J Virol. 2000 Sep;74(17):7794-802. Unique Identifier : AIDSLINE
Macrophages and dendritic cells are known to play an important role in
the establishment and persistence of human immunodeficiency virus (HIV)
infection. Besides antiretroviral therapy, several immune-based
interventions are being evaluated with the aim of achieving better
control of virus replication in reservoir cells. Murabutide is a safe
synthetic immunomodulator presenting a capacity to enhance nonspecific
resistance against viral infections and to target cells of the
reticuloendothelial system. In this study, we have examined the ability
of Murabutide to control HIV type 1 (HIV-1) replication in acutely
infected monocyte-derived macrophages (MDMs) and dendritic cells
(MDDCs). Highly significant suppression of viral replication was
consistently observed in Murabutide-treated cultures of both cell types.
Murabutide 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 terminal repeat circular form and viral mRNA transcripts.
This HIV-1-suppressive activity was not mediated by inhibiting cellular
DNA synthesis or by activating p38 mitogen-activated protein kinase.
Furthermore, Murabutide-stimulated 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 provide evidence
that a clinically acceptable immunomodulator can activate multiple
effector pathways in macrophages and in dendritic cells, rendering them
nonpermissive for HIV-1 replication.
JOURNAL ARTICLE Acetylmuramyl-Alanyl-Isoglutamine/*ANALOGS &
DERIVATIVES/ PHARMACOLOGY Adjuvants, Immunologic/*PHARMACOLOGY
Antigens, CD4/METABOLISM Cytokines/METABOLISM Dendritic
Cells/METABOLISM/*VIROLOGY DNA, Viral/METABOLISM Human HIV-1/*DRUG
EFFECTS In Vitro Macrophages/METABOLISM/*VIROLOGY Receptors,
CCR5/METABOLISM RNA, Viral/METABOLISM Support, Non-U.S. Gov't
Transcription, Genetic Virus Integration/DRUG EFFECTS Virus