Identification of a synthetic muramyl peptide derivative with enhanced Nod2 stimulatory capacity.

Muramyl peptides (MPs) represent the building blocks of bacterial peptidoglycan, a critical component of bacterial cell walls. MPs are well characterized for their immunomodulatory properties, and numerous studies have delineated the role of MPs or synthetic MP analogs in host defense, adjuvanticity and inflammation. More recently, Nod1 and Nod2 have been identified as the host sensors for specific MPs, and, in particular, Nod2 was shown to detect muramyl dipeptide (MDP), a MP found in both Gram-positive and Gram-negative bacterial cell walls.

Up-regulation of NOD1 and NOD2 through TLR4 and TNF-alpha in LPS-treated murine macrophages.

NOD1 (Card4) and NOD2 (Card15) are thought to be responsible for cytoplasmic defense against bacterial entry. To gain further knowledge about how their expressions are regulated in murine macrophages, we investigated the expression of NOD1 and NOD2 mRNAs after stimulation with various endotoxins, lipopolysaccharide, lipoteichoic acid and peptidoglycan. In macrophage RAW264.

Immune deficiency in HIV-1 infection: novel therapeutic approaches targeting innate and adaptive responses.

HIV-1 is a lentivirus capable of infecting CD4(+) T-lymphocytes and CD4-expressing innate immune cells. Infection with HIV-1 leads to rapid and early depletion of mucosal CD4(+) T-cells, and to the establishment of viral reservoirs that are resistant to the most potent antiretroviral therapy currently available. Commonly observed virus-induced adaptive immune defects consist of weak-to-absent HIV-specific CD4 T-cell responses and of inappropriate or inefficient CD8(+) cytotoxic T-lymphocyte activity.

Differentially expressed genes in HIV-1-infected macrophages following treatment with the virus-suppressive immunomodulator murabutide.

The synthetic immunomodulator murabutide has been found to suppress human immunodeficiency virus type-1 (HIV-1) replication, in macrophages, through a regulated expression of cellular factors needed at different steps in the virus replication cycle. To identify cellular genes implicated in the murabutide-induced virus inhibition, we have carried out a differential display analysis on HIV-1-infected macrophages that were treated, or not, with murabutide. Sequencing of the differentially regulated cDNA bands and verification of the reproducibility of the murabutide effects, by reverse transcription-polymerase chain reaction or by Northern blotting, revealed an up-regulated expression of 21 genes and a down-regulation of seven others.

A phase I study of a six-week cycle of immunotherapy with Murabutide in HIV-1 patients naive to antiretrovirals.

Background: Limitations in the use of antiretroviral therapy suggest the need for additional approaches to enhance immune restoration and the control of HIV-1 replication. Therefore, we evaluated the clinical tolerance and biological effects of immunotherapy with the synthetic immunomodulator Murabutide in 9 treatment-naive HIV-1 patients presenting with CD4+ lymphocyte counts >500 cells/mm3 and plasma viral loads <30.000 copies/ml.

Clinical and immunological effects of a 6 week immunotherapy cycle with murabutide in HIV-1 patients with unsuccessful long-term antiretroviral treatment.

In an effort to evaluate the potential of non-specific immunotherapy in restoring global immunity, we have examined the clinical tolerance and biological effects of a 6 week administration of the immunomodulator, murabutide, in chronically infected HIV-1 patients. Forty-two subjects, presenting weak immune reconstitution and ineffective virus suppression following long-term highly active antiretroviral therapy (HAART), were randomized to receive, or not, murabutide 7 mg/day on five consecutive days/week. Clinical and immunological parameters were monitored before and after the immunotherapy period.

Clinical tolerance and immunologic effects after single or repeated administrations of the synthetic immunomodulator murabutide in HIV-1-infected patients.

Correction of the virus-induced deficits in innate immunity of HIV-infected subjects could well contribute to enhanced immune recovery and efficacious control of viral replication. The safe synthetic immunomodulator Murabutide (ISTAC Biotechnology, Lille, France) has been found to regulate the function of antigen-presenting cells and to selectively activate CD4 lymphocytes leading to dramatic suppression of HIV replication, in vitro. Therefore, as a first step toward the evaluation of the immunotherapeutic potential of Murabutide in HIV disease, we have conducted two phase 1/2 clinical trials to address the safety and the immunologic effects of Murabutide administration into HIV-infected subjects receiving antiretroviral therapy.