FIG. 1.

Comparison of different regimens of cyclophosphamide administration in SIV infection for regulatory T cell depletion and cytoreduction. Parameters of low-dose cyclophosphamide administration for Treg depletion are shown in (A–E). The percentage of CD4⁺ T cells expressing FoxP3 (Tregs) (A) decreased at each treatment, while CD3⁺ T cells (B) remained depleted through both treatments. LDC was marked with minimal immune activation as shown with CD69 expression on CD8⁺ T cells (C) and CD4⁺ T cells (D), with a reduction in plasma viral load in one animal and no reactivation in the other (E). Figures (F–O) show the parameters of high-dose cyclophosphamide administration to elite controllers for cytoreduction. Total lymphocytes (F), CD3⁺ T cells (G), CD4⁺ T cells (H), CD8⁺ T cells (I), and CD20⁺ cells (J) were all massively depleted with treatment. Recovery was accompanied by reciprocal immune activation as demonstrated by expression of Ki-67 (K) and HLA-DR/CD38 coexpression (L) on CD8⁺ T cells. Complimentary viral reactivation (M) occurred during the immune activation, resulting in pVLs reaching the levels of acute infection. Slight increases in kidney biomarkers creatinine (N) and urea nitrogen (O) were observed. Figures (P–T) show the parameters of modified high-dose cyclophosphamide administration in RMs infected with the pathogenic SIVmac239 treated with antiretroviral therapy (ART). Total lymphocytes (P) and CD3⁺ T cells (Q) were depleted to a lesser extent with the modified regimen and did not result in an observable increase in pVLs (R). However, cyclophosphamide with ART became highly toxic as demonstrated by creatinine (S) and urea nitrogen (T). Treatment durations are marked by highlighted areas on graphs. ART; dpt, day posttreatment; HDC, high-dose cyclophosphamide; LDC, low-dose cyclophosphamide; mHDC, modified high-dose cyclophosphamide; pVLs, plasma viral loads; RMs, rhesus macaques; SIV, simian immunodeficiency virus; Tregs, regulatory T cells.