PERMISSIVENESS OF KUPFFER CELLS FOR SIMIAN IMMUNODEFICIENCY VIRUS (SIV) AND MORPHOLOGICAL-CHANGES IN THE LIVER OF RHESUS-MONKEYS AT DIFFERENT PERIODS OF SIV INFECTION

The pathogenesis of liver injury, which remains unclear in the course of human immunodeficiency virus infection, can be investigated in simi an immunodeficiency virus-infected macaques, which develop an immunode ficiency disease resembling human acquired immune deficiency syndrome (AIDS). We studied the livers of 21 monkeys infected with simian immun odeficiency virus (SIVmac251) for 4 days to 39 months and detected vir al antigens in Kupffer cells, macrophages, and lymphocytes in 65% of t he livers tested. Virus-containing cells were present in 5 out of 9 li vers tested as early as 4 days postinoculation. The number of positive cells as well as their content in viral proteins substantially increa sed in sinusoidal cells with the progression of the disease. Morpholog ical features and double immunolabeling indicated that Kupffer cells c onstituted the predominant cell type containing viral antigens. The pr esence of multinucleated giant cells displaying the ultrastructural fe atures of resident liver macrophages was another sign of the productiv e infection of Kupffer cells in vivo, which was attested by the observ ation of budding, immature, and mature SIV particles. Kupffer cell hyp erplasia and hypertrophy were evident and appeared to be related to th e development of SIV infection, because a close correlation was found between antigenemia and the surface area occupied by these cells. The Kupffer cells contained apoptotic lymphocytes, indicating that residen t liver macrophages could play a role in the uptake of such cells from the blood. The production of tumor necrosis factor alpha (TNF alpha) and, possibly, interferon-alpha by Kupffer cells, the expression of va scular adhesion molecule-1, (VCAM-1), intralobular and periportal infl ammation, and the proliferation and expansion of bile duct cells were other signs of liver involvement in SIV infection.