Understanding the basis of CD4 + T-cell depletion in macaques infected by a simian–human immunodeficiency virus

• Published in: Vaccine 2002-05, Vol.20 (15), p.1934-1937
• Main Authors: Etemad-Moghadam, Bijan, Rhone, Daniela, Steenbeke, Tavis, Sun, Ying, Manola, Judith, Gelman, Rebecca, Fanton, John W, Racz, Paul, Tenner-Racz, Klara, Axthelm, Michael K, Letvin, Norman L, Sodroski, Joseph
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Biological and medical sciences; CD4 + T-cell depletion; CD4-Positive T-Lymphocytes - pathology; CD4-Positive T-Lymphocytes - virology; Cytopathogenic Effect, Viral - genetics; Experimental viral diseases and models; Fundamental and applied biological sciences. Psychology; Genes, env; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - genetics; HIV Envelope Protein gp120 - physiology; HIV-1 - genetics; HIV-1 - pathogenicity; HIV-1 - physiology; Infectious diseases; Macaca mulatta; Medical sciences; Membrane Fusion; Microbiology; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - genetics; Simian Immunodeficiency Virus - pathogenicity; Simian Immunodeficiency Virus - physiology; Simian–human immunodeficiency virus; Structure-Activity Relationship; Viral diseases; Virology; Virus Replication
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/S0264-410X(02)00072-5

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.