Nonhuman Primate Models of Intrauterine Cytomegalovirus Infection

Abstract

Congenital human cytomegalovirus (HCMV) infection has long been recognized as a threat to the developing fetus, even though studies have shown that only a subset of congenital infections results in clinical signs of disease. Among the estimated 8000 children who develop sequelae from congenital CMV infection each year in the United States alone, most suffer permanent developmental defects within the central nervous system. Because there is currently no approved vaccine for HCMV, and anti-HCMV drugs are not administered to gravid women with congenital infection because of potential toxicity to the fetus, there is a clear clinical need for effective strategies that minimize infection in the mother, transplacental transmission of the virus, and/or fetal disease. Animal models provide a method to understand the mechanisms of HCMV persistence and pathogenesis, and allow for testing of novel strategies that limit prenatal infection and disease. The rhesus macaque model is especially well suited for these tasks because monkeys and humans share strong developmental, immunological, anatomical, and biochemical similarities due to their close phylogenetic relationship. This nonhuman primate model provides an invaluable system to accelerate the clinical development of promising new therapies for the treatment of human disease. This review addresses salient findings with the macaque model as they relate to HCMV infection and potential avenues of discovery, including studies of intrauterine CMV infection. The complexity of the natural history of HCMV is discussed, along with the ethical and logistical issues associated with studies during pregnancy, the recent contributions of animal research in this field of study, and future prospects for increasing our understanding of immunity against HCMV disease.

Rhesus CMV: an emerging animal model for human CMV

“…However, more severe disease was observed upon intra-cranial inoculation of the fetus [30]. Similar to humans, severity of neurological defects was much higher when infections occurred during the Wrst trimester of infection [28]. Thus, intrauterine infection with RhCMV clearly resembles some of the features of congenital HCMV infection.…”

“…In addition, recent observations suggest that hearing loss in children born to latently infected mothers occurred at the same frequency, albeit with slower progression, as in infants from primary infected mothers [27]. The close developmental, immunological, anatomical, and biochemical similarities between RM and humans render RhCMV particularly suited for the development of models for congenital CMV infection (recently reviewed in [28]). While natural congenital infection is diYcult to detect in a monkey colony, intrauterine inoculation is being used to study the eVect of CMV infection on the developing fetus.…”

Cytomegalovirus pp65 limits dissemination but is dispensable for persistence

“…Since an intact immune system is required for this "immunological brake" mechanism to function, the lack of pp65-mediated control likely contributes to the high level of dissemination observed in immunocompromised individuals, such as transplant recipients, or in fetuses with immature immune systems. In RMs, RhCMV can cause severe sequelae, including spontaneous abortions, when injected into the developing fetus (70,71). Since the immune-dominance of pp65 is conserved in HCMV, it is likely that this "antivirulence" function is conserved as well.…”

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

“…[17][18][19] Among the several described animal models, only guinea pig CMV, rhesus macaque CMV and porcine CMV are known to cross the placenta and cause fetal infection. 17,18,20,21 Another animal model that has provided considerable insight into the correlation between CMV neuropathogenesis and immune protection is the murine CMV (MCMV) model. 22 To overcome the shortfall of the inability of MCMV to cross the placenta, investigators have directly injected the virus into either the placenta or embryo.…”