Abstract
Understanding early events of HIV transmission within mucosal tissues is vital for developing effective prevention strategies. Here, we report that primary stromal fibroblasts isolated from endometrium, cervix, foreskin, male urethra, and intestines significantly increase HIV infection of CD4+ T cells–by up to 37-fold for R5-tropic HIV and 100-fold for X4-tropic HIV–without themselves becoming infected. Fibroblasts were more efficient than dendritic cells at trans-infection and mediate this response in the absence of the DC-SIGN and Siglec-1 receptors. In comparison, mucosal epithelial cells secrete antivirals and inhibit HIV infection. These data suggest that breaches in the epithelium allow external or luminal HIV to escape an antiviral environment to access the infection-favorable environment of the stromal fibroblasts, and suggest that resident fibroblasts have a central, but previously unrecognized, role in HIV acquisition at mucosal sites. Inhibiting fibroblast-mediated enhancement of HIV infection should be considered as a novel prevention strategy.
Highlights
HIV is transmitted primarily by traversing mucosa
To determine whether endometrial stromal fibroblasts (eSF), the most abundant cells in the endometrial stroma, affect the efficiency of HIV infection of permissive cells, we infected PHA-activated PBMCs with NLENG1I in the absence or presence of a pure population of eSF (S1 Fig)
Tissue-derived CD4+ T cells, naturally permissive to infection without exogenous activation, were susceptible to eSF-mediated enhancement of HIV infection (S2 Fig)
Summary
HIV is transmitted primarily by traversing mucosa. the efficiency of sexual HIV transmission is poor, perhaps as infrequent as 1 per 1,000 episodes of sexual encounter, drivers of epithelial disruption, such as genital ulcers, markedly increase infection risk [1, 2]. Breaches in the epithelium may increase access of HIV to sub-epithelial components, including early cellular targets such as CD4+ T cells [3]. Access to this compartment increases viral contact with resident dendritic cells (DCs), which inefficiently infected, can capture virions and transfer them to CD4+ T cells by trans-infection. Upon infection or inflammation of the mucosa, iDCs differentiate into mature DCs (mDCs), which have a higher trans-infection capacity [5] and use the lectin Siglec-1 instead of DC-SIGN to mediate viral transfer [6, 7]. MDCs that migrate to lymph nodes in response to infection may fuel viral spread by forming conjugates with lymphoid CD4+ T cells [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
