P12.10
Background: Elucidating the mechanisms underlying the natural control of HIV-1 mother to child transmission during the first trimester of pregnancy may help determine biologic correlates of protection against HIV-1 transmission in human mucosa. The decidua basalis (uterine mucosa) is the main materno-fetal interface.
Decidual macrophages (dM) and natural killer (dNK) express functionnal TLR7/8. Since HIV-1 ssRNA encodes for TLR 7/8 ligands that can mediate direct activation of the immune system, we investigated the potent role of TLR7/8 in the control of HIV-1 infection in the decidua.
Methods: Deciduas were obtained from HIV-1 negative women undergoing elective abortions (8–12 weeks of amenorrhea). Decidual explants or purified dM were stimulated with R848 (TLR7/8 ligand). The culture supernatants were collected for soluble factor quantification. The explants and dM were then used for flow cytometry experiments or infected with R5 HIV-1 or HIV-1/VSV-G-luciferase pseudotype. HIV-1 entry was assessed by supernatant transfer experiment. Postentry steps were investigated by PCR quantification. The role of R848 on the dNK cytotoxic potential was measured by flow cytometry.
Results: HIV-1 replication was blocked efficiently in decidual explants or purified dM when R848 was added prior to infection and to a lesser extent when added several days after infection. Stimulated explants and dM produced high levels of MIP-1α, MIP-1β and Rantes and decreased significantly the expression of HIV-1 coreceptors. HIV-1 entry was inhibited by decidual soluble factors. The number of proviral copies was decreased in stimulated dM. TLR7/8 stimulated dM activated indirectly dNK cytotoxicity.
Conclusions: Our findings provide evidence that TLR7/8 exerts a durable and long lasting anti-HIV-1 effect by targeting several steps of HIV-1 replication cycle and by activating the immune system.These findings could provide strategies for blocking HIV-1 infection of mucosa.
