| Popis: |
The identification of SEVI fibrils in semen represents an interesting novel opportunity to prevent sexual HIV transmission. For the first time, this study demonstrated the development of peptides that block the fibrillation of PAP248-286 by a novel, structure-based mechanism. We generated peptide inhibitors that specifically delay PAP248-286 fibril formation in vitro and thus SEVI mediated enhancement of HIV-1 infection is abrogated. This approach might help to develop inhibitors that block assembly of Abeta or alpha synuclein, which are involved in amyloid-related diseases such as Alzheimer’s and Parkinson’s disease. Many topical microbicides effectively inhibit HIV infection in vitro. Nonetheless, they almost invariably failed to prevent viral transmission in vivo. One possible reason for this discrepancy is that the preclinical testing of microbicides does not realistically reflect the conditions of sexual transmission of HIV-1. Here, I have demonstrated that candidate microbicides targeting viral components exert reduced efficacies in the presence of semen, the main vector for HIV transmission. This diminished antiviral activity results from the ability of semen to enhance the infectiousness of HIV particles. Interestingly, MVC, a HIV entry inhibitor that binds to the CCR5 co-receptor, displayed strong antiviral activity in the presence of semen. My results imply that the in vitro efficacy of microbicides should be determined in the presence of semen to identify the best candidates for the prevention of sexual HIV-1 transmission. If we extend our in vitro findings to the in vivo setting, this would suggest that “next-generation” microbicides should include components targeting cellular components the virus needs to replicate, but also factors in semen that enhance HIV infectivity, such as semen amyloid. This currently seems to be the most promising way to reduce sexual HIV-1 transmission. |
