Infection of macaques with chimeric simian–human immunodeficiency virus (SHIV) provides an excellent in vivo model for examining the influence of envelope on HIV-1 pathogenesis. Infection with a pathogenic CCR5 (R5)–specific enveloped virus, SHIV_SF162P, was compared with infection with the CXCR4 (X4)–specific SHIV_SF33A.2. Despite comparable levels of viral replication, animals infected with the R5 and X4 SHIV had distinct pathogenic outcomes. SHIV_SF162P caused a dramatic loss of CD4⁺ intestinal T cells followed by a gradual depletion in peripheral CD4⁺ T cells, whereas infection with SHIV_SF33A.2 caused a profound loss in peripheral T cells that was not paralleled in the intestine. These results suggest a critical role of co-receptor utilization in viral pathogenesis and provide a reliable in vivo model for preclinical examination of HIV-1 vaccines and therapeutic agents in the context of the HIV-1 envelope protein.