Monocyte activation and differentiation augment human endogenous retrovirus expression: Implications for inflammatory brain diseases

Human endogenous retroviruses (HERVs) have been implicated as causative age nts in diseases characterized by inflammation and macrophage activation, su ch as multiple sclerosis. Because monocyte activation and differentiation i nfluence retroviral transcription and replication, we investigated the cont ribution of these processes to the expression of four HERV families (HERV-W , HERV-K, HERV-E, and HERV-H) in human monocytes, and autopsied brain tissu e from patients with brain diseases associated with increased macrophage ac tivity. Reverse transcriptase-polymerase chain reaction analysis of primary macrophages and U937 monocytoid cells stimulated with phorbol-12-myristate -13-acetate or lipopolysaccharide revealed three- to ninefold increases in HERV-W, HERV-K, and HERV-H RNA levels. In addition, elevated reverse transc riptase activity and HERV RNA were detectable in supernatants from PMA-stim ulated U937 cultures, properties that could be attenuated with the inhibito r of monocyte differentiation threonine-lysine-proline. In contrast, stimul ation of monocytes decreased or had no effect on HERV-E expression. Compare d with controls, HERV-W and HERV-K expression was increased in brain tissue from patients with multiple sclerosis or human immunodeficiency virus infe ction or AIDS, with concomitant elevated tumor necrosis factor-alpha levels . Similarly, elevated HERV-W levels were detected in patients with Alzheime r's dementia only when tumor necrosis factor-alpha expression was also evid ent (2 of 6 cases). The detection of several HERVs in inflammatory brain di seases and the capacity to augment HERV expression in monocytes with compou nds that influence cellular activity suggest that increased expression of t hese viruses is a consequence of increased immune activity rather than caus ative of distinct diseases.