Comprehensive analysis of nef functions selected in simian immunodeficiency virus-infected macaques.
A variety of simian immunodeficiency virus (SIVmac) nef mutants have been investigated to clarify which in vitro Nef functions contribute to efficient viral replication and pathogenicity in rhesus macaques. Most of these nef alleles, however, were only functionally characterized for their ability to down-modulate CD4 and class I major histocompatibility complex (MHC-I) cell surface expression and to enhance SIV replication and infectivity. To obtain information on the in vivo relevance of more recently established Nef functions, we examined the ability of a large panel of constructed SIVmac Nef mutants and of variants that emerged in infected macaques to down-regulate CD3, CD28, and MHC-II and to up-regulate the MHC-II-associated invariant chain (Ii). We found that all these four Nef functions were restored in SIV-infected macaques. In most cases, however, the initial mutations and the changes selected in vivo affected several in vitro Nef functions. For example, truncated Nef proteins that emerged in animals infected with SIVmac239 containing a 152-bp deletion in nef efficiently modulated both CD3 and Ii surface expression. Overall, our results suggest that the effect of Nef on each of the six cellular receptors investigated contributes to viral fitness in the infected host but also indicate that modulation of CD3, MHC-I, MHC-II, or Ii surface expression alone is insufficient for SIV virulence.
Schindler
Michael
M
Department of Virology, Universitätsklinikum, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
Münch
Jan
J
Brenner
Matthias
M
Stahl-Hennig
Christiane
C
Skowronski
Jacek
J
Kirchhoff
Frank
F
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D018106:CD28 Antigens / Q000032:analysis; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D005786:Gene Expression Regulation; D005814:Genes, Viral; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D019169:Jurkat Cells; D008164:Luminescent Proteins / Q000032:analysis; D008253:Macaca mulatta; D009154:Mutation; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000302:isolation & purification / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
D000944:Antigens, Differentiation, B-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008164:Luminescent Proteins; C429284:NEF protein, SIV; D054334:Viral Regulatory and Accessory Proteins; C045084:invariant chain; D049452:Green Fluorescent Proteins