Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors

Abstract

Xenotropic murine leukemia virus-related virus (XMRV) is a recently discovered gammaretrovirus that has been linked to prostate cancer and chronic fatigue syndrome. This virus is therefore an important potential human pathogen and, as such, it is essential to understand its host cell tropism. Intriguingly, infectious virus has been recovered from patient-derived peripheral blood mononuclear cells. These cells express several antiviral restriction factors that are capable of inhibiting the replication of a wide range of retroviruses, including other gamma retroviruses. This raises the possibility that, similar to HIV, XMRV may have acquired resistance to restriction. We therefore investigated the susceptibility of XMRV to a panel of different restriction factors. We found that both human APOBEC3 and tetherin proteins are able to block XMRV replication. Expression of human TRIM5α, however, had no effect on viral infectivity. There was no evidence that XMRV expressed countermeasures to overcome restriction. In addition, the virus was inhibited by factors from nonhuman species, including mouse Apobec3, tetherin, and Fv1 proteins. These results have important implications for predicting the natural target cells for XMRV replication, for relating infection to viral pathogenicity and pathology, and for the design of model systems with which to study XMRV-related diseases.

Evaluation of Cellular Determinants Required for In Vitro Xenotropic Murine Leukemia Virus-Related Virus Entry into Human Prostate Cancer and Noncancerous Cells

“…This finding is consistent with a recent study, which shows XMRV infection of the benign prostatic epithelial (PrEC) and stromal (PrSC) cells that may consist of fibroblast cells, as well as other cell types in the stroma (12). Related studies have similarly documented XMRV infection of not only prostatic stromal fibroblasts (PrSC) but also human cells of many different tissue types (11,37), as well as cells from various animal species (37). The authors of these studies have proposed that the in vivo susceptibility to XMRV cannot be determined by the Xpr1 receptor expression alone but that the ability of different cell types to either transactivate the XMRV viral promoter or to restrict virus replication define how efficient the virus can spread in certain tissues (11).…”

“…Related studies have similarly documented XMRV infection of not only prostatic stromal fibroblasts (PrSC) but also human cells of many different tissue types (11,37), as well as cells from various animal species (37). The authors of these studies have proposed that the in vivo susceptibility to XMRV cannot be determined by the Xpr1 receptor expression alone but that the ability of different cell types to either transactivate the XMRV viral promoter or to restrict virus replication define how efficient the virus can spread in certain tissues (11). Recent studies have also shown that XMRV infectivity can be limited by the presence of known host restriction factors to retroviral replication, such as the human APOBEC3 and tetherin proteins, as well as mouse APOBEC3, tetherin, and Fv1 proteins (11,28).…”

“…The authors of these studies have proposed that the in vivo susceptibility to XMRV cannot be determined by the Xpr1 receptor expression alone but that the ability of different cell types to either transactivate the XMRV viral promoter or to restrict virus replication define how efficient the virus can spread in certain tissues (11). Recent studies have also shown that XMRV infectivity can be limited by the presence of known host restriction factors to retroviral replication, such as the human APOBEC3 and tetherin proteins, as well as mouse APOBEC3, tetherin, and Fv1 proteins (11,28). It is noteworthy that a number of human cells, including breast cells have been shown to be susceptible to infection by the mouse mammary tumor virus (MMTV) (13,14), in spite of the fact that the human orthologue of the murine transferrin receptor 1 (Trf1), which is the known cellular receptor for MMTV, is not able to support viral entry in human cells (32).…”

Lack of evidence for human infection with Xenotropic murine leukemia virus-related virus in the Brazilian Amazon basin

“…Positive serological fi ndings from previous studies may have also been the result of cross reactions 7 ; however, antibodies specifi c to the virus were apparently detected 8,9 . Other studies showed a prevalence of between 1-3% in the general (i.e., healthy) population, which indicated a possible role of blood transfusions in the dissemination of the virus 10,11 .…”

Interferon-Induced Tetherin Restricts Vesicular Stomatitis Virus Release in Neurons

“…Tetherin forms a bridge between virions and the plasma membrane (Sato et al, 2009). Tetherin contributes to antiviral activity against various enveloped viruses, including Ebola, Marburg, Lassa, KSHV, HIV-1, HIV-2, SIV, MLV, E1AV, VSV, HTLV-1, XMRV, and spumaviruses ( Jouvenet et al, 2009;Kaletsky et al, 2009;Le Tortorec and Neil, 2009;Mansouri et al, 2009;Miyakawa et al, 2009;Sakuma et al, 2009;Groom et al, 2010;Weidner et al, 2010;Xu et al, 2011).…”