We and others have reported that the vast majority of virus-producing CD4⁺ T cells during the acute infection of rhesus macaques with simian immunodeficiency virus (SIV) or CXCR4 (X4)-using simian/human immunodeficiency viruses (SHIVs) exhibited a nonactivated phenotype. These findings have been extended to show that resting CD4⁺ T lymphocytes collected from SIV- or X4-SHIV-infected animals during the first 10 days of infection continue to release virus ex vivo. Furthermore, we observed high frequencies of integrated viral DNA (up to 5.1 × 10⁴ DNA copies per 10⁵ cells) in circulating resting CD4⁺ T cells during the first 10 days of the infection. Integration of SIV DNA was detected only in memory CD4⁺ T cells and SHIVs preferentially integrated into resting naïve CD4⁺ T cells. Taken together, these results show that during the acute infection large numbers of resting CD4⁺ T cells carry integrated nonhuman primate lentiviral DNA and are the major source of progeny virions irrespective of coreceptor usage. Prompt and sustained interventions are therefore required to block the rapid systemic dissemination of virus and prevent an otherwise fatal clinical outcome.