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Journal of Virology, May 2004, p. 5513-5519, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5513-5519.2004

Induction of Disease by a Molecularly Cloned Highly Pathogenic Simian Immunodeficiency Virus/Human Immunodeficiency Virus Chimera Is Multigenic

Reza Sadjadpour, Theodore S. Theodore, Tatsuhiko Igarashi, Olivia K. Donau, Ronald J. Plishka, Alicia Buckler-White, and Malcolm A. Martin^*

Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 29 September 2003/ Accepted 12 January 2004

One of three full-length infectious molecular clones of SHIV_DH12R, designated SHIV_DH12R-CL-7 and obtained from productively infected rhesus monkey peripheral blood mononuclear cells, directed rapid and irreversible loss of CD4⁺ T cells within 3 weeks of its inoculation into Indian rhesus monkeys. Induction of complete CD4⁺ T-cell depletion by SHIV_DH12R-CL-7 was found to be dependent on inoculum size. The acquisition of this pathogenic phenotype was accompanied by the introduction of 42 amino acid substitutions into multiple genes of parental nonpathogenic SHIV_DH12. Transfer of the entire SHIV_DH12R-CL-7 env gene into the genetic background of nonpathogenic SHIV_DH12 failed to confer the rapid CD4⁺ T-lymphocyte-depleting syndrome; similarly, the substitution of gag plus pol sequences from SIV_smE543 for analogous SIV_mac239 genes in SHIV_DH12R-CL-7 attenuated the pathogenic phenotype. Amino acid changes affecting multiple viral genes are necessary, but insufficient by themselves, to confer the prototypically rapid and irreversible CD4⁺ T-cell-depleting phenotype exhibited by molecularly cloned SHIV_DH12R-CL-7.

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* Corresponding author. Mailing address: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Center Dr., Bethesda, MD 20892. Phone: (301) 496-4012. Fax: (301) 402-0226. E-mail: malm{at}nih.gov.

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Journal of Virology, May 2004, p. 5513-5519, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5513-5519.2004

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