Abstract
BackgroundSexual transmission accounts for the majority of HIV-1 infections. In over 75% of cases, infection is initiated by a single variant (transmitted/founder virus). However, the determinants of virus selection during transmission are unknown. Host cell-cell interactions in the mucosa may be critical in regulating susceptibility to infection. We hypothesized in this study that specific immune modulators secreted by uterine epithelial cells modulate susceptibility of dendritic cells (DC) to infection with HIV-1.Methodology/Principal FindingsHere we report that uterine epithelial cell secretions (i.e. conditioned medium, CM) decreased DC-SIGN expression on immature dendritic cells via a transforming growth factor beta (TGF-β) mechanism. Further, CM inhibited dendritic cell-mediated trans infection of HIV-1 expressing envelope proteins of prototypic reference. Similarly, CM inhibited trans infection of HIV-1 constructs expressing envelopes of transmitted/founder viruses, variants that are selected during sexual transmission. In contrast, whereas recombinant TGF- β1 inhibited trans infection of prototypic reference HIV-1 by dendritic cells, TGF-β1 had a minimal effect on trans infection of transmitted/founder variants irrespective of the reporter system used to measure trans infection.Conclusions/SignificanceOur results provide the first direct evidence for uterine epithelial cell regulation of dendritic cell transmission of infection with reference and transmitted/founder HIV-1 variants. These findings have immediate implications for designing strategies to prevent sexual transmission of HIV-1.
Highlights
Since it was initially reported over 25 years ago, HIV-1 infection has remained the most challenging health issue [1]
We found a similar pattern of inhibition of dendritic cells (DC)-SIGN by conditioned medium (CM) obtained from ECC-1, a well-differentiated uterine epithelial cell line [35] (Figure S1)
To more fully define the time interval necessary for altering DC-SIGN expression, immature DC were acutely treated with CM from ECC-1 or primary uterine epithelial cells (UEC) for 48 hr prior to FACS analysis of DC-SIGN expression
Summary
Since it was initially reported over 25 years ago, HIV-1 infection has remained the most challenging health issue [1]. Whereas tangible progress has been made with regards to treatment and prevention efforts [2], there is little knowledge about the biology of sexual transmission, the predominant mode of HIV-1 acquisition [3,4]. This presents a major hurdle for strategies to reduce mucosal transmission of HIV-1, such as microbicides and vaccines. Recent studies examining sequence composition of transmitted viruses indicate that infection is initiated by a single variant in over 75% of heterosexual HIV-1 transmission [6,7,8,9,10]. We hypothesized in this study that specific immune modulators secreted by uterine epithelial cells modulate susceptibility of dendritic cells (DC) to infection with HIV-1
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