Nef (protein)
Nef, or Negative Factor, is a small, myristoylated protein (approximately 27-35 kDa depending on the viral strain) expressed by primate lentiviruses, most notably Human Immunodeficiency Virus (HIV-1) and Simian Immunodeficiency Virus (SIV). It is considered an accessory protein because it is not strictly required for viral replication in vitro, but it plays a crucial role in viral pathogenesis and disease progression in vivo.
Nef is expressed early in the viral replication cycle and localizes primarily to the cytoplasmic face of the plasma membrane. It is a highly versatile protein and exerts its effects through multiple mechanisms, including:
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Downregulation of cell surface receptors: Nef reduces the surface expression of CD4, the primary receptor for HIV-1 entry into CD4+ T cells. This prevents superinfection of infected cells and allows for efficient release of virions. It also downregulates MHC-I (Major Histocompatibility Complex class I) which helps infected cells evade cytotoxic T lymphocyte (CTL) recognition, and MHC-II.
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Alteration of T cell activation: Nef can modulate T cell signaling pathways, leading to enhanced viral replication and immune evasion. This includes influencing the activity of kinases and other signaling molecules involved in T cell activation.
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Enhancement of viral infectivity: Nef can increase the infectivity of released virions, making them more efficient at infecting new target cells. The precise mechanisms for this are still being investigated.
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Modulation of cellular trafficking: Nef interacts with cellular adaptor proteins and trafficking machinery to reroute cellular proteins and organelles, influencing immune function and viral spread.
The presence of a functional nef gene is strongly correlated with high viral loads and accelerated progression to AIDS in HIV-1 infection. SIV strains with deleted or mutated nef genes often result in attenuated infections in primates, highlighting the importance of Nef in disease pathogenesis. Because of its key role in HIV/SIV pathogenesis, Nef is a target for potential therapeutic interventions, though developing drugs that effectively inhibit Nef function has proven challenging.