MECHANISM OF HIV PATHOGENESIS - ROLE OF SUPERANTIGENS IN DISEASE

Initial infection with human immunodeficiency virus (HIV) results in a burst of viremia and an ensuing spread of virus to secondary lymphoid organs, after which a ''latency'' period occurs with little or no vir us detectable in the circulation. The term latent period has been show n to be a misnomer, because substantial viral replication occurs durin g this time in lymph nodes, although clinically there appears to be fe w symptoms of disease. However, a telling indicator of active infectio n during this period is the initiation of decline in CD4(+) T-cell num bers. A number of hypotheses have been postulated for the mechanism(s) , as of yet not fully elucidated, by which T cells are depleted. Altho ugh quiescent cells can be infected, it has been shown that replicatio n of HIV in CD4+ T cells requires cellular activation. The levels of v iremia early in infection indicate that a large number of cells are ac tively infected, further suggesting that a mechanism must exist by whi ch HIV activates a large pool of cells and ultimately causes their dep letion. One possible mechanism for activation would be the presence of an HIV-encoded superantigen. Superantigens are proteins that are poly clonal stimulators of CD4(+) T lymphocytes. This occurs as a result of their ability to form a trimolecular complex with MHC class II molecu les on antigen-presenting cells and the VP-specific region on the T-ce ll receptor. Thus, superantigen activation of T cells is antigen-nonsp ecific. The prototype superantigens are the staphylococcal enterotoxin s. Putative viral superantigens include a protein from mouse mammary t umor virus and related retroviruses, rabies nucleocapsid, and the Nef protein of HIV. Nef is required for optimal HIV pathogenesis, and this may be due to its superantigen properties, where CD4 cells are transf ormed to the activated state for virus replication.