new study by scientists on the Florida campus of The Scripps Research
Institute shows, in cell culture, a natural compound can virtually
eliminate human immunodeficiency virus (HIV) in infected cells. The
compound defines a novel class of HIV anti-viral drugs endowed with the
capacity to repress viral replication in acutely and chronically
HIV/AIDS pandemic continues to affect 34 million individuals worldwide,
including more than 3 million children, according to the World Health
Organization. Current treatment involves the use of several
antiretroviral drugs, termed Highly Active Antiretroviral Therapy
(HAART), which can extend the life expectancy of HIV-positive
individuals and decrease viral load without, however, eradicating the
know that there are reservoirs of HIV that aren’t being eliminated by
current treatment and that keep replenishing the infection,” said Susana
Valente, a Scripps Research biologist who led the study. “Viral
production from these cellular reservoirs that harbor an integrated
viral genome is not affected by current antiretroviral drugs, which only
stop novel rounds of infection. The compound in the current study
virtually eliminates all viral replication from already-infected cells
where HIV hides.”
The new study, published in the July 20, 2012 issue of the journal Cell Host and Microbe,
focused on a medically promising compound known as Cortistatin A. This
natural product was isolated in 2006 from a marine sponge, Corticium simplex,
discovered more than 100 years ago. In 2008, Scripps Research chemist
Phil Baran and his team won the global race to synthesize the compound,
presenting an efficient and economical method.
the new study, Valente and her colleagues collaborated with the Baran
lab, using a synthetic version of the compound, didehydro-Cortistatin A,
to study the compound’s effect on two strains of HIV. The strains were
HIV-1, the most common form of the virus, and HIV-2, which is
concentrated in West Africa and some parts of Europe.
results showed that the compound reduced viral production by 99.7% from
primary CD4+T cells (a type of immune cell) isolated from patients
without levels of the virus in their bloodstream and who had been under
HAART treatment for a long period of time. When the compound was added
to other antiviral treatments, it further reduced by 20 percent viral
replication from CD4+T cells isolated from patients with detectable
amounts of virus in their bloodstreams.
inhibitor works by binding tightly to the viral protein known as Tat, a
potent activator of HIV gene expression, effectively preventing the
virus from replicating even at miniscule concentrations—making it the
most potent anti-Tat inhibitor described to date, Valente said.
interesting feature of this compound is that withdrawal of the drug
from cell culture does not result in virus rebound, which is normally
observed with other antiretrovirals.
most antiretroviral compounds block only new infections,
didehydro-Cortistatin A reduces viral replication from already-infected
cells, potentially limiting cell-to-cell transmission.
new inhibitor already has a drug-like structure, is effective at very
low concentrations, and has no toxicity associated with it, at least at
the cellular level, the study noted.
first author of the study “Potent Suppression of Tat-dependent HIV
Transcription by didehydro-Cortistatin A” is Guillaume Mousseau of
Scripps Research. In addition to Valente and Baran, other authors
include Mark A. Clementz, Wendy N. Bakeman, Nisha Nagarsheth, Michael
Cameron, and Jun Shi of Scripps Research; and Rémi Fromentin and Nicolas
Chomont of the Vaccine and Gene Therapy Institute.
study was supported by the National Institutes of Health’s National
Institute of Allergy and Infectious Diseases (NIAID) and the