Impact of Nef-Mediated Downregulation of Major Histocompatibility Complex Class I on Immune Response to Simian Immunodeficiency Virus

New England Primate Research Center, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102, USA.
Journal of Virology (Impact Factor: 4.44). 01/2005; 78(23):13335-44. DOI: 10.1128/JVI.78.23.13335-13344.2004
Source: PubMed


Functional activities that have been ascribed to the nef gene product of simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) include CD4 downregulation, major histocompatibility complex (MHC) class I downregulation, downregulation of other plasma membrane proteins, and lymphocyte activation. Monkeys were infected experimentally with SIV containing difficult-to-revert mutations in nef that selectively eliminated MHC downregulation but not these other activities. Monkeys infected with these mutant forms of SIV exhibited higher levels of CD8(+) T-cell responses 4 to 16 weeks postinfection than seen in monkeys infected with the parental wild-type virus. Furthermore, unusual compensatory mutations appeared by 16 to 32 weeks postinfection which restored some or all of the MHC-downregulating activity. These results indicate that nef does serve to limit the virus-specific CD8 cellular response of the host and that the ability to downregulate MHC class I contributes importantly to the totality of nef function.

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    • "P values from the Wilcoxon matched-pairs test are shown. responses by HLA-I down-regulation (Lewis et al., 2008; Swigut et al., 2004), though why this is not additionally manifested in higher plasma viral load remains an open question. "
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    ABSTRACT: Nef plays a major role in HIV-1 pathogenicity. We studied HIV-1 subtype C infected individuals in acute/early (n=120) or chronic (n=207) infection to investigate the relationship between Nef-mediated CD4/HLA-I down-regulation activities and disease progression, and the influence of immune-driven sequence variation on these Nef functions. A single Nef sequence per individual was cloned into an expression plasmid, followed by transfection of a T cell line and measurement of CD4 and HLA-I expression. In early infection, a trend of higher CD4 down-regulation ability correlating with higher viral load set point was observed (r=0.19, p=0.05), and higher HLA-I down-regulation activity was significantly associated with faster rate of CD4 decline (p=0.02). HLA-I down-regulation function correlated inversely with the number HLA-associated polymorphisms previously associated with reversion in the absence of the selecting HLA allele (r=−0.21, p=0.0002). These data support consideration of certain Nef regions in HIV-1 vaccine strategies designed to attenuate the infection course.
    Virology 11/2014; s 468–470:214–225. DOI:10.1016/j.virol.2014.08.009 · 3.32 Impact Factor
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    • "Indeed, disruption of Nef motifs involved in CD4 downregulation and enhancement of viral infectivity revealed that these Nef functions were critical for viral replication in early SIV infection, and thus that HLA-I downregulation alone was not adequate for SIV virulence [55]. In addition, although Nef sequences with efficient HLA-I downregulation activity were selected during early SIV and HIV infection [33,56], elimination of this function did not significantly impact SIV viral loads [56]. Furthermore, while Nef-mediated CD4 downregulation is typically maintained or enhanced throughout the HIV-1 disease course [33], Nef’s HLA-I downregulation activity appears to be maintained in chronic infection [48], but is reported to diminish after progression to AIDS [33]. "
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    ABSTRACT: The highly genetically diverse HIV-1 group M subtypes may differ in their biological properties. Nef is an important mediator of viral pathogenicity; however, to date, a comprehensive inter-subtype comparison of Nef in vitro function has not been undertaken. Here, we investigate two of Nef's most well-characterized activities, CD4 and HLA class I downregulation, for clones obtained from 360 chronic patients infected with HIV-1 subtypes A, B, C or D. Single HIV-1 plasma RNA Nef clones were obtained from N=360 antiretroviral-naive, chronically infected patients from Africa and North America: 96 (subtype A), 93 (B), 85 (C), and 86 (D). Nef clones were expressed by transfection in an immortalized CD4+ T-cell line. CD4 and HLA class I surface levels were assessed by flow cytometry. Nef expression was verified by Western blot. Subset analyses and multivariable linear regression were used to adjust for differences in age, sex and clinical parameters between cohorts. Consensus HIV-1 subtype B and C Nef sequences were synthesized and functionally assessed. Exploratory sequence analyses were performed to identify potential genotypic correlates of Nef function. Subtype B Nef clones displayed marginally greater CD4 downregulation activity (p = 0.03) and markedly greater HLA class I downregulation activity (p < 0.0001) than clones from other subtypes. Subtype C Nefs displayed the lowest in vitro functionality. Inter-subtype differences in HLA class I downregulation remained statistically significant after controlling for differences in age, sex, and clinical parameters (p < 0.0001). The synthesized consensus subtype B Nef showed higher activities compared to consensus C Nef, which was most pronounced in cells expressing lower protein levels. Nef clones exhibited substantial inter-subtype diversity: cohort consensus residues differed at 25% of codons, while a similar proportion of codons exhibited substantial inter-subtype differences in major variant frequency. These amino acids, along with others identified in intra-subtype analyses, represent candidates for mediating inter-subtype differences in Nef function. Results support a functional hierarchy of subtype B > A/D > C for Nef-mediated CD4 and HLA class I downregulation. The mechanisms underlying these differences and their relevance to HIV-1 pathogenicity merit further investigation.
    Retrovirology 09/2013; 10(1):100. DOI:10.1186/1742-4690-10-100 · 4.19 Impact Factor
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    • "Similar evidence based on in vivo selection implicating MHC-I restricted activity of CD8 þ T cells comes from a study of a SIV- mac239 variant engineered to be incapable of the MHIC-I downregulation via Nef, but intact for other Nef functions. The SIVmac239 variant underwent extensive mutation in vivo in infected macaques to restore the capacity to down-regulate MHC-I, associated with a relative loss of control of viral replication, supporting the importance of MHC-I restricted killing by CD8 þ T cells (Swigut et al. 2004). CD8 þ T cells could potentially contribute to control of viral replication via both cytolytic and noncytolytic mechanisms, including production of antiviral cytokines or chemokines, including MIP-1b (Cocchi et al. 1995; Gauduin 1998). "
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    ABSTRACT: Nonhuman primate (NHP) disease models for AIDS have made important contributions to the search for effective vaccines for AIDS. Viral diversity, persistence, capacity for immune evasion, and safety considerations have limited development of conventional approaches using killed or attenuated vaccines, necessitating the development of novel approaches. Here we highlight the knowledge gained and lessons learned in testing vaccine concepts in different virus/NHP host combinations. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor Perspectives in Medicine 06/2012; 2(6):a007310. DOI:10.1101/cshperspect.a007310 · 9.47 Impact Factor
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