A molecular clone of simian-human immunodeficiency virus (DeltavpuSHIV(KU-1bMC33)) with a truncated, non-membrane-bound vpu results in rapid CD4(+) T cell loss and neuro-AIDS in pig-tailed macaques.
We report on the role of vpu in the pathogenesis of a molecularly cloned simian-human immunodeficiency virus (SHIV(KU-1bMC33)), in which the tat, rev, vpu, env, and nef genes derived from the uncloned SHIV(KU-1b) virus were inserted into the genetic background of parental nonpathogenic SHIV-4. A mutant was constructed (DeltavpuSHIV(KU-1bMC33)) in which 42 of 82 amino acids of Vpu were deleted. Phase partitioning studies revealed that the truncated Vpu was not an integral membrane protein, and pulse-chase culture studies revealed that cells inoculated with DeltavpuSHIV(KU-1bMC33) released viral p27 into the culture medium with slightly reduced kinetics compared with cultures inoculated with SHIV(KU-1bMC33). Inoculation of DeltavpuSHIV(KU-1bMC33) into two pig-tailed macaques resulted in a severe decline of CD4(+) T cells and neurological disease in one macaque and a more moderate decline of CD4(+) T cells in the other macaque. These results indicate that a membrane-bound Vpu is not required for the CD4(+) T cell loss and neurological disease in SHIV-inoculated pig-tailed macaques. Furthermore, because the amino acid substitutions in the Tat and Rev were identical to those previously reported for the nonpathogenic SHIV(PPc), our results indicate that amino acid substitutions in the Env and/or Nef were responsible for the observed CD4(+) T cell loss and neurological disease after inoculation with this molecular clone.
McCormick-Davis
C
C
Departments of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Dalton
S B
SB
Hout
D R
DR
Singh
D K
DK
Berman
N E
NE
Yong
C
C
Pinson
D M
DM
Foresman
L
L
Stephens
E B
EB
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000473:pathology / Q000821:virology*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002213:Capsid / Q000378:metabolism; D036022:Capsid Proteins; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002490:Central Nervous System / Q000473:pathology / Q000821:virology; D020805:Central Nervous System Viral Diseases / Q000276:immunology / Q000821:virology*; D003001:Cloning, Molecular; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D015683:Gene Products, gag / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology / Q000821:virology; D008254:Macaca nemestrina; D008969:Molecular Sequence Data; D017384:Sequence Deletion / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D019562:Viral Load; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054301:gag Gene Products, Human Immunodeficiency Virus; D000086082:Viroporin Proteins
D036022:Capsid Proteins; D004279:DNA, Viral; D015683:Gene Products, gag; D015699:HIV Envelope Protein gp120; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C074737:p27 gag protein, Human immunodeficiency virus; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins