Lactic acid produced by optimal vaginal Lactobacillus species potently inactivates HIV-1 by several mechanisms including promoting inhibition of virion-associated reverse transcriptase activity and viral RNA degradation

Background. An optimal vaginal microbiota dominated by Lactobacillus spp. protects women against acquiring and transmitting HIV in contrast to a nonoptimal vaginal microbiota exemplified by bacterial vaginosis (BV); however, the virucidal activity of carboxylic acid metabolites present in vaginal fluid is not well defined. Here we determined the HIV-1 virucidal activity of lactic acid (LA), short chain fatty acids (SCFAs) and succinic acid under conditions observed in women with a Lactobacillus-dominated vaginal microbiota compared to women with BV and examined the mechanism by which LA inactivates HIV-1. The ability of LA to inactivate HSV-2 and HPV16 was also examined. Results: LA was >10-fold more potent at inactivating an HIV-1 transmitted/founder strain than SCFAs (acetic, butyric, and propionic acid) and succinic acid when tested at an equivalent 20 mM of protonated acid at pH 4.2 (p£0.05). While LA decreased HIV-1 infectivity by >10³-fold, virions were intact, expressing a similar gp120:p24 ratio, and showed a 2-fold decrease in CD4 binding compared to the untreated control (p£0.05). Treatment of recombinant gp120 with LA revealed no major conformational changes by small angle X-ray scattering. LA treatment of HIV-1 at pH 3.8 resulted in an 80% decrease in virion-associated reverse transcriptase activity compared to untreated virus, which was more potent than acetic acid or HCl-adjusted media at pH 3.8. LA decreased HIV-1 virion-associated RNA levels by ~50% compared to untreated virus (p<0.001), acetic acid or HCl acidified media, with this effect potentiated in the presence of cervicovaginal fluid. In contrast, HSV-2 virucidal activity of LA was similar to acetic acid and HCl-acidified media while HPV16 was acid-resistant. Conclusions: These findings reveal LA’s potent and specific HIV-1 virucidal activity, mediated by its membrane permeant properties, compared to SCFAs and succinic acid, with implications for the vaginal transmission of HIV-1 to partners and neonates during birth.