Susceptibility of porcine endogenous retrovirus to anti‐retroviral inhibitors

Abstract

Background Porcine endogenous retrovirus (PERV) is an endogenous retrovirus that poses a risk of iatrogenic transmission in the context of pig-to-human xenotransplantation. The lack of a means to control PERV infection in the context of pig-to-human xenotransplantation is a major concern in the field. In this study, we set out to evaluate the ability of currently licensed anti-HIV drugs, and other types of anti-retroviral compounds, to inhibit PERV infection in vitro. Methods We used target cells stably expressing one of the known PERV viral receptors, an infectious molecular clone, PERV-A 14/220, and at least one drug from each class of anti-retroviral inhibitors as well as off-label drugs shown to have anti-viral activities. The susceptibility of PERV-A 14/220 LacZ to the anti-retroviral drugs was determined from infected cells by histochemical staining. Results We extend the results of previous studies by showing that, in addition to raltegravir, dolutegravir is found to have a potent inhibitory activity against PERV replication (IC50 8.634 ±0.336 and IC50 3.06 ± 0.844 nm, respectively). The anti-HIV drug zidovudine (AZT) showed considerable anti-PERV activity with IC50 of 1.923 ±0.691 μm as well. Conclusions The study results indicate that some of the licensed antiretroviral drugs may be useful for controlling PERV infection. However, the efficacy at nanomolar concentrations put forward integrase inhibitors as a drug that has the potential to be useful in the event that xenotransplantation recipients have evidence of PERV transmission and replication.

PERVading strategies and infectious risk for clinical xenotransplantation

“…Selecting porcine donor tissue with fully degenerate PERV sequences does however reduce the in vitro frequency of infection from these tissues and thus is expected to proportionately reduce the likelihood of in vivo infection. If such an event occurred, in vitro studies have shown that human‐tropic PERV is susceptible to antiviral therapies, adding a prophylactic layer of therapeutic control to the donor preventative considerations described above.…”

The 2017 IXA Presidential Lecture: Recent developments in xenotransplantation

“…PERV transmission was not detected in a long‐term follow‐up of burns patients treated with living pig skin, nor in recipients of microencapsulated porcine islets . Furthermore, PERV is sensitive to clinical anti‐retroviral agents . Nevertheless, some have argued that elimination of PERV from the porcine genome is essential to guard against the possibility of PERV transmission in the clinical setting, although this view is controversial …”

Regulation of Clinical Xenotransplantation—Time for a Reappraisal

“…27 Available antiviral agents also have activity against PERV. 33–35 Multiple intrinsic mechanisms seem to further limit the infectivity of PERV for human cells despite the presence of PERV receptors. 36 A variety of other approaches have been suggested including the selection of pigs with reduced PERV loci, including those used in a New Zealand clinical trial without evidence of PERV transmission, though this trial was in nonimmunosuppressed patients.…”