In vivo inactivation of Nef ITAM motif of chimeric simian/human immunodeficiency virus SHIVsbg-YE correlates with absence of increased virulence in Chinese rhesus macaques.
SHIVsbg, expressing Vpu, Tat, Rev, and Env proteins of HIV-1 Lai, was shown to be infectious for rhesus macaques. In this study, we mutated SHIVsbg Nef amino acids 17-18 from RQ to YE, conferring to SHIVsbg-YE the ability to replicate in vitro in unstimulated macaque PBMC. Juvenile macaques inoculated intravenously or orally with SHIVsbg-YE developed persistent infection. All macaques lost weight during the first 17 weeks but recovered afterward. All animals developed a strong HIV-specific humoral immune response. Viruses isolated 2 years postinoculation lost the ability to replicate in unstimulated macaque PBMC. Point mutations or 33-bp-wide deletions in the nef ITAM motif were responsible for this phenotype and correlated with clinical improvement of the infected macaques. These data demonstrate that the ITAM domain is inactivated in animals developing an acute antiviral immune response and may be detrimental to viral replication, perhaps by interfering with other well-conserved functions of SIV Nef protein.
Lafont
Bernard A P
BA
INSERM Unité 544-Institut de Virologie-Université Louis Pasteur, F-67000 Strasbourg, France.
Gloeckler
Liliane
L
Beyer
Christian
C
Einius
Sylvain
S
Gut
Jean Pierre
JP
Aubertin
Anne Marie
AM
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D015483:HIV Antibodies / Q000097:blood; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000472:pathogenicity; D054334:Viral Regulatory and Accessory Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D014774:Virulence; D014779:Virus Replication
D015483:HIV Antibodies; C429284:NEF protein, SIV; D011993:Recombinant Fusion Proteins; D054334:Viral Regulatory and Accessory Proteins