The maximal virulence of HIV-1 requires Nef, a virally encoded peripheral membrane protein. Nef binds to the adaptor protein (AP) complexes of coated vesicles, inducing an expansion of the endosomal compartment and altering the surface expression of cellular proteins including CD4 and class I major histocompatibility complex.
Nef affects the cell surface expression of several cellular proteins. It down-regulates CD4, CD8, CD28, and major histocompatibility complex class I and class II proteins, but upregulates the invariant chain of MHC II (CD74). To modulate cell surface receptor expression, Nef utilizes several strategies, linked to distinct regions within the Nef protein.
Since all these receptors are essential for proper functions of the immune system, modulation of their surface expression by Nef has profound effects on anti-HIV immune responses. Down-regulation of MHC I protects HIV-infected cells from host CTL response, whereas down-modulation of CD28 and CD4 probably limits the adhesion of a Nef-expressing T cell to the antigen-presenting cell, thus promoting the movement of HIV-infected cells into circulation and the spread of the virus.