51,53 SEVI significantly enhances binding of wild-type HIV-1 particles and virions lacking Env, although the absolute levels of CA p24 are about 30-fold lower in the absence of Env.48 SEVI

enhances in vitro HIV infection in a dose- and time-dependent manner, and its effects are seen across different envelopes.54 Infection enhancement, however, appears to be donor dependent.54 Further experiments showed that SEVI enhanced infection with R5-, X4- and dual-tropic HIV-1 clones. Importantly, the enhancing effect of SEVI was most pronounced at low concentrations of virus, resembling conditions of sexual HIV-1 transmission.48 In general, these authors stated that SEVI may promote virus attachment to genital surfaces, penetration of the mucosal barrier, and subsequent dissemination to lymphoid organs by increasing Navitoclax manufacturer HIV-1 virion binding to epithelial cells and to migrating DCs.48 This

is in accordance with confocal microscopy data that shows the presence of seminal fluid enhances binding of virions to epithelial BMN-673 cells in ex vivo CV tissue.55 Using dose/response assays, it was determined that 1–3 virions, in the presence of SEVI, are sufficient for productive HIV-1 infection of PBMCs.48 The effect of SEVI enhancement was tested in hCD4/hCCR5-transgenic rats inoculated with either HIV-1 YU2 or SEVI-treated HIV-1.48 Tail vein inoculation with SEVI-treated HIV-1 increased the cDNA copy numbers in splenectomy extracts by fivefold.48 Further testing of SEVI in animal models is warranted, as reproducibility of the enhancing effect in vitro varies according selleck screening library to the laboratory and assay conditions employed, casting doubts about the relevance of this phenomenon. Another possible enhancing effect of semen is mediated by electrostatic interaction of spermatozoa with HIV-1 virions, involving negatively charged heparin sulfate. This complex can transmit virus directly to DC-SIGN on DCs.56 Once the spermatozoa are internalized by DCs, the DCs undergo phenotypic maturation and produce IL-10.56 Other receptors on spermatozoa may also be involved. Roan et al.51 hypothesized that SEVI, because

of its highly cationic nature, may bind to target cells by interacting with cell-surface heparan sulfate proteoglycans (HSPG), naturally occurring anionic carbohydrate polymers that are closely related in structure to heparin sulfate. They hypothesized that HSPG antagonists would inhibit the viral enhancing effects of SEVI.51 Surfen, a HSPG antagonist, induced a dose-dependent inhibition of SEVI at concentrations of 6.25 μm with the maximal inhibitory plateau occurring at 50–100 μm.57 Surfen appeared to directly inhibit SEVI and not compromise the infectivity of the virions.57 Electrostatic interactions between SP and microbicides may also hamper the efficacy of HIV-1 prevention products. The antiviral activity of several anionic polymer microbicide candidates (e.g.