We have recently shown that XMRV replication is inhibited by human A3G, human A3F, and murine APOBEC3, suggesting that XMRV does not efficiently replicate and spread in cells that express these host proteins, and may depend on infection of cells that express low levels of these factors. To determine whether XMRV replicates in human PBMCs, we will quantify XMRV replication in PBMCs. We will also quantify the extent of A3 protein expression in normal prostate tissues and prostate carcinomas. To determine the incidence of XMRV in prostate cancer, we will obtain prostate tumors and carry out sensitive PCR assays to determine the extent of XMRV infection. We will also develop ELISA and western blot assays for XMRV detection. To test the hypothesis that co-infection with HIV-1 will lead to the degradation of A3 proteins and allow XMRV to replicate more efficiently, we will determine the incidence of XMRV co-infection in HIV-1 infected individuals with lymphomas and other malignancies. We previously showed that XMRV replication is sensitive to the HIV-1 integrase inhibitor raltegravir. We will carry out mutational analysis of XMRV integrase to identify mutations that confer raltegravir resistance. We will also select for raltegravir-resistant XMRV variants in cell lines and compare the mutations to those selected in HIV-1.
|Paprotka, Tobias; Delviks-Frankenberry, Krista A; Cingöz, Oya et al. (2011) Recombinant origin of the retrovirus XMRV. Science 333:97-101|
|Chaipan, Chawaree; Dilley, Kari A; Paprotka, Tobias et al. (2011) Severe restriction of xenotropic murine leukemia virus-related virus replication and spread in cultured human peripheral blood mononuclear cells. J Virol 85:4888-97|
|Paprotka, Tobias; Venkatachari, Narasimhan J; Chaipan, Chawaree et al. (2010) Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs. J Virol 84:5719-29|