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Blood, 15 November 2001, Vol. 98, No. 10, pp. 3006-3015
IMMUNOBIOLOGY
Prostratin: activation of latent HIV-1 expression
suggests a potential inductive adjuvant therapy for
HAART
Joseph Kulkosky,
Derek M. Culnan,
Jeanette Roman,
Geethanjali Dornadula,
Matthias Schnell,
Michael R. Boyd, and
Roger J. Pomerantz
From the Dorrance H. Hamilton Laboratories, Center for
Human Virology, Division of Infectious Diseases, Department of
Medicine, Jefferson Medical College, Thomas Jefferson University,
Philadelphia, PA; and the Molecular Targets Drug Discovery Program and
Development, Center for Cancer Research, National Cancer Institute,
Frederick, MD.
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.
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