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 i nhibits 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 CDS-depleted phytohemagglutinin-ac tivated lymphocytes from HIV-1-infected subjects and on the outcome of HIV- 1 infection in severe combined immunodeficiency mice reconstituted with hum an 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 e vident in cultures harboring R5, X4-R5, or X4 HIV-1 isolates, was not linke d to inhibition of cellular DNA synthesis, and did not correlate with beta -chemokine release. Moreover, c-myc mRNA expression was down-regulated in M urabutide-treated cells, suggesting potential interference of the immunomod ulator with the nuclear transport of viral preintegration complexes. On the other hand, daily treatment of HIV-1-infected hu-PBL-SCID mice with Murabu tide significantly reduced the viral loads in plasma and the proviral DNA c ontent in human peritoneal cells. These results are the first to demonstrat e that a clinically acceptable synthetic immunomodulator with an ability to enhance the host's nonspecific immune defense mechanisms against infection s can directly regulate cellular factors in infected lymphocytes, leading t o controlled HIV-1 replication.