Background:  Infection with Xenotropic MuLV-related Retrovirus (XMRV), a g-retrovirus, has been identified in association with familial cases of prostate carcinoma and in patients with chronic fatigue syndrome, although an etiological link remains to be established. In light of these studies, the development of an animal model to study XMRV dissemination, tissue tropism and pathogenicity is essential for understanding its role and infection transmission.

Methods:  We experimentally infected 5 healthy rhesus macaques with XMRV intravenously. At days 6 or 7 (acute infection), 2 macaques were euthanized, as were the others during chronic infection at days 146 and 289 post infection. Extensive tissue collections were done from various organs at necropsy to evaluate both the tissue and cell tropism at various times post infection using FISH to the entire genome and IHC via detection of XMRV gag using a cross reactive monoclonal antibodies to murine spleen focus-forming virus (SFFV).

Results:  Both methods were concordant for the detection of XMRV in the various organs tested and showed a wide dissemination of replicating virus even when the plasma viral load was undetectable. Of interest was the finding that isolated lymphoid cells and primarily CD4⁺ T cells were found positive in most lymphoid organs including spleen, lymph nodes, and gastrointestinal tract, while in lung, XMRV⁺ cells exhibited a macrophage morphology. The frequency of infected cells appeared to decrease in spleen while increasing in the gastrointestinal tract from acute to chronic infection. XMRV infection was however not restricted to bone marrow derived cells, but showed distinct target specificities in various organs. Using IHC, foci of infected epithelial cells were detected in prostate, seminal vesicles and epididymis while XMRV⁺ cells in the testes were interstitial. In the lone female animal, XMRV⁺ epithelial and fibroblast like cells were detected in the vagina and cervix suggesting that the virus may be transmitted sexually. While XMRV dissemination was complete at day 6 post infection, the prostate was positive only during the acute infection in these healthy animals, while other reproductive organs were similarly positive during the chronic phase.

Conclusions:  We believe to have established a validated animal model of human XMRV infection, suitable to test its long-term chronic effect, pathogenesis, and immunity and to validate future vaccines. The organ-specific target-cell distribution is intriguing and remains to be studied in more detail.