Proline 78 Is Crucial for Human Immunodeficiency Virus Type 1 Nef To Down-Regulate Class I Human Leukocyte Antigen

Abstract

Human immunodeficiency virus type 1 Nef down-regulates human leukocyte antigen class I (HLA-I) in T lymphocytes, and the down-regulation involves the Nef proline-rich domain (PRD) containing four prolines at positions 69, 72, 75, and 78. We used a Sendai virus vector with nef and examined regulation by Nef of HLA-I and CD4 in suspension cultures of cells such as T lymphocytes. Analyses of a series of PRD substitution mutants indicated that, because the substitution of Pro78 with Ala abolished down-regulation of HLA-I but not of CD4, Pro78 is important for HLA-I down-regulation in T lymphocytes

Human Immunodeficiency Virus Type 1 Nef Domains Required for Disruption of Major Histocompatibility Complex Class I Trafficking Are Also Necessary for Coprecipitation of Nef with HLA-A2

“…2C and D). A partial effect of mutating the acidic domain and the first polyproline domain of Nef is consistent with prior reports (21,25,32). All of these mutants, except D 123 G, were active at CD4 downmodulation ( Fig.…”

“…Multiple studies have identified a subset of Nef domains that are required for its effects on MHC-I (1,6,13,21,32). These studies have utilized a variety of cell types and expression systems to characterize each mutant.…”

“…The dileucine motif in Nef that is needed for the acceleration of CD4 endocytosis is dispensable for the disruption of MHC-I trafficking. In addition, regions of Nef that are needed to reduce MHC-I cell surface expression (N-terminal alpha helix, polyproline, and acidic domains) are dispensable for CD4 downmodulation (1,6,12,21,32).…”

Virus Evasion of MHC Class I Molecule Presentation

“…Nef increases the pathogenicity of HIV in several ways, including down-modulation of cell surface MHC class I molecules (28,30). Specific regions of Nef that are involved in MHC class I down-regulation have been identified (29,41). CTL killing of HIV-1-infected primary cells is inefficient if Nef is expressed, and the resistance of the infected cells is due to MHC class I down-regulation (42).…”

Impaired Nef Function Is Associated with Early Control of HIV-1 Viremia

“…Of these 4 polymorphisms, only R19K is located near a residue or motif (namely, M20) that has been associated with this function (Fig. 6B) (58,63,(71)(72)(73)(74)(75)(76)(77). To directly examine their impact on Nef, forward mutations corresponding to each of the 4 polymorphisms were introduced individually into the baseline clone (AC01b_F) whose sequence most closely resembled the B/HXB2 nef consensus sequence and backward mutations were introduced into the predominant follow-up clone (AC01f_A) to revert each of these polymorphisms individually.…”