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

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Abstract

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.

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Acknowledgments

We thank Ezinne K. Okoro for helpful discussion. This study was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture (MEXT) of Japan and by a grant-in-aid for AIDS research from the Ministry of Health, Labor, and Welfare of Japan. SCM and FM were supported by a scholarship from the International Priority Graduate Programs, Advanced Graduate Courses for International Students (Doctoral Course), MEXT, Japan.

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  1. Center for AIDS Research, Kumamoto University, 2-2-1 Chuo-ku, Honjo, Kumamoto, 860-0811, Japan

    Stanley C. Meribe, Zafrul Hasan, Macdonald Mahiti, Francis Mwimanzi, Mako Toyoda, Hiroyuki Gatanaga, Shinichi Oka & Takamasa Ueno

  2. Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan

    Masahiko Mori & Toshiyuki Miura

  3. Department of Paediatrics, University of Oxford, Oxford, UK

    Masahiko Mori

  4. AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan

    Hiroyuki Gatanaga & Shinichi Oka

  5. Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Tadashi Kikuchi, Toshiyuki Miura, Ai Kawana-Tachikawa & Aikichi Iwamoto

  6. International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan

    Takamasa Ueno

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Meribe, S.C., Hasan, Z., Mahiti, M. et al. Association between a naturally arising polymorphism within a functional region of HIV-1 Nef and disease progression in chronic HIV-1 infection. Arch Virol 160, 2033–2041 (2015). https://doi.org/10.1007/s00705-015-2480-5

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