Restricted Replication of Xenotropic Murine Leukemia Virus-Related Virus in Pigtailed Macaques

Although xenotropic murine leukemia virus-related virus (XMRV) has been previously linked to prostate cancer andmyalgic encephalomyelitis/chronic fatigue syndrome, recent data indicate that results interpreted as evidence of human XMRV infection reflect laboratory contamination rather than authentic in vivo infection. Nevertheless, XMRV is a retrovirus of undefined patho-genic potential that is able to replicate in human cells. Here we describe a comprehensive analysis of twomale pigtailed ma-caques (Macaca nemestrina) experimentally infected with XMRV. Following intravenous inoculation with>1010 RNA copy equivalents of XMRV, viral replication was limited and transient, peaking at<2,200 viral RNA (vRNA) copies/ml plasma and becoming undetectable by 4 weeks postinfection, though viral DNA (vDNA) in peripheral bloodmononuclear cells remained detectable through 119 days of follow-up. Similarly, vRNAwas not detectable in lymph nodes by in situ hybridization despite detectable vDNA. Sequencing of cell-associated vDNA revealed extensive G-to-A hypermutation, suggestive of APOBEC-mediated viral restriction. Consistent with limited viral replication, we found transient upregulation of type I interferon re-sponses that returned to baseline by 2 weeks postinfection, no detectable cellular immune responses, and limited or no spread to prostate tissue. Antibody responses, including neutralizing antibodies, however, were detectable by 2 weeks postinfection and maintained throughout the study. Both animals were healthy for the duration of follow-up. These findings indicate that XMR