Emerging infectious diseases and xenotransplantation

Abstract

A total of 335 infectious diseases was reported in the global human population between 1940 and 2004, the majority of which were caused by zoonotic pathogens [1]. Although viral pathogens constitute only 25%, some have spread worldwide with most starting from Central Africa. These include human immunodeficiency virus (HIV) causing acquired immunodeficiency syndromes (AIDS), chikungunya virus and West Nile virus, which also cause severe diseases in humans. HIV-1 and HIV-2, for example, are the result of trans-species transmission from non-human primates [2] to humans sometime in the last century. The spread of two henipaviruses causing fatal diseases in horses, pigs and humans has been observed in Asia and Australia, and although these viruses represent transspecies transmissions from bats, secondary transmissions from pigs to humans have also occurred. These and many other examples of emerging infectious diseases call for strong safety considerations in the field of xenotransplantation. Whereas known viruses can easily be eliminated from donor pigs, strategies should be developed to detect new zoonotic pathogens. In addition, all pigs carry porcine endogenous retroviruses (PERVs) in their genome. Two of these, PERV-A and PERV-B, as wells as recombinant PERV-A/C are able to infect human cells. The greatest threat appears to come from the recombinant PERV-A/C viruses as they appear to have an increased infectivity [3,4]. An increase in PERV expression was not observed in multitransgenic pigs expressing DAF, TRAIL and HLAE, generated to prevent immune rejection [5]. Our laboratory has developed a variety of strategies to prevent PERV transmission following xenotransplantation: (i) selection of animals that do not harbour PERV-C genomes in order to prevent recombination, (ii) selection of PERV-A and PERV-B low-producers [6], (iii) development of an antiviral vaccine to protect xenotransplant recipients [7] and (iv) generation of transgenic pigs in which PERV expression is inhibited via RNA interference. Inhibition of PERV expression using either synthetic small interfering (si) RNA or short hairpin (sh) RNA was demonstrated in PERV infected human cells [8], in primary pig cells [9] and in all transgenic piglets born [10]. A second generation of pigs expressing PERV-specific siRNA is now under study and experiments have been started to introduce multiple shRNA. Supported by Deutsche Forschungsgemeinschaft, DFG, DE729/4.