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Previously, we described the derivation of a pathogenic strain of simian–human immunodeficiency virus (SHIVKU-2) consisting of the tat, rev, vpu,and envgenes of HIV-1 (strain HXB2) in a genetic background of SIVmac239 that causes AIDS and productive infection of the CNS in rhesus macaques (Macca mulatta) (Raghavan et al.,1997, Brain Pathol.7, 851–861). We report here on the characterization of a molecular clone of SHIVKU-2, designated SHIVKU-2MC4, that caused CD4+T cell loss as well as neurological and renal disease in macaques. DNA sequence analysis of selected SIV regions of SHIVKU-2MC4revealed 10 nucleotide changes in the LTR, whereas Gag, Vif, Vpr, Vpx, and Nef had 1, 1, 1, 2, and 13 predicted amino acid substitutions, respectively, compared to SIVmac239. DNA sequence analysis of HIV-1 derived regions of SHIVKU-2MC4revealed 2, 1, 2, and 18 predicted amino acid substitutions in the Tat, Rev, Vpu, and Env proteins, respectively, when compared to SHIV-4. Unlike the parental SHIV-4, which is not tropic for macrophages, SHIVKU-2MC4replicated efficiently in macrophage cultures as determined by p27 assays. However, despite the numerous changes in the Env protein and newly acquired tropism for macrophages, SHIVKU-2MC4, like the parental SHIV-4, used CXCR4 exclusively as its coreceptor for entry into susceptible cells. Inoculation of SHIVKU-2MC4into two rhesus macaques resulted in severe infection in which the numbers of circulating CD4+T cells in the blood declined rapidly by 2 weeks postinoculation and virus producing cells in the peripheral blood mononuclear cells were identified throughout the course of infection. At the time of euthanasia (20 and 22 weeks), both macaques had lost a significant amount of weight and had no circulating CD4+T cells. In addition, one macaque developed intension tremors and uncoordinated movements. Virological examination of tissues at necropsy revealed active virus replication in both lymphoid and nonlymphoid tissues such as the lung and brain. Histological examination revealed that the induced immunodeficiency was associated with lymphoid depletion of the lymph nodes and spleen, opportunistic infections, lentiviral encephalitis, and severe glomerulosclerosis of the kidney. This molecular clone will serve as the basis for analyzing the molecular determinants through which SHIVKU-2causes severe CD4+T cell loss, neurological disease, and SHIV nephropathy in rhesus macaques.