Pathogenic determinants of the mucosally transmissible CXCR4-specific SHIVSF33A2 map to env region

Infection of rhesus macaques with chimeric simian-human immunodeficiency vi ruses (SHIV) is an established method to study AIDS pathogenesis and is inc reasingly used to assess the efficacy of vaccine and antiviral candidates. For these reasons, a detailed understanding of those molecular determinants , which confer pathogenic potential to SHIV viruses, should assist in both rational experimental design and interpretation of results. In this report, we describe the development and in vivo characterization of a pathogenic m olecular clone, SHIVSF33A2, which contains an envelope sequence derived fro m the CXCR4-dependent isolate, HIV-I-SF33. Proviral DNA, amplified from a r hesus macaque infected with the pathogenic isolate SHIVSF33A, was substitut ed into the corresponding region of the parental, nonpathogenic SHIVSF33 ge nome creating the molecular clone SHIVSF33A2. Coreceptor specificity of SHI VSF33A2 was determined to be CXCR4 specific. Naive rhesus macaques were pro ductively infected after a single exposure to cell-free SHIVSF33A2 by eithe r the intravenous (IV) or intravaginal (IVAG) routes. Animals infected with SHIVSF33A2 suffered a severe loss of peripheral CD4(+) T cells and high ac ute plasma viremia with development of simian AIDS 9 months after inoculati on. Sequence analysis identified 25 discreet amino acid changes within the V1-V5 regions of the envelope protein when compared with the nonpathogenic parental virus. These data indicate that domains within the HIV-I envelope protein are sufficient to define pathogenic potential in the context of the SIVmac239 genome.