Severe Combined Immunodeficient Mice Engrafted with Macaque Peripheral Blood Leukocytes Support Replication of SIVsmm

Abstract

Peripheral blood leukocytes (PBLs) from normal pigtail macaques were engrafted into severe combined immunodeficient C.B-17 scidlscid (SCID) mice to develop a small animal model in which to study and identify genetic determinants responsible for the acutely lethal disease syndrome induced by SIVsmmPBjl4 (SIV-PBJ14) in pigtail macaques. In vivo infection of macaques with SIV-PBj14 results in acute disease in all animals and death of most animals, depending on the route of infection, due to immune activation and production of inflammatory cytokines. A small animal model in which a similar acute disease syndrome was induced would facilitate screening of virus variants to identify regions of the SIV-PBj14 genome responsible for the unique phenotype. Although intraperitoneal inoculation of SCID mice with SIV-PBj14-infected PBLs or uninfected PBLs followed by cell-free SIV-PBj14 produced chimeric mac-PBL-SCID mice that supported SIV replication, obvious clinical signs of disease were not observed. SIV-infected macaque PBLs were recovered from spleen, bone marrow, peripheral blood, and the peritoneal cavity; cell-free SIV was recovered from peritoneal lavage fluid and serum or plasma. PBLs that were mitogen stimulated and SIV-PBj14 infected in vitro migrated rapidly and were recovered from the spleen and bone marrow as early as 1 day after inoculation of mice. The mac-PBL-SCID model may be useful for screening potential drug or immunomodulatory therapies before testing in macaques.