The synthetic immunomodulator Murabutide controls human immunodeficiency virus type 1 replication at multiple levels in macrophages and dendritic cells

Macrophages and dendritic cells are known to play an important role in the establishment and persistence of human immunodeficiency virus (HIV) infecti on. Besides antiretroviral therapy, several immune-based interventions are being evaluated with the aim of achieving better control of virus replicati on in reservoir cells. Murabutide is a safe synthetic immunomodulator prese nting a capacity to enhance nonspecific resistance against viral infections and to target cells of the reticuloendothelial system. In this study, we h ave examined the ability of Murabutide to control HIV type 1 (HIV-1) replic ation in acutely infected monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs). Highly significant suppression of viral replication was con sistently observed in Murabutide-treated cultures of both cell types. Murab utide did not affect virus entry, reverse transcriptase activity, or early proviral DNA formation in the cytoplasm of infected cells, However, treated MDMs and MDDCs showed a dramatic reduction in nuclear viral two-long termi nal repeat circular form and viral mRNA transcripts. This HIV-1-suppressive activity was not mediated by inhibiting cellular DNA synthesis or by activ ating p38 mitogen-activated protein kinase. Furthermore, Murabutide-stimula ted cells expressed reduced CD4 and CCR5 receptors and secreted high levels of beta-chemokines, although neutralization of the released chemokines did not alter the HIV-1-suppressive activity of Murabutide. These results prov ide evidence that a clinically acceptable immunomodulator can activate mult iple effector pathways in macrophages and in dendritic cells, rendering the m nonpermissive for HIV-1 replication.