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Journal of Virology, January 2001, p. 278-291, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.278-291.2001

In Vivo Attenuation of Simian Immunodeficiency Virus by Disruption of a Tyrosine-Dependent Sorting Signal in the Envelope Glycoprotein Cytoplasmic Tail

Patricia N. Fultz,1 Patricia J. Vance,2 Michael J. Endres,2 Binli Tao,1 Jeffrey D. Dvorin,3 Ian C. Davis,1,4 Jeffrey D. Lifson,5 David C. Montefiori,6 Mark Marsh,7 Michael H. Malim,3 and James A. Hoxie2,*

Department of Microbiology1 and Department of Comparative Medicine,4 University of Alabama, Birmingham, Alabama 35294; Hematology-Oncology Division2 and Department of Microbiology,3 University of Pennsylvania, Philadelphia, Pennsylvania 19104; AIDS Vaccine Program, SAIC Frederick, NCI Frederick Cancer Research and Development Center, Frederick, Maryland 217015; Department of Surgery, Duke University Medical Center, Durham, North Carolina 277106; and MRC Laboratory for Molecular Cell Biology and Department of Biochemistry, University College London, London, United Kingdom7

Received 22 June 2000/Accepted 27 September 2000

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 (Yxxphi ) 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 SIVmac239Delta 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-SIV 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 SIVmac239Delta 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 Yxxphi signal plays an important role in SIV pathogenesis. Moreover, because mutations in this motif may attenuate SIV 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.

* Corresponding author. Mailing address: Rm. 356, Biomedical Research Building II/III, University of Pennsylvania, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-0261. Fax: (215) 573-7356. E-mail: hoxie{at}mail.med.upenn.edu.

Journal of Virology, January 2001, p. 278-291, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.278-291.2001


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