Rev-independent simian immunodeficiency virus strains are nonpathogenic in neonatal macaques.
The viral protein Rev is essential for the export of the subset of unspliced and partially spliced lentiviral mRNAs and the production of structural proteins. Rev and its RNA binding site RRE can be replaced in both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) by the constitutive RNA transport element CTE of the simian type D retroviruses. We used neonatal macaques as a sensitive animal model to evaluate the pathogenicity of a pair of SIV mutant strains generated from Rev-independent molecular clones of SIVmac239 which differ only in the presence of the nef open reading frame. After high primary viremia, all animals remained persistently infected at levels below the threshold of detection. All macaques infected as neonates developed normally, and none showed any signs of immune dysfunction or disease during follow-up ranging from 2.3 to 4 years. Therefore, the Rev-RRE regulatory mechanism plays a key role in the maintenance of high levels of virus propagation, which is independent of the presence of nef. These data demonstrate that Rev regulation plays an important role in the pathogenicity of SIV. Replacement of Rev-RRE by the CTE provides a novel approach to dramatically lower the virulence of a pathogenic lentivirus. These data further suggest that antiretroviral strategies leading to even a partial block of Rev function may modulate disease progression in HIV-infected individuals.
von Gegerfelt
Agneta S
AS
Human Retrovirus Pathogenesis Section, National Cancer Institute, Frederick, Maryland 21702-1201, USA.
Liska
Vladimir
V
Li
Pei-Lin
PL
McClure
Harold M
HM
Horie
Kyoji
K
Nappi
Filomena
F
Montefiori
David C
DC
Pavlakis
George N
GN
Marthas
Marta L
ML
Ruprecht
Ruth M
RM
Felber
Barbara K
BK
D000818:Animals; D000831:Animals, Newborn; D000914:Antibodies, Viral / Q000097:blood; D015693:Gene Products, nef / Q000235:genetics; D015694:Gene Products, rev / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D015752:Genes, env / Q000502:physiology; D008253:Macaca mulatta; D016366:Open Reading Frames; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity*; D013997:Time Factors; D014766:Viremia; D014774:Virulence
D000914:Antibodies, Viral; D015693:Gene Products, nef; D015694:Gene Products, rev