We found, unexpectedly, that the SIVcpz strains that are closely related to the ancestral viruses of groups M and N, as well as the lineages of SIVcpz that are not associated with any known HIV-1 infections in humans, are all significantly less pathogenic or non-pathogenic in hu-BLT mice compared with HIV-1, manifesting significantly lower degrees of CD4+ T-cell depletion and cell activation compared with uninfected controls and HIV-1-infected animals. The gene discussed is CD4; the disease is HIV-1 infection.