An R5-tropic SHIV CHN19P4 was previously generated using a primary HIV-1 subtype-C envelope. We have further characterized this SHIV in two species of macaques. To determine whether this isolate is transmissible vaginally, female pigtailed macaques were inoculated with 2x10 3 TCID 50 of SHIV CHN19P4 by the vaginal route. Animals became infected with a high peak plasma viremia (> 10 7 viral copies/mL) and rapid seroconversion. The viremia was accompanied by CD4+ lymphocytopenia in the gut lamina propria lymphocyte (LPL) population. Comparable CD4+ T-cell loss was not seen in peripheral blood and colonic lymph nodes. These findings demonstrate a unique R5-tropic SHIV that can be used to study enveloperelated issues in vaginal transmission of the most prevalent subtype of HIV-1. We also found that rhesus macaques intravenously inoculated with 1× 10 3 TCID 50 of SHIV CHN19P4 became infected and showed CD4+ lymphocytopenia in the gut LPL population. Despite inactivation of the vpu gene in SHIV CHN19P4, the virus appears to target mainly gut-associated lymphoid tissues during the initial stage of infection as has been described for SHIV SF162P, another R5-tropic (subtype B) recombinant virus. Our data indicate that the R5-mediated CD4+ lymphocytopenia in the gut is likely independent of HIV-1 genotypes and of the function of vpu at the acute phase of viral infection.