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The anti-HIV activity of lactic acid and short chain fatty acids associated with eubiosis and bacterial vaginosis
thesisposted on 27.02.2017, 01:22 by Aldunate, Muriel
During eubiosis, considered to be a healthy vaginal state unique to each woman, lactic acid (LA)-producing vaginal microbiota (VMB) strongly acidify the vagina primarily with LA, to an average pH ~3.5. In contrast, the polymicrobial syndrome, bacterial vaginosis (BV), is characterised by an elevated pH and an increase in mixed short chain fatty acids (SCFAs) produced by BV-associated bacteria (BVAB). BV is considered is a major risk factor for sexually transmitted infections (STIs), including HIV. Several studies report a LA-producing VMB and acidic vaginal conditions as being associated with reduced susceptibility to HIV, whereas BV appears to increase susceptibility. Despite these observations, the potential roles of LA and SCFA metabolites in modulating HIV transmission remains largely unexplored. In this study, the anti-HIV activity of VMB acid metabolites associated with eubiosis and BV are investigated, as well as the chemical properties that confer virucidal activity and the mechanisms by which this virucidal activity is achieved. Under conditions that approximate eubiosis, LA demonstrated potent inactivation of HIV-1, whilst BV-associated SCFAs had no observable virucidal activity, under BV conditions. These findings have important implications for HIV-infected women with BV, who could have a reduced capacity to inactivate HIV, shed into the vagina when virucidal LA is replaced by non-virucidal BV-associated SCFAs. Furthermore, this could serve to explain observations of increased HIV vaginal shedding in HIV-infected women and increased likelihood of HIV transmission to their male partners. Interestingly, sexually transmitted HIV-1 strains, known to have established an infection in a new recipient (transmitted/founder), appear to have a reduced susceptibility to VMB acid metabolites. This potentially novel trait could contribute to their success in establishing new infections after sexual transmission. Evaluation of related carboxylic acids employed in a structure activity relationship analysis, revealed that anti-HIV activity was primarily associated with α-hydroxy acids, of which LA was amongst the most potent. LA also demonstrated stereochemically-dependent virucidal activity with each HIV-1 subtype having a unique inactivation profile. This suggests that inactivation is not a nonspecific phenomenon but rather susceptibility to VMB acid metabolites is influenced by viral characteristics and indicates that LA could target one or more viral proteins. Investigations of LA virucidal mechanisms showed that LA had multiple effects on HIV membrane and internal viral proteins each with varying contributions to the overall observed HIV-1 inactivation. Furthermore, the inactivation of HIV-1 by VMB acid metabolites was distinct from enveloped HSV-2 and non-enveloped HPV-16 viral STIs under these experimental conditions. Collectively, the results presented in this study suggests that LA and BV-associated SCFAs play a role in modulating HIV transmission, particularly female-to-male heterosexual transmission. By characterising the virucidal activity, chemical properties and virucidal mechanisms of VMB acid metabolites against HIV-1, new insights have been provided into how eubiosis or BV-associated VMB acid metabolites may impact HIV transmission in vivo, and revealed chemical elements which could inform the future development of improved strategies for BV management that could directly and/or indirectly protect against HIV at the vaginal mucosa, where the majority of HIV transmissions occur.