Experimental co-transmission of simian immunodeficiency virus (SIV) and the macaque homologs of the Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV)

Abstract

Macaque RFHV and LCV are close homologs of human KSHV and EBV, respectively. No experimental model of RFHV has been developed due to the lack of a source of culturable infectious virus. Screening of macaques at the Washington National Primate Research Center detected RFHV in saliva of SIV-infected macaques from previous vaccine studies. A pilot experimental infection of two naïve juvenile pig-tailed macaques was initiated by inoculation of saliva from SIV-infected pig-tailed and cynomolgus macaque donors, which contained high levels of DNA of the respective species-specific RFHV strain. Both juvenile recipients developed SIV and RFHV infections with RFHV DNA detected transiently in saliva and/or PBMC around week 16 post-infection. One juvenile macaque was infected with the homologous RFHVMn from whole saliva of a pig-tailed donor, which had been inoculated into the cheek pouch. This animal became immunosuppressed, developing simian AIDS and was euthanized 23 weeks after inoculation. The levels of RFHV DNA in saliva and PBMC remained below the level of detection after week 17, showing no reactivation of the RFHVMn infection during the rapid development of AIDS. The other juvenile macaque was infected with the heterologous RFHVMf from i.v. inoculation of purified virions from saliva of a cynomolgus donor. The juvenile recipient remained immunocompetent, developing high levels of persistent anti-RFHV and -SIV antibodies. After the initial presence of RFHVMf DNA in saliva and PBMC decreased to undetectable levels by week 19, all attempts to reactivate the infection through additional inoculations, experimental infection with purified SRV-2 or SIV, or immunosuppressive treatments with cyclosporine or dexamethasone were unsuccessful. An heterologous LCV transmission was also detected in this recipient, characterized by continual high levels of LCVMf DNA from the cynomolgus donor in both saliva and PBMC, coupled with high levels of anti-LCV antibodies. The macaque was sacrificed 209 weeks after the initial inoculation. Low levels of LCVMf DNA were detected in salivary glands, tonsils and other lymphoid organs, while RFHVMf DNA was below the level of detection. These results show successful co-transmission of RFHV and LCV from saliva and demonstrate differential lytic activation of the different gammaherpesvirus lineages due to presumed differences in biology and tropism and control by the host immune system. Although this initial pilot transmission study utilized only two macaques, it provides the first evidence for experimental transmission of the macaque homolog of KSHV, setting the stage for larger transmission studies to examine the differential activation of rhadinovirus and lymphocryptovirus infections and the pathological effects of immunosuppression.

KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection

“…Accordingly, KSHV persistence is predominantly observed in mice with reconstituted human im-mune system components (humanized mice) in the presence of EBV, and these dual-infected mice develop PEL-like tumors (McHugh et al, 2017). In good agreement, EBV and KSHV orthologs are also co-transmitted in monkeys (Bruce et al, 2018), KSHV is primarily found in co-existence with EBV in Cameroonian children (Labo et al, 2019), and EBV supports persistence of B cell infection by KSHV in vitro (Faure et al, 2019). Moreover, the high prevalence of EBV in the adult human population (>95%) makes it likely that KSHV co-exists in the presence of EBV in most adult individuals (Dunmire et al, 2018).…”

Probing Reconstituted Human Immune Systems in Mice With Oncogenic γ-Herpesvirus Infections

“…Interestingly, KSHV infection only persists in humanized mice upon co-infection with EBV ( 23 , 38 ). Similarly, both viruses or their monkey orthologues seem to be co-transmitted in both macaques and humans ( 39 , 40 ). Furthermore, EBV supports KSHV infection of B cells in vitro ( 41 ).…”