Human leukocyte antigen (HLA) class I down-regulation by human immunodeficiency virus type 1 negative factor (HIV-1 Nef): what might we learn from natural sequence variants?

Abstract

HIV-1 causes a chronic infection in humans that is characterized by high plasma viremia, progressive loss of CD4+ T lymphocytes, and severe immunodeficiency resulting in opportunistic disease and AIDS. Viral persistence is mediated in part by the ability of the Nef protein to down-regulate HLA molecules on the infected cell surface, thereby allowing HIV-1 to evade recognition by antiviral CD8+ T lymphocytes. Extensive research has been conducted on Nef to determine protein domains that are required for its immune evasion activities and to identify critical cellular co-factors, and our mechanistic understanding of this process is becoming more complete. This review highlights our current knowledge of Nef-mediated HLA class I down-regulation and places this work in the context of naturally occurring sequence variation in this protein. We argue that efforts to fully understand the critical role of Nef for HIV-1 pathogenesis will require greater analysis of patient-derived sequences to elucidate subtle differences in immune evasion activity that may alter clinical outcome.

Keywords: HIV-1; HLA class I; Nef; cytotoxic T lymphocyte; host immune selection pressure; immune evasion; viral sequence diversity.

Figure 1

Presentation of viral peptide antigens by Human Leukocyte Antigen (HLA) class I. Human immunodeficiency virus type 1 (HIV-1) proviral gene expression, including RNA transcription (a) and protein translation (b); generates functional viral proteins (c) as well as truncated or mis-folded proteins that are degraded by the cellular proteasome complex to form short antigenic peptides (d); These peptides are transported from the cytoplasm into the endoplasmic reticulum (ER) (e) where they can be loaded onto HLA-I molecules. Peptide/HLA complexes traffic from the ER through the Golgi and secretory vesicle (SV) network to the plasma cell membrane, where the peptide antigens are presented to circulating cytotoxic T lymphocytes (CTL) (f); The viral Nef protein shuttles HLA molecules located at the cell surface or within the trans-Golgi network into lysosomal compartments (g); where they are degraded. In the absence of Nef-mediated HLA down-regulation, antigen-specific CTL respond to stimulation by releasing cytotoxic molecules, including perforin and granzymes, resulting in elimination of the virus-infected cell (h).