Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: Association with disease progression and influence of immune pressure

  • Jaclyn K Mann ,
  • Denis Chopera ,
  • Saleha Omarjee ,
  • Xiaomei T Kuang ,
  • Anh Q Le ,
  • Gursev Anmole ,
  • Ryan Danroth ,
  • Philip Mwimanzi ,
  • Tarylee Reddy ,
  • ,
  • Mopo Radebe ,
  • Philip JR Goulder ,
  • Bruce D Walker ,
  • Salim Abdool Karim ,
  • Vladimir Novitsky ,
  • Carolyn Williamson ,
  • Mark A Brockman ,
  • Zabrina L Brumme ,
  • Thumbi Ndung'u

Virology | , pp. 214-225

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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.