Search

Half of the people living with HIV are women. Younger women remain disproportionally affected in endemic areas, but infection rates in older women are rising worldwide. The vaginal microbiome influences genital inflammation and HIV infection risk. Multiple factors, including age, induce vaginal microbial alterations, characterized by high microbial diversity that generate high concentrations of short-chain fatty acids (SCFAs), known to modulate neutrophil function. However, how SCFAs may modulate innate anti-HIV protection by neutrophils is unknown. To investigate SCFA-mediated alterations of neutrophil function, blood neutrophils from younger and older women were treated with SCFAs (acetate, butyrate and propionate) at concentrations within the range reported during bacterial vaginosis, and phenotype, migration and anti-HIV responses were evaluated. SCFA induced phenotypical changes preferentially in neutrophils from older women. Butyrate decreased CD66b and increased CD16 and CD62L expression, indicating low activation and prolonged survival, while propionate increased CD54 and CXCR4 expression, indicating a mature aged phenotype. Furthermore, acetate and butyrate significantly inhibited neutrophil migration in vitro and specifically reduced α-defensin release in older women, molecules with anti-HIV activity. Following HIV stimulation, SCFA treatment delayed NET release and dampened chemokine secretion compared to untreated neutrophils in younger and older women. Our results demonstrate that SCFAs can impair neutrophil-mediated anti-HIV responses.

Women acquire HIV through sexual transmission, with increasing incidence in women >50 years old. Identifying protective mechanisms in the female genital tract (FGT) is important to prevent HIV-acquisition in women as they age. Human genital and blood neutrophils inactivate HIV by releasing neutrophil extracellular traps (NETs), an innate protective mechanism against HIV-infection. However, how NET formation is triggered by HIV in different tissues and whether this mechanism is affected by aging remain unknown. We demonstrate that the mechanisms that trigger NET release in response to HIV are different in blood and genital tissues, and that NET release decreases with aging. In blood neutrophils, HIV stimulation independently activated calcium pathways and endosomal TLR8, but aging reduced calcium responses, resulting in delayed NET release. In contrast, calcium responses were absent in genital neutrophils and NET release was triggered preferentially through TLR8 activation, but aging impaired this pathway. HIV induced NET formation through non-lytic pathways in blood and FGT neutrophils, except for a small subset of NETs that incorporated annexin V and lactoferrin predominantly in blood, suggesting proinflammatory and lytic NET release. Our findings demonstrate that blood neutrophils cannot model genital neutrophil responses which has important implications to understanding protection against HIV acquisition. [ABSTRACT FROM AUTHOR]