Background:  FTY720 is a drug that causes retention of lymphocytes in lymphatic tissues, resulting in the depletion of lymphocytes from blood and peripheral tissues. Previous studies have shown that administration of FTY720 during chronic lymphocytic choriomeningitis virus (LCNV) infection of mice can decrease and even eliminate virus burden. We address the hypothesis that therapeutic use of FTY720 in simian-human immunodeficiency virus (SHIV) -infected rhesus macaques could also lead to a decrease in viremia.

Methods:  FTY720 was administered intravenously to 3 SHIV_SF162P3-infected rhesus macaques 39, 7, or 6 weeks after infection; 3 control macaques (47, 48, or 6 weeks of infection) did not receive drug. Because an effective dose has not been reported in rhesus macaques, FTY720 was first given at 0.004 mg/kg on days 0, 1, 2, 14, 15, and 16, followed by 0.1 mg/kg on days 28, 29, 30, 42, 43, and 44. Blood was collected 8 times throughout and 4 times during 47 days following the last injection. Plasma virus load, proviral DNA, and CD4 and 8 T cell numbers were analyzed. Statistical significance was determined by unpaired t test of mean data and the standard error of the mean.

Results:  Only the 0.1-mg/kg FTY720 dose resulted in a statistically significant reduction in mean blood CD4 T cells to 33% of pre-drug levels (p = 0.0024). CD4 T cells returned to normal levels within 5 days after each treatment period. CD8 T cells were not affected by FTY720. None of the 3 untreated macaques exhibited significant reductions in CD4 or 8 T cells. SHIV_SF162P3 viremia typically peaks within 3 weeks of infection and returns to low virus set-points within 12 weeks. FTY720 treatment did not lead to significant deviations from this pattern of viral control. Plasma viral loads progressed from a range of 10⁴ to 10² copies/mL before treatment to 10⁴ to temporarily undetectable levels on the last day of treatment. SHIV_SF162P3 was not eliminated, however, as plasma viremia and proviral DNA persisted during 47 days of follow-up.

Conclusions:  FTY720 administration did not result in a significant decrease or increase in SHIV_SF162P3 burden in the macaques, indicating no therapeutic effect at the doses and schedules outlined here. This study has identified an effective FTY720 regimen that reduces blood CD4⁺ cells in rhesus macaques. Future work is needed to evaluate whether this regimen can also reduce rectal or vaginal mucosal CD4⁺ cells and thereby decrease susceptibility to SHIV infection in a preclinical macaque model.