In vivo mutational analysis of the N-terminal region of HIV-1 Nef reveals critical motifs for the development of an AIDS-like disease in CD4C/HIV transgenic mice

Virology
Zaher HannaPaul Jolicoeur

Abstract

HIV-1 Nef is a critical determinant of pathogenicity in humans and transgenic (Tg) mice. To gain a better understanding of the molecular mechanisms by which Nef induces an AIDS-like disease in Tg mice, a mutational analysis of the N-terminal domain, involved in anchoring Nef to the plasma membrane, was carried out. The pathogenic effects of these Nef mutant alleles were evaluated in Tg mice by FACS analysis and by histopathological assessment. Mutation of the myristoylation site (G2A) completely abrogated the development of the AIDS-like organ disease in Tg mice, although partial downregulation of the CD4 cell surface protein and depletion of peripheral CD4+ T-cells, but not of CD4(+)CD8+ thymocytes, still occurred. Despite that, the peripheral CD4+ T cells expressing Nef(G2A) show normal spontaneous proliferation in vivo or after stimulation in vitro, including in an allogenic mixed leukocyte reaction (MLR). Three other internal deletion mutants of Nef, spanning amino acids 8-17 (Nef(Delta8-17)), 25-35 (Nef(Delta25-35)), and 57-66 (Nef(Delta57-66)), were also studied. Nef(Delta8-17) retained full pathogenic potential, although Nef(Delta25-35) and Nef(Delta57-66) Tg mice were free of organ disease. However, Nef(Delta25-35) Tg m...Continue Reading

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Citations

Sep 19, 2007·Clinical Journal of the American Society of Nephrology : CJASN·Leslie A Bruggeman
Aug 11, 2005·Current HIV/AIDS Reports·Rohan Hazra, Crystal Mackall
Oct 9, 2007·Journal of Molecular Biology·Ronald P TribleThomas E Smithgall
Sep 23, 2010·Biophysical Journal·Michael S KentJohn R Engen
May 11, 2006·Virology·Oliver T FacklerHans-Georg Kräusslich
Apr 24, 2016·Biochemical and Biophysical Research Communications·Manjeet KumarRaj Kamal Tripathi
Sep 5, 2009·Journal of the American Society of Nephrology : JASN·Leslie A Bruggeman
Aug 18, 2006·Journal of the American Society of Nephrology : JASN·Mamdouh AlbaqumiPeter J Nelson
Sep 22, 2006·Journal of the American Society of Nephrology : JASN·Yiqin ZuoIekuni Ichikawa
Jun 6, 2009·Journal of the American Society of Nephrology : JASN·Paul RosenstielPaul Klotman
Sep 25, 2017·SAHARA J : Journal of Social Aspects of HIV/AIDS Research Alliance·B J Mohapi, E M Pitsoane
Mar 20, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Huanhuan L CuiDmitri Sviridov

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