Susceptibility of the human retrovirus XMRV to antiretroviral inhibitors

<p>Abstract</p> <p>Background</p> <p>XMRV (xenotropic murine leukemia virus-related virus) is the first known example of an exogenous gammaretrovirus that can infect humans. A limited number of reports suggest that XMRV is intrinsically resistant to many of the antiretroviral drugs used to treat HIV-1 infection, but is sensitive to a small subset of these inhibitors. In the present study, we used a novel marker transfer assay to directly compare the antiviral drug sensitivities of XMRV and HIV-1 under identical conditions in the same host cell type.</p> <p>Results</p> <p>We extend the findings of previous studies by showing that, in addition to AZT and tenofovir, XMRV and HIV-1 are equally sensitive to AZddA (3'-azido-2',3'-dideoxyadenosine), AZddG (3'-azido-2',3'-dideoxyguanosine) and adefovir. These results indicate that specific 3'-azido or acyclic nucleoside analog inhibitors of HIV-1 reverse transcriptase (RT) also block XMRV infection with comparable efficacy <it>in vitro</it>. Our data confirm that XMRV is highly resistant to the non-nucleoside RT inhibitors nevirapine and efavirenz and to inhibitors of HIV-1 protease. In addition, we show that the integrase inhibitors raltegravir and elvitegravir are active against XMRV, with EC₅₀values in the nanomolar range.</p> <p>Conclusions</p> <p>Our analysis demonstrates that XMRV exhibits a distinct pattern of nucleoside analog susceptibility that correlates with the structure of the pseudosugar moiety and that XMRV is sensitive to a broader range of antiretroviral drugs than has previously been reported. We suggest that the divergent drug sensitivity profiles of XMRV and HIV-1 are partially explained by specific amino acid differences in their respective protease, RT and integrase sequences. Our data provide a basis for choosing specific antiretroviral drugs for clinical studies in XMRV-infected patients.</p

Susceptibility of Human Lymphoid Tissue Cultured ex vivo to Xenotropic Murine Leukemia Virus-Related Virus (XMRV) Infection

BACKGROUND: Xenotropic murine leukemia virus-related virus (XMRV) was generated after a recombination event between two endogenous murine leukemia viruses during the production of a prostate cancer cell line. Although the associations of the XMRV infection with human diseases appear unlikely, the XMRV is a retrovirus of undefined pathogenic potential, able to replicate in human cells in vitro. Since recent studies using animal models for infection have yielded conflicting results, we set out an ex vivo model for XMRV infection of human tonsillar tissue to determine whether XMRV produced by 22Rv1 cells is able to replicate in human lymphoid organs. Tonsil blocks were infected and infection kinetics and its pathogenic effects were monitored RESULTS: XMRV, though restricted by APOBEC, enters and integrates into the tissue cells. The infection did not result in changes of T or B-cells, immune activation, nor inflammatory chemokines. Infectious viruses could be recovered from supernatants of infected tonsils by reinfecting DERSE XMRV indicator cell line, although these supernatants could not establish a new infection in fresh tonsil culture, indicating that in our model, the viral replication is controlled by innate antiviral restriction factors. CONCLUSIONS: Overall, the replication-competent retrovirus XMRV, present in a high number of laboratories, is able to infect human lymphoid tissue and produce infectious viruses, even though they were unable to establish a new infection in fresh tonsillar tissue. Hereby, laboratories working with cell lines producing XMRV should have knowledge and understanding of the potential biological biohazardous risks of this virus

Increased HLA-DR homozygosity associated with pre-eclampsia.

It is generally accepted that maternal recognition of paternally derived fetal antigens occurs during normal pregnancy and may be beneficial for implantation and maintenance of gestation. Thus, we have investigated the human leukocyte class II DR antigens (HLA-DR), whose role in self and non-self recognition is well known, in women with pre-eclampsia, their partners and in control couples. The HLA-DR antigens were tested in 70 pre-eclamptic primigravidae women and their partners and 70 healthy control couples using the serological Terasaki technique. Our results did not show any particular HLA-DR antigen to be correlated with pre-eclampsia, but a statistically significant increase of only one identifiable HLA-DR antigen, which was presumed to express homozygosity at the HLA-DR locus, in the pre-eclamptic women and their partners: 67.1 versus 7. 9% in the control couples (P < 0.000001). The analysis of HLA-DR compatibility between pre-eclamptic women and their partners showed a statistically highly significant increase of the female-to-male compatibility (P = 0.0003) and a lower but significant male-to-female compatibility in comparison with controls (P = 0.014). From our results, it emerges that HLA-DR homozygosity and reduced antigenic disparity seem to be associated to a major risk for pre-eclampsia, which consequently appears to be a 'couple's disease'

Increased HLA-DR homozygosity associated with pre-eclampsia.

It is generally accepted that maternal recognition of paternally derived fetal antigens occurs during normal pregnancy and may be beneficial for implantation and maintenance of gestation. Thus, we have investigated the human leukocyte class II DR antigens (HLA-DR), whose role in self and non-self recognition is well known, in women with pre-eclampsia, their partners and in control couples. The HLA-DR antigens were tested in 70 pre-eclamptic primigravidae women and their partners and 70 healthy control couples using the serological Terasaki technique. Our results did not show any particular HLA-DR antigen to be correlated with pre-eclampsia, but a statistically significant increase of only one identifiable HLA-DR antigen, which was presumed to express homozygosity at the HLA-DR locus, in the pre-eclamptic women and their partners: 67.1 versus 7. 9% in the control couples (P < 0.000001). The analysis of HLA-DR compatibility between pre-eclamptic women and their partners showed a statistically highly significant increase of the female-to-male compatibility (P = 0.0003) and a lower but significant male-to-female compatibility in comparison with controls (P = 0.014). From our results, it emerges that HLA-DR homozygosity and reduced antigenic disparity seem to be associated to a major risk for pre-eclampsia, which consequently appears to be a 'couple's disease'

HLA-DR in couples associated with preeclampsia: background and updating by DNA sequencing. J

The placenta acts as an immunological barrier between the mother and the fetal "graft", allowing two antigenically different organisms to tolerate one another. In placentae from preeclamptic women, we have demonstrated, by an ultrastructural assessment and an immunohistochemical study, a placental barrier breakage leading to the mixing of maternal and fetal antigenically different blood. This condition could be responsible for the triggering of a maternal rejection reaction that we presume to be at the basis of the preeclamptic syndrome. Thus, we have investigated the Human Leukocyte class II DR antigens (HLA-DR), whose role in self and non-self recognition is well known, in women with preeclampsia, their partners and in control couples using the serological Terasaki tecnique. The results showed a statistically significant increase of HLA-DR homozygosity and a reduced antigenic variety in the preeclamptic women and their partners with respect to controls. In this update, we have examined the 2nd exon of the human gene, HLA-DRB1, on the short arm of the chromosome 6 using DNA sequence-based typing (S-BT) PCR in 56 preeclamptic couples and 64 control couples. The results have confirmed the significant excess of HLA-DR homozygosity in couples associated with preeclampsia versus controls. From our results, it emerges that HLA-DR homozygosity and the reduced antigenic variety seem to be associated to a major risk for preeclampsia, which further appears to be a "couple's disease"