk of bacterial vaginosis [119,120]. The association between high-risk sexual behaviour and bacterial vaginosis may thus, in part, be confounded by other STIs as was illustrated in the study by Cherpes et al.[119]. They found that incident bacterial vaginosis was associated with number of sex partners in univariate analysis, but after adjusting for HSV-2 infection, this association was not statistically significant anymore, whereas there was a significant association between positive HSV-2 serology and incident bacterial vaginosis [119]. Furthermore, data from experimental and clinical research suggest that T. vaginalis alters the composition of the vaginal microbiota toward a bacterial vaginosis state and that endosymbionts carried by T. vaginalis promote survival of bacterial vaginosis-associated bacteria [45,121,122].

Clinical data also support an argument that bacterial vaginosis is an opportunistic reproductive tract infection rather than a classic STI. So far, no causative agent for bacterial vaginosis has been identified that is transmitted between sex partners and treatment of male partners of women with bacterial vaginosis fails to decrease recurrences [123]. Furthermore sexual practices that carry a minimal risk of transmission of an STI are associated with bacterial vaginosis, including receptive oral sex and non-penetrative digital–genital contact [124]. Another argument against bacterial vaginosis being an STI is the observations of bacterial vaginosis in sexually inexperienced women. Table 3 gives an overview of studies that have compared the prevalence of bacterial vaginosis in virgins and sexually active women. These data, however, have to be interpreted with caution as the validity of self-reported sexual behaviour is low. Possible explanations for the occurrence of bacterial vaginosis in these women include oral sex, and douching or other intra-vaginal practices. Regarding the latter risk factors, the evidence is not conclusive, as some studies have found an association with bacterial vaginosis that is not confirmed by the other studies [59,129–131]. In conclusion, data do suggest that high-risk sexual behaviour, that is having multiple sex partners, does not per se increase the risk of bacterial vaginosis, but that the risk is rather increased by sexual activity and interference with the vaginal mucosa. This led Verstraelen et al.[115] to coin the term ‘sexually enhanced disease’. The complex relationship between disturbances of the vaginal microbiota, sexual behaviour, STIs, and HIV risk is presented in Fig. 1.

Table 3:
Prevalence of bacterial vaginosis in women who reported that they never had sexual intercourse vs. women who had passed their sexual debut.
Fig. 1:
Schematic representation of risk factors for disturbances of the vaginal microbiota and risk of HIV.

There is now compelling evidence that oral and injection/implant hormonal contraceptives is protective against bacterial vaginosis [132]. This is all the more interesting as the use of injectable hormonal contraceptives has been found to be associated with an increased risk of HIV acquisition in some but not all observational studies [133], and both injectable and oral contraceptives have been associated with untoward pro-inflammatory changes in the cervical immune mediator levels [57].

Studies from the United States have consistently found bacterial vaginosis by classic Nugent score to occur more frequently in African-American women. These racial characteristics in occurrence of bacterial vaginosis apparently cannot be fully explained by known risk factors, including sexual behaviour, presence of another STI, smoking, contraceptive use, douching and socio-economic status [75,134]. But studies that used culture-independent techniques to characterize the vaginal microbiota have found racial differences in the composition of the ‘healthy’ vaginal microbiota [5,6], healthy African-American women having more often a vaginal microbiota that is not dominated by lactobacilli as compared to Caucasian women. Zhou et al. hypothesized that healthy African-American women have more often a vaginal microbiota that is less resilient to stress than Caucasian women. Ravel et al.[5] found that a vaginal microbiota that is dominated by L. crispatus is less frequent in African-American women than in Caucasian women, whereas this type of microbiota has been found to be more stable and less prone to shifts towards a disturbed microbiota [135]. These observations need to be confirmed in larger population studies in different countries and continents. The reasons why women of different race or ethnicity may have a different composition of their vaginal microbiota and are thus more prone to disturbances of the vaginal microbiota that enhance their risk of acquiring HIV infection, are unclear. It has been hypothesized that host genetic factors may play a role among other factors, including nutrition, stress, depression and environmental exposures [5].

