Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART.
Prostratin is a unique phorbol ester that stimulates protein kinase C activity but is nontumor promoting. Remarkably, prostratin is also able to inhibit de novo human immunodeficiency virus type 1 (HIV-1) infection yet up-regulate viral expression from latent proviruses. Prostratin's lack of tumor promotion, coupled with its ability to block viral spread yet induce latent proviral expression, prompted studies to determine whether this compound could serve as an inductive adjuvant therapy for patients treated with highly active antiretroviral therapy (HAART). The current experiments indicate that prostratin is a potent mitogen for mononuclear phagocytes possessing many of the activities of phorbol myristate acetate (PMA) with notable functional differences. Prostratin, like PMA, accelerates differentiation of the myeloid cell-lines, HL-60 and THP-1, as well as mononuclear phagocytes from bone marrow and peripheral blood. Enzyme-linked immunosorbent assay and gene array analyses indicate significant changes in the expression of proteins and messenger RNA after treatment of cells with prostratin, consistent with phagocyte activation and differentiation. Prostratin blocks HIV-1 infection relating to down-regulation of CD4 receptor expression. The array analysis indicates a similar down-regulation of the HIV-1 coreceptors, CXCR4 and CCR5, and this may also reduce viral infectivity of treated host cells. Finally, prostratin is capable of up-regulating HIV-1 expression from CD8+ T lymphocyte-depleted peripheral blood mononuclear cells of patients undergoing HAART. This novel observation suggests the agent may be an excellent candidate to augment HAART by inducing expression of latent HIV-1 with the ultimate goal of eliminating persistent viral reservoirs in certain individuals infected with HIV-1.
Kulkosky
J
J
Dorrance H. Hamilton Laboratories, Center for Human Virology, Division of Infectious Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA. joseph.kulkosky@mail.tju.edu
Culnan
D M
DM
Roman
J
J
Dornadula
G
G
Schnell
M
M
Boyd
M R
MR
Pomerantz
R J
RJ
D023241:Antiretroviral Therapy, Highly Active; D015704:CD4 Antigens / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000473:pathology; D008213:Lymphocyte Activation; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D011533:Proviruses / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D019562:Viral Load; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency
D015704:CD4 Antigens; D010703:Phorbol Esters; D012333:RNA, Messenger; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C070999:prostratin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate