Changes in human immunodeficiency virus type 1 envelope glycoproteins responsible for the pathogenicity of a multiply passaged simian-human immunodeficiency virus (SHIV-HXBc2).
In vivo passage of a poorly replicating, nonpathogenic simian-human immunodeficiency virus (SHIV-HXBc2) generated an efficiently replicating virus, KU-1, that caused rapid CD4(+) T-lymphocyte depletion and AIDS-like illness in monkeys (S. V. Joag, Z. Li, L. Foresman, E. B. Stephens, L.-J. Zhao, I. Adany, D. M. Pinson, H. M. McClure, and O. Narayan, J. Virol. 70:3189-3197, 1996). The env gene of the KU-1 virus was used to create a molecularly cloned virus, SHIV-HXBc2P 3.2, that differed from a nonpathogenic SHIV-HXBc2 virus in only 12 envelope glycoprotein residues. SHIV-HXBc2P 3.2 replicated efficiently and caused rapid and persistent CD4(+) T-lymphocyte depletion in inoculated rhesus macaques. Compared with the envelope glycoproteins of the parental SHIV-HXBc2, the SHIV-HXBc2P 3.2 envelope glycoproteins supported more efficient infection of rhesus monkey peripheral blood mononuclear cells. Both the parental SHIV-HXBc2 and the pathogenic SHIV-HXBc2P 3.2 used CXCR4 but none of the other seven transmembrane segment receptors tested as a second receptor. Compared with the parental virus, viruses with the SHIV-HXBc2P 3.2 envelope glycoproteins were more resistant to neutralization by soluble CD4 and antibodies. Thus, changes in the envelope glycoproteins account for the ability of the passaged virus to deplete CD4(+) T lymphocytes rapidly and specify increased replicative capacity and resistance to neutralization.
Cayabyab
M
M
Department of Cancer Immunology/AIDS, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Karlsson
G B
GB
Etemad-Moghadam
B A
BA
Hofmann
W
W
Steenbeke
T
T
Halloran
M
M
Fanton
J W
JW
Axthelm
M K
MK
Letvin
N L
NL
Sodroski
J G
JG
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002461:Cell Line, Transformed; D004279:DNA, Viral; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008253:Macaca mulatta; D008262:Macrophage Activation; D008264:Macrophages / Q000821:virology; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D016865:Reassortant Viruses / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D012692:Serial Passage; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
D004279:DNA, Viral; D006023:Glycoproteins; D014759:Viral Envelope Proteins