Understanding the basis of CD4(+) T-cell depletion in macaques infected by a simian-human immunodeficiency virus.
The efficacy of candidate AIDS vaccines to mediate protection against viral infection and pathogenesis is evaluated, at a preclinical stage, in animal models. One model that is favored because the infecting virus is closely related to HIV-1 and because of the rapidity of pathogenic outcomes is the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae. We investigated the basis for the depletion of CD4(+) T lymphocytes in a SHIV-macaque model. Molecularly cloned SHIVs, SHIV-89.6 and SHIV-KB9, differ in the ability to cause CD4(+) T-cell loss at a given level of virus replication in monkeys. The envelope glycoproteins of the pathogenic SHIV-KB9 mediate membrane-fusion in cultured T lymphocytes more efficiently than the envelope glycoproteins of the non-pathogenic SHIV-89.6. The minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity was sufficient to convert SHIV-89.6 into a virus that causes profound CD4(+) T-cell depletion in monkeys. Conversely, two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins also attenuated the CD4(+) T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4(+) T lymphocytes in vivo.
Etemad-Moghadam
Bijan
B
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Rhone
Daniela
D
Steenbeke
Tavis
T
Sun
Ying
Y
Manola
Judith
J
Gelman
Rebecca
R
Fanton
John W
JW
Racz
Paul
P
Tenner-Racz
Klara
K
Axthelm
Michael K
MK
Letvin
Norman L
NL
Sodroski
Joseph
J
D019943:Amino Acid Substitution; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000821:virology*; D003588:Cytopathogenic Effect, Viral / Q000235:genetics; D015752:Genes, env; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D008253:Macaca mulatta; D008561:Membrane Fusion; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D013329:Structure-Activity Relationship; D014779:Virus Replication
D015699:HIV Envelope Protein gp120