In vivo attenuation of simian immunodeficiency virus by disruption of a tyrosine-dependent sorting signal in the envelope glycoprotein cytoplasmic tail

被引:68
作者
Fultz, PN
Vance, PJ
Endres, MJ
Tao, BL
Dvorin, JD
Davis, IC
Lifson, JD
Montefiori, DC
Marsh, M
Malim, MH
Hoxie, JA
机构
[1] Univ Penn, Div Hematol Oncol, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA
[3] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA
[4] Univ Alabama Birmingham, Dept Comparat Med, Birmingham, AL 35294 USA
[5] NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, AIDS Vaccine Program, Frederick, MD 21701 USA
[6] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA
[7] UCL, MRC, Mol Cell Biol Lab, London, England
[8] UCL, Dept Biochem, London, England
关键词
D O I
10.1128/JVI.75.1.278-291.2001
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Attenuated simian immunodeficiency viruses (SIVs) have been described that produce low levels of plasma virion RNA and exhibit a reduced capacity to cause disease. These viruses are particularly useful in identifying viral determinants of pathogenesis. In the present study, we show that mutation of a highly conserved tyrosine (Tyr)-containing motif (Yxx phi) in the envelope glycoprotein (Env) cytoplasmic tail (amino acids YRPV at positions 721 to 724) can profoundly reduce the in vivo pathogenicity of SIVmac239. This domain constitutes both a potent endocytosis signal that reduces Env expression on infected cells and a sorting signal that directs Env expression to the basolateral surface of polarized cells. Rhesus macaques were inoculated with SIVmac239 control or SIVmac239 containing either a Tyr-721-to-Ile mutation (SIVmac239Y/I) or a deletion of Tyr-721 and the preceding glycine (Delta GY). To assess the in vivo replication competence, all viruses contained a stop codon in nef that has been shown to revert during in vivo but not in vitro replication. All three control animals developed high viral loads and disease. One of two animals that received SIVmac239Y/I and two of three animals that received SIVmac239 Delta GY remained healthy for up to 140 weeks with low to undetectable plasma viral RNA levels and normal CD4(+) T-cell percentages. These animals exhibited ongoing viral replication as determined by detection of viral sequences and culturing of mutant viruses from peripheral blood mononuclear cells and persistent anti-SN antibody titers. In one animal that received SIVmac239Y/I, the Ile reverted to a Tyr and was associated with a high plasma RNA level and disease, while one animal that received SIVmac239 Delta GY also developed a high viral load that was associated with novel and possibly compensatory mutations in the TM cytoplasmic domain. In all control and experimental animals, the nef stop codon reverted to an open reading frame within the first 2 months of inoculation, indicating that the mutant viruses had replicated well enough to repair this mutation. These findings indicate that the Yxx phi signal plays an important role in SIV pathogenesis. Moreover, because mutations in this motif may attenuate SN through mechanisms that are distinct from those caused by mutations in nef, this Tyr-based sorting signal represents a novel target for future models of SIV and human immunodeficiency virus attenuation that could be useful in new vaccine strategies.
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收藏
页码:278 / 291
页数:14
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