HIV-1 Nef: a master manipulator of the membrane trafficking machinery mediating immune evasion

Many viral genomes encode a limited number of proteins, illustrating their innate efficiency in bypassing host immune surveillance. This concept of genomic efficiency is exemplified by the 9 kb RNA genome of human immunodeficiency virus 1 (HIV-1), encoding 15 proteins sub-divided according to function. The enzymatic group includes proteins such as the drug targets reverse transcriptase and protease. In contrast, the accessory proteins lack any known enzymatic or structural function, yet are essential for viral fitness and HIV-1 pathogenesis. Of these, the HIV-1 accessory protein Nef is a master manipulator of host cellular processes, ensuring efficient counterattack against the host immune response, as well as long-term evasion of immune surveillance. In particular, the ability of Nef to downmodulate major histocompatibility complex class I (MHC-I) is a key cellular event that enables HIV-1 to bypass the host's defenses by evading the adaptive immune response.

In this article, we briefly review how various pathogenic viruses control cell-surface MHC-I, and then focus on the mechanisms and implications of HIV-1 Nef-mediated MHC-I downregulation via modulation of the host membrane trafficking machinery.

The extensive interaction network formed between Nef and numerous membrane trafficking regulators suggests that Nef's role in evading the immune surveillance system intersects multiple host membrane trafficking pathways.

Nef's ability to evade the immune surveillance system is linked to AIDS pathogenesis. Thus, a complete understanding of the molecular pathways that are subverted by Nef in order to downregulate MHC-I will enhance our understanding of HIV-1's progression to AIDS.