Mechanism of HIV pathogenesis: role of superantigens in disease.

Abstract

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 virus detectable in the circulation. The term latent period has been shown to be a misnomer, because substantial viral replication occurs during this time in lymph nodes, although clinically there appears to be few symptoms of disease. However, a telling indicator of active infection during this period is the initiation of decline in CD4+ T-cell numbers. A number of hypotheses have been postulated for the mechanism(s), as of yet not fully elucidated, by which T cells are depleted. Although quiescent cells can be infected, it has been shown that replication of HIV in CD4+ T cells requires cellular activation. The levels of viremia early in infection indicate that a large number of cells are actively infected, further suggesting that a mechanism must exist by which HIV activates a large pool of cells and ultimately causes their depletion. One possible mechanism for activation would be the presence of an HIV-encoded superantigen. Superantigens are proteins that are polyclonal stimulators of CD4+ T lymphocytes. This occurs as a result of their ability to form a trimolecular complex with MHC class II molecules on antigen-presenting cells and the Vbeta-specific region on the T-cell receptor. Thus, superantigen activation of T cells is antigen-nonspecific. The prototype superantigens are the staphylococcal enterotoxins. Putative viral superantigens include a protein from mouse mammary tumor 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 transformed to the activated state for virus replication.