title: Understanding the basis of CD4(+) T-cell depletion in macaques infected by a simian-human immunodeficiency virus.
abstract: 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.
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors: Bijan
authors: B
authors: Etemad-Moghadam
authors: Daniela
authors: D
authors: Rhone
authors: Tavis
authors: T
authors: Steenbeke
authors: Ying
authors: Y
authors: Sun
authors: Judith
authors: J
authors: Manola
authors: Rebecca
authors: R
authors: Gelman
authors: John W
authors: JW
authors: Fanton
authors: Paul
authors: P
authors: Racz
authors: Klara
authors: K
authors: Tenner-Racz
authors: Michael K
authors: MK
authors: Axthelm
authors: Norman L
authors: NL
authors: Letvin
authors: Joseph
authors: J
authors: Sodroski
mesh_terms: 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
chemical_list: D015699:HIV Envelope Protein gp120