Deletion of the vpu sequences prior to the env in a simian-human immunodeficiency virus results in enhanced Env precursor synthesis but is less pathogenic for pig-tailed macaques.
The Vpu protein of human immunodeficiency virus type 1 (HIV-1) has been reported to enhance virion release from infected cells and to down-regulate the expression of CD4 on infected cells. Previous studies have shown that Vpu and the envelope glycoprotein precursor (gp160) are translated from different reading frames of the same bicistronic messenger RNA (mRNA). In order to assess the effect of the Vpu sequences 5' to the Env open reading frame on Env biosynthesis and pathogenesis, we have constructed a deletion mutant of a molecularly cloned chimeric simian--human immunodeficiency virus (SHIV(KU-1bMC33)) in which the entire coding region of vpu upstream of env had been deleted (novpuSHIV(KU-1bMC33)). While both SHIV(KU-1bMC33) and novpuSHIV(KU-1bMC33) synthesized comparable amounts of env mRNA in infected cells, the novpuSHIV(KU-1bMC33)-infected cells synthesized more Env precursor when standardized against the p57 Gag precursor protein. While more Env was synthesized than Gag in novpuSHIV(KU-1bMC33)-infected cells, pulse--chase analysis revealed that p27 Gag protein was released from infected cells with delayed kinetics, a reflection of the lack of a Vpu protein. Inoculation of novpuSHIV(KU-1bMC33) into two pig-tailed macaques resulted in no loss of circulating CD4(+) T cells. However, replicating virus could be detected in the lymphoid tissues (lymph nodes, spleen, thymus) 1 year after inoculation and the thymus of one of the macaques exhibited severe atrophy. The results of these studies indicate that the Vpu coding sequences upstream of Env may attenuate the level of Env precursor biosynthesis but significantly contribute to the pathogenesis of this SHIV in pig-tailed macaques.
Stephens
Edward B
EB
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. estephen@kumc.edu
McCormick
Coleen
C
Pacyniak
Erik
E
Griffin
Darcy
D
Pinson
David M
DM
Sun
Francis
F
Nothnick
Warren
W
Wong
Scott W
SW
Gunderson
Robert
R
Berman
Nancy E J
NE
Singh
Dinesh K
DK
D000818:Animals; D001284:Atrophy; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D004279:DNA, Viral / Q000032:analysis; D017353:Gene Deletion; D015686:Gene Products, env / Q000032:analysis / Q000096:biosynthesis*; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D054298:Human Immunodeficiency Virus Proteins; D008198:Lymph Nodes / Q000821:virology; D008254:Macaca nemestrina; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000032:analysis / Q000096:biosynthesis*; D016865:Reassortant Viruses / Q000235:genetics / Q000472:pathogenicity*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity*; D013154:Spleen / Q000821:virology; D013950:Thymus Gland / Q000473:pathology / Q000821:virology; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics; D014774:Virulence; D014779:Virus Replication; D000086082:Viroporin Proteins
D004279:DNA, Viral; D015686:Gene Products, env; D054298:Human Immunodeficiency Virus Proteins; D011498:Protein Precursors; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins