Mouse retrovirus mediates porcine endogenous retrovirus transmission into human cells in long-term human-porcine chimeric mice

Abstract

Porcine endogenous retrovirus (PERV) is a potential pathogen in clinical xenotransplantation; transmission of PERV in vivo has been suggested in murine xenotransplantation models. We analyzed the transmission of PERV to human cells in vivo using a model in which immunodeficient NOD/SCID transgenic mice were transplanted with porcine and human lymphohematopoietic tissues. Our results demonstrate, we believe for the first time, that human and pig cells can coexist long-term (up to 25 weeks) without direct PERV infection of human cells. Despite the transplantation of porcine cells that did not produce human-tropic PERV, human cells from the chimeric mice were frequently found to contain PERV sequences. However, this transmission was due to the pseudotyping of PERV-C (a virus without human tropism) by xenotropic murine leukemia virus, rather than to de novo generation of human-tropic PERV. Thus, pseudotyping might account for the PERV transmission previously observed in mice. The absence of direct human cell infection following long-term in vivo coexistence with large numbers of porcine cells provides encouragement regarding the potential safety of using pigs that do not produce human-tropic PERV as source animals for transplantation to humans.

Infectious risk in xenotransplantation

“…Despite this lack of tropism, PERV sequences were found in human cells. This transmission was the result of pseudotyping of PERV-C by murine leukemia virus, a feature that exaggerated the infectivity of PERV for human cells [29 ]. This observation was confirmed in a series of experiments including human-tropic PERV-A and PERV-B [30 ].…”

Transient transmission of porcine endogenous retrovirus to fetal lambs after pig islet tissue xenotransplantation

“…Although PERV DNA and PERV env RNA sequences were consistently identified in the intact xenografts, indicating persistent intragraft transcription of PERV sequences and possibly PERV replication, no PERV transmission to host mouse tissues was demonstrated. Other groups have reported a low incidence of PERV transmission to host mouse tissues after transplantation of pig islet tissue 15 , 16 , 32 but independent studies have suggested that this may be due to pseudotyping of PERV by xenotropic murine leukemia virus 33 , 34 because mice lack the appropriate PERV receptor 22 . Although fetal lamb tissues can express ovine endogenous retrovirus (OERV) transcripts, the production and release of endogenous retrovirus by fetal lamb cells is unclear and virions have not been reported 35 .…”

“…We speculate that in the case of clinical xenotransplantation, heavy immunosuppression of transplant recipients may facilitate intragraft PERV replication, pig cell microchimerism and PERV transmission to host tissues. In view of host range restrictions, however, receptor‐mediated cell entry 40 into novel hosts, such as humans, may require recombination between different PERV subclasses 41 and/or pseudotyping with host endogenous retrovirus(es) 33 , 34 . Both cell entry and integration of PERV sequences into the host genome therefore represent vital targets for intercepting PERV transmission 40 , 42 , 43 .…”

Porcine endogenous retroviruses: What are the risks of infection transmission in xenotransplantation?

“…In addition, it is still unknown whether murine endogenous viruses influence PERV infection in this model. When the adequacy of the models is evaluated, it is still debatable whether PERV can be transmitted by themselves or whether they must be pseudotyped by xenotropic endogenous retroviruses of the host species (Yang et al, 2004), which makes the model under consideration inapplicable to human xenotransplantation, because these viruses can be absent in the DNA of human germinal cells.…”