Nef proteins from simian immunodeficiency virus-infected chimpanzees interact with p21-activated kinase 2 and modulate cell surface expression of various human receptors.
The accessory Nef protein allows human immunodeficiency virus type 1 (HIV-1) to persist at high levels and to cause AIDS in infected humans. The function of HIV-1 group M subtype B nef alleles has been extensively studied, and a variety of in vitro activities believed to be important for viral pathogenesis have been established. However, the function of nef alleles derived from naturally simian immunodeficiency virus (SIV)-infected chimpanzees, the original host of HIV-1, or from the HIV-1 N and O groups resulting from independent zoonotic transmissions remains to be investigated. In the present study we demonstrate that SIVcpz and HIV-1 group N or O nef alleles down-modulate CD4, CD28, and class I or II MHC molecules and up-regulate surface expression of the invariant chain (Ii) associated with immature major histocompatibility complex (MHC) class II. Furthermore, the ability of Nef to interact with the p21-activated kinase 2 was generally conserved. The functional activity of HIV-1 group N and O nef genes did not differ significantly from group M nef alleles. However, SIVcpz nef genes as a group showed a 1.8- and 2.0-fold-higher activity in modulating CD28 (P = 0.0002) and Ii (P = 0.016) surface expression, respectively, but were 1.7-fold less active in down-regulating MHC class II molecules (P = 0.006) compared to HIV-1 M nef genes. Our finding that primary SIVcpz nef alleles derived from naturally infected chimpanzees modulate the surface expression of various human cellular receptors involved in T-cell activation and antigen presentation suggests that functional nef genes helped the chimpanzee virus to persist efficiently in infected humans immediately after zoonotic transmission.
Kirchhoff
Frank
F
Department of Virology, Universitatsklinikum, 89081 Ulm, Germany. frank.kirchhoff@medizin.uni-ulm.de
Schindler
Michael
M
Bailer
Nicola
N
Renkema
G Herma
GH
Saksela
Kalle
K
Knoop
Volker
V
Müller-Trutwin
Michaela C
MC
Santiago
Mario L
ML
Bibollet-Ruche
Frederic
F
Dittmar
Matthias T
MT
Heeney
Jonathan L
JL
Hahn
Beatrice H
BH
Münch
Jan
J
D000328:Adult; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D015693:Gene Products, nef / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D002679:Pan troglodytes / Q000821:virology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D054311:nef Gene Products, Human Immunodeficiency Virus; D054462:p21-Activated Kinases
D018106:CD28 Antigens; D015704:CD4 Antigens; D015693:Gene Products, nef; D000949:Histocompatibility Antigens Class II; D054311:nef Gene Products, Human Immunodeficiency Virus; C515907:PAK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases