Viral genomes and arterial disease

Recent studies suggest that the initial stages of human atherogenesis may be defined as inordinate inflammatory-proliferative responses of intimal arterial cells, interacting with circulating lymphocytes and monocyte/macrophages, to multiple focal stimuli. The latter include transmembrane signal transductions induced by cytokines and growth factors as well as by activated immune cells releasing vasoregulatory molecules affecting local transarterial lipoprotein transport and metabolism. The observed discriminating cell proliferation and characteristic focal eccentric intimal thickening of spontaneous atheroma may thus result from the phenotypic expression of transformed cell clones with selective proliferative advantages and yet unaffected by tissue immune responses. A suggested mechanism for such cell transformation is the partial expression of widely distributed herpesvirus genomes, resulting in the induction of clonal expansion and enhancement of selective cell growth in transfected host cells. Major obstacles for the unambiguous laboratory demonstration of a direct cause/effect relationship between herpes induced cellular transformation and early human atheroma are (1) potential loss of recognizable viral transforming sequences in the host cell genome by the "hit and run" mechanism originally proposed by Skinner in 1976 and (2) irreversible cytopathic effects induced by these viruses in experimentally infected human cells in vitro, preventing any long-term proliferative or metabolic studies. The observation that immortalized cultured rabbit arterial cells retain for many generations marked mitogenic activity and accelerated lipoprotein uptake after herpesvirus transfection suggested to us the possibility of developing a reproducible in vivo laboratory model in inbred rabbits. To that end, discrete intraarterial injections of fragments of HSV-1 or HSV-2 genomes were made via specially designed catheters in temporarily isolated arterial segments of Watanabe heritable hyperlipemic rabbits. While normolipemic heterozygous animals developed segmental, highly localized, proliferative intimal tumors, containing over 95% HHF35 (+) smooth muscle cells with RAM 11 (+) macrophages and platelets attached to the endothelial surface in 30-60 days, no lesions were found in placebo-injected controls. When hyperlipemic homozygous rabbits were similarly tested, they manifested at injected loci larger intimal lesions containing abundant lipid-laden macrophages and smooth muscle cells before typical rabbit fatty streaks developed elsewhere. These findings suggest that selective transfection with viral genome sequences may indeed induce specific growth promoters for intimal arterial smooth muscle cells and thus play an important role during the initial stages of atherogenesis.