Induction of disease by a molecularly cloned highly pathogenic simian immunodeficiency virus/human immunodeficiency virus chimera is multigenic

One of three full-length infectious molecular clones of SHIVDH12R, designated SHIVDH12R-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 SHIVDH12R-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 SHIVDH12. Transfer of the entire SHIVDH12R-CL-7 env gene into the genetic background of nonpathogenic SHIVDH12 failed to confer the rapid CD4(+) T-lymphocyte-depleting syndrome; similarly, the substitution of gag plus pol sequences from SIVsmE543 for analogous SIVmac239 genes in SHIVDH12R-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 SHIVDH12R-CL-7.