HIV immune evasion disruption of antigen presentation by the HIV Nef protein

Abstract

The Human Immunodeficiency Virus (HIV) Nef protein is necessary for high viral loads and for timely progression to AIDS. Nef plays a number of roles, but its effect on antigen presentation and immune evasion are among the best characterized. Cytotoxic T lymphocytes (CTLs) recognize and lyse virally infected cells by detecting viral antigens in complex with host major histocompatibility complex class I (MHC-I) molecules on the infected cell surface. The HIV Nef protein disrupts antigen presentation at the cell surface by interfering with the normal trafficking pathway of MHC-I and thus reduces CTL recognition and lysis of infected cells. The molecular mechanism by which Nef causes MHC-I downmodulation is becoming more clear, but some questions remain. A better understanding of how Nef disrupts antigen presentation may lead to the development of drugs that enhance the ability of the anti-HIV CTLs to control HIV disease.

Figure 1

The genome of HIV-1 and a detailed view of domains in Nef. (A) Three reading frames are shown to reveal HIV-1 genes and their relative genome locations. Open reading frames are shown as rectangular boxes. The spliced reading frames, tat and rev, are shown as boxes connected by lines. (B) Domains in Nef that are pertinent to reducing the surface expression of MHC-I and their proposed functions in either of the two models of MHC-I downmodulation.

Figure 2

Antigen presentation by class-I major histocompatibility complexes (MHC-I). Intracellular peptides (antigens) are produced through protein synthesis and subsequent breakdown by proteasomes. The peptides are then transported into the endoplasmic reticulum through the transporter associated with antigen processing (TAP) and loaded onto MHC-I molecules. Complete MHC-I molecules are transported through the Golgi Network out to the plasma membrane (PM) where the antigen is recognized as “self” or “non-self” by the T Cell Receptor (TCR) on a CD8⁺ CTL. Cells expressing MHC-I in complex with “non-self” peptides are lysed to minimize spread of infection.

Figure 3

Nef-induced endocytosis of MHC-I. In this model, Nef is bound by the acidic cluster sorting protein, PACS-2, and localized to the trans-Golgi network (TGN). Nef binds to the Src Family kinase (SFK), Hck, which activates the tyrosine kinase ZAP-70. ZAP-70 then binds to and activates PI-3-Kinase. PI-3-Kinase creates PIP₃ on the inner leaflet of the plasma membrane (PM), which recruits the ARF-6 GEF, ARNO, subsequently recruiting and activating ARF-6. MHC-I is then internalized by an ARF-6 – dependent mechanism into endosomes. Nef then recruits AP-1, which transports MHC-I to the TGN.

Figure 4

Nef reroutes newly synthesized MHC-I into the endolysosomal network. Nef binds to the cytoplasmic tail of MHC-I early in the secretory pathway. Nef blocks normal secretion of MHC-I to the plasma membrane by recruiting AP-1 to redirect MHC-I into the endosomal network. β-COP is then required to transport MHC-I bound to Nef from the endosomal network into late endosomal compartments for subsequent degradation in lysosomes.