Evaluation of Crimean-Congo hemorrhagic fever virus in vitro inhibition by chloroquine and chlorpromazine, two FDA approved molecules.

Crimean-Congo hemorrhagic virus (CCHFV) causes hemorrhagic fever with high case mortality rates and is endemic in south-eastern Europe, Africa, and Asia. The limited catalog of specific treatment, highlight the necessity to look for additional therapeutic solutions. Previous experiments suggested that CCHFV enters the cells via a clathrin dependent pathway. Therefore, we have evaluated the potential anti-CCHFV activity of several molecules targeting this entry possibility. We identified two molecules chloroquine and chlorpromazine. Neutralization and virus yield reduction assays were tested in Vero E6 and Huh7 cells on two different CCHFV strains. Several combinations, including ribavirin, were assayed to test a potential synergistic effect. The two molecules inhibited CCHFV, and depending on the virus and the cell lines, the 50% inhibitory concentration (IC50) values for chloroquine and chlorpromazine ranged from 28 to 43 and 10.8-15.7 µM, respectively. Time-of-addition studies demonstrated that these molecules had a direct effect on CCHFV infectivity and spread. The antiviral activity of the two molecules was still effective even when added up to 6h post-infection and up to 24h. The selectivity index ranging from 3 to 35 lead us to evaluate combinations with ribavirin. Combinations of ribavirin and chloroquine or chlorpromazine were synergistic against CCHFV. Though the low chlorpromazine selectivity index suggests the need for a chemical improvement, our present study highlights chloroquine as the main drug having the potential for drug repurposing.

[Retroviral restriction factors : from Fv1 to TRIM5α]. / Les facteurs de restriction rétrovirale : de Fv1 à TRIM5α.

During their evolution, mammals have developed cellular factors interfering with retroviral replication, known as « restriction factors ¼. The prototype of these factors, Fv1, was characterized in the late 60's and blocks MLV infection. Some Fv1-like factors interfering with complex retroviruses, including HIV, have recently been discovered in primate cells. These restriction factors are referred to as Ref1, which blocksMLVreplication in human cells, and Lv1, which blocks the infection of non-human primate cells by various retroviruses, including MLV and HIV. These factors are all saturable by an excess of virus, target the viral capsid and interfere with an early step of viral replication. Lv1 and Ref1 have recently been found to be species-specific variants of a single protein called TRIM5α, a member of the TRIM protein family. The mechanism of action of these factors is still unknown. The existence of natural inhibitors of retroviral infection raises new hopes for the development of therapeutic tools against HIV infection.