Association between a naturally arising polymorphism within a functional region of HIV-1 Nef and disease progression in chronic HIV-1 infection

• Published in: Archives of virology Vol. 160; no. 8; pp. 2033 - 2041
• Main Authors: Meribe, Stanley C., Hasan, Zafrul, Mahiti, Macdonald, Mwimanzi, Francis, Toyoda, Mako, Mori, Masahiko, Gatanaga, Hiroyuki, Kikuchi, Tadashi, Miura, Toshiyuki, Kawana-Tachikawa, Ai, Iwamoto, Aikichi, Oka, Shinichi, Ueno, Takamasa
• Format: Journal Article
• Language: English
• Published: Vienna Springer Vienna 01.08.2015; Springer Nature B.V
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; Biomedical and Life Sciences; Biomedicine; Chronic Disease; codons; data collection; disease course; Disease Progression; Down-Regulation; Female; gene expression regulation; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; HIV; HIV infections; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - virology; HIV-1 - classification; HIV-1 - genetics; HIV-1 - isolation & purification; HIV-1 - physiology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Infections; Infectious Diseases; isoleucine; Male; Medical Microbiology; Medicine; Molecular Sequence Data; mutation; nef Gene Products, Human Immunodeficiency Virus - genetics; nef Gene Products, Human Immunodeficiency Virus - metabolism; open reading frames; Original Article; Phylogeny; Polymorphism; Polymorphism, Genetic; reverse transcriptase polymerase chain reaction; RNA; Viral Load; Virology; Japan; Clinical Disease Outcome; Alternative Amino Acid; Plasma Viral Load; High Plasma Viral Load; Functional Motif
• ISSN: 0304-8608; 1432-8798
• DOI: 10.1007/s00705-015-2480-5

HIV-1 Nef mediates downregulation of HLA class I (HLA-I) through a number of highly conserved sequence motifs. We investigated the in vivo implication(s) of naturally arising polymorphisms in functional motifs in HIV-1 Nef that are associated with HLA-I downregulation, including the acidic cluster, polyproline, di-arginine and Met-20 regions. Plasma samples from treatment-naive, chronically HIV-1 infected subjects were collected after obtaining informed consent, and viral RNA was extracted and amplified by nested RT-PCR. The resultant nef amplicons were sequenced directly, and subtype-B sequences with an intact open reading frame (n = 406) were included in our analyses. There was over-representation of isoleucine at position 20 (Ile-20) in our dataset when compared to sequences in the Los Alamos sequence database (17.7 vs. 6.9 %, p  = 0.0309). The presence of having Ile-20 in Nef was found to be associated with higher median plasma viral load ( p  = 0.013), independent of associated codons or viral lineage effects, whereas no clinical association was found with polymorphisms in the other functional motifs. Moreover, introduction of a Met-20-to-Ile mutation in a laboratory strain SF2 Nef resulted in a modest, albeit not statistically significant, increase in HLA class I downregulation activity ( p  = 0.06). Taken together, we have identified a naturally arising polymorphism, Ile-20, within HIV-1 subtype B Nef that is associated with poorer disease outcome.