Nef alleles from children with non-progressive HIV-1 infection modulate MHC-II expression more efficiently than those from rapid progressors

Background: It has been established that defective nef genes and differences in the Nef-mediated downmodulation of CD4 and MHC-I cell surface expression can be associated with different rates of HIV-1 disease progression. Objective: To evaluate whether nef alleles derived from perinatally HIV-1-infected children showing no, slow or rapid disease progression differ in their abilities to downmodulate mature MHC-II or to upregulate the invariant chain (Ii) associated with immature MHC-II complexes. Methods: Nef alleles derived from HIV-1 -infected children were cloned into expression vectors and proviral HIV-1 constructs co-expressing Nef and enhanced green fluorescence protein via an internal ribosomal entry site. Nef-mediated modulation of CD4, MHC-I, MHC-II or Ii surface expression was analysed by flow cytometric analysis of Jurkat T cells, monocytic THP-1 cells, CD4 T cells and macrophages transduced with vesicular stomatitis virus G-pseudotyped HIV-1 nef variants or transiently transfected HeLa class II transactivator cells. Results: Nef alleles derived from HIV-1 -infected children with non-progressive infection were significantly more active in the upregulation of Ii and downregulation of MHC-II than those derived from rapid progressors. Conclusion: Nef alleles particularly active in interfering with MHC-II antigen presentation are more frequently found in perinatally HIV-1-infected non-progressors than rapid progressors. Possibly in the context of an immature host immune system, strongly impaired MHC-II function might contribute to lower levels of immune activation and a decelerated loss of CD4 T cells. (C) 2007 Lippincott Williams & Wilkins.