Complete Rescue of HTLV-1[sub.p12KO] Infectivity by Depletion of Monocytes Together with NK and CD8[sup.+] T Cells

The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1[sub.WT] (wild type) and HTLV-1[sub.p12KO] (Orf-1 knockout) infectivity, but seroconversion to either virus is not sustained over time, suggesting a progressive decrease in virus expression. These results raise the hypotheses that either HTLV-1 persistence depends on a monocyte reservoir or monocyte depletion provides a transient immune evasion benefit. To test these hypotheses, we simultaneously depleted NK cells, CD8[sup.+] T cells, and monocytes (triple depletion) prior to exposure to HTLV-1[sub.WT] or HTLV-1[sub.p12KO] . Remarkably, triple depletion resulted in exacerbation of infection by both viruses and complete rescue of HTLV-1[sub.p12KO] infectivity. Following triple depletion, we observed rapid and sustained seroconversion, high titers of antibodies against HTLV-1 p24Gag, and frequent detection of viral DNA in the blood and tissues of all animals when compared with depletion of only CD8[sup.+] and NK cells, or monocytes alone. The infection of macaques with HTLV-1[sub.WT] or HTLV-1[sub.p12KO] was associated with higher plasma levels of IL-10 after 21 weeks, while IL-6, IFN-γ, IL-18, and IL-1β were only elevated in animals infected with HTLV-1[sub.WT] . The repeat depletion of monocytes, NK, and CD8[sup.+] cells seven months following the first exposure to HTLV-1 did not further exacerbate viral replication. These results underscore the contribution of monocytes in orchestrating anti-viral immunity. Indeed, the absence of orf-1 expression was fully compensated by the simultaneous depletion of CD8[sup.+] T cells, NK cells, and monocytes, underlining the primary role of orf-1 in hijacking host immunity.