Interventions to reduce disturbances of the vaginal microbiota and maintain a healthy vaginal environment

In populations where the prevalence of bacterial vaginosis and intermediate flora is high, for example, in Southern Africa, a sizeable proportion of HIV infections are attributable to disturbances of the vaginal microbiota. Van de Wijgert et al.[61] estimated that in their cohort of women in Uganda and Zimbabwe, 17% of new HIV infections were attributable to bacterial vaginosis and 12% to intermediate flora. Interventions that can reduce the incidence and prevalence of disturbances of the vaginal microbiota could thus have an important impact on the spread of HIV.

Treatment of bacterial vaginosis with metronidazole was part of the STI mass treatment intervention that was tested in the randomized controlled trial in Rakai, Uganda [89]. No effect was found on the prevalence of bacterial vaginosis or on the incidence of HIV infection. The explanation has to be sought in the high recurrence rates of bacterial vaginosis after treatment, the reasons for which are not clear. Suppressive antibacterial therapy has been shown to reduce the rate of recurrences in two trials in the United States and in Kenya [136,137]. An alternative approach that may be promising is the use of probiotics, defined as ‘live microorganisms which when administered in adequate amounts confer a health benefit to the host’ [138]. In their 2009 review, Senok et al.[139] identified four randomized controlled trials of probiotics in combination with antibiotics or an estriol preparation. Results suggest a beneficial effect on the short-term cure rate of bacterial vaginosis, but the evidence was not yet strong enough to recommend probiotics for the treatment of bacterial vaginosis. A trial comparing oral metronidazole with a Lactobacillus acidophilus vaginal-probiotic containing also oestriol and oral metronidazole with 2% vaginal clindamycin cream did not find any significant effect of the interventions on the 6-month recurrence of bacterial vaginosis [140]. The challenge is in finding a strain or combination of strains that colonizes the vagina and persists after treatment [141]. Experiments with primates suggest that the way forward may be transfer of the whole vaginal content of healthy women [142]. In a primate model restoring the resistance to uropathogenic E. coli could be partially achieved by vaginal instillation of a mixture of selected lactobacilli, but fully achieved only by swabbing and transferring the whole vaginal content from healthy animals [142]. These findings underscore the importance of the integrals of bacterial communities rather than individual microbiome players.

Prevention of disturbances of the vaginal microbiota could in theory be achieved by acting on risk factors for bacterial vaginosis and intermediate flora. So far, two randomized trials have assessed the effects of a behavioural intervention on the incidence or persistence of bacterial vaginosis with disappointing results. An intervention of douching cessation found an effect on the occurrence of bacterial vaginosis only among women who reported as reason for douching cleansing after menstruation [143]. A behavioural intervention targeting women who have sex with women did not find an effect on the persistence of bacterial vaginosis, although there was an effect on their behaviour [144].


There is strong evidence that bacterial vaginosis increases the risk of acquiring HIV infection in women. Recent studies also found less severe disturbances of the vaginal microbiota, that is, intermediate flora, as assessed by the Nugent scoring system, to be associated with an increased incidence of HIV. Considering the high prevalence of disturbances of the vaginal microbiota in some populations, especially in African populations or populations from African descent, disturbances of the vaginal microbiota may play an important role in the spread of HIV. However, efforts to reduce the occurrence of bacterial vaginosis and intermediate flora are hampered by the fact that the causes and mechanisms of disturbances of the vaginal microbiota are poorly understood.

In the United States, racial differences have been found in the occurrence of bacterial vaginosis and intermediate flora that cannot fully be explained by variations in known risk factors. Studies among healthy women of different ethnic background in the United States suggest that there are racial differences in the composition of the vaginal microbiota which begs the question what is to be considered ‘healthy’ [23]. Larger population-based studies comparing functional and genetic characteristics of the vaginal microbiota in different geographic areas of the world are needed to confirm or reject differences based on host genetic background, to define ‘health’ and to establish the microbiological correlates of HIV transmission risk that may vary from one population to another. If differences are confirmed and the risk factors as well as population-specific norms are established, we would be one step closer to understanding variations in the spread of HIV.


A.B. wrote the first outline and draft. V.J. and A.B. wrote the parts on the epidemiology. T.C. and R.N.F. wrote the parts dealing with the microbiological and immunological aspects. All authors reviewed the manuscript and contributed to the conclusions.

Conflicts of interest

There are no conflicts of interest.


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      bacterial vaginosis; HIV transmission; intermediate flora; vaginal microbiome

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