Selective regulation of human immunodeficiency virus-infected CD4(+) lymphocytes by a synthetic immunomodulator leads to potent virus suppression in vitro and in hu-PBL-SCID mice.
We have previously observed that the synthetic immunomodulator Murabutide inhibits human immunodeficiency virus type 1 (HIV-1) replication at multiple levels in macrophages and dendritic cells. The present study was designed to profile the activity of Murabutide on CD8-depleted phytohemagglutinin-activated lymphocytes from HIV-1-infected subjects and on the outcome of HIV-1 infection in severe combined immunodeficiency mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice). Maintaining cultures of CD8-depleted blasts from 36 patients in the presence of Murabutide produced dramatically reduced levels of viral p24 protein in the supernatants. This activity correlated with reduced viral transcripts and proviral DNA, was evident in cultures harboring R5, X4-R5, or X4 HIV-1 isolates, was not linked to inhibition of cellular DNA synthesis, and did not correlate with beta-chemokine release. Moreover, c-myc mRNA expression was down-regulated in Murabutide-treated cells, suggesting potential interference of the immunomodulator with the nuclear transport of viral preintegration complexes. On the other hand, daily treatment of HIV-1-infected hu-PBL-SCID mice with Murabutide significantly reduced the viral loads in plasma and the proviral DNA content in human peritoneal cells. These results are the first to demonstrate that a clinically acceptable synthetic immunomodulator with an ability to enhance the host's nonspecific immune defense mechanisms against infections can directly regulate cellular factors in infected lymphocytes, leading to controlled HIV-1 replication.
Bahr
G M
GM
Laboratoire d'Immunologie Moleculaire de l'Infection et de l'Inflammation, Institut Pasteur de Lille, France. georges.bahr@pasteur-lille.fr
Darcissac
E C
EC
Castéran
N
N
Amiel
C
C
Cocude
C
C
Truong
M J
MJ
Dewulf
J
J
Capron
A
A
Mouton
Y
Y
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000276:Adjuvants, Immunologic; D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000821:virology*; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004279:DNA, Viral / Q000097:blood; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000097:blood / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D016513:Mice, SCID; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger; D012367:RNA, Viral / Q000097:blood; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*
D000276:Adjuvants, Immunologic; D016207:Cytokines; D004279:DNA, Viral; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015375:Receptors, Interleukin-2; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C033575:murabutide