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Prostratin: A new therapeutic agent targeting viral
reservoirs
Microbicides: An essential new HIV prevention strategy
Prostratin: A new therapeutic agent targeting viral
reservoirs
The positive impact of current anti-HIV treatments in decreasing
the rate of AIDS progression and death among people living
with HIV is undeniable. However, several studies show that
even in patients with undetectable plasma viremia (<50 copies/ml),
virus rebounds after the interruption of Highly Active Antiretroviral
Therapy (HAART) due to the presence of pockets – or reservoirs – of
latently infected cells. It is now clear that HAART alone cannot
cure HIV. And since the long-term use of HAART is associated
with metabolic disorders and toxicities, the identification
of new anti-HIV agents with novel mechanisms of action is an
important therapeutic goal.
Prostratin was initially isolated as the active constituent
of extracts of the tropical plant, homalanthus nutans, used
in traditional Samoan herbal medicine for the treatment of “yellow
fever” (i.e., hepatitis). The potent antiviral activity
of prostratin, combined with its ability to activate HIV expression
from latently infected cells, indicates that prostratin may
be an important candidate for further development in new anti-HIV
therapeutic protocols.
In May of 2001, AIDS Research Alliance was granted an exclusive
license by the National Institutes of Health (NIH) to develop
prostratin as an anti-HIV drug targeting viral reservoirs.
In conjunction with this license, ARA announced in November
2001 a landmark agreement to benefit the people of Samoa, whose
indigenous healers have used prostratin medically for generations.
AIDS Research Alliance was then awarded an NIH
grant under the NIH-Development of AIDS Related Therapeutics
Program (NIH-DART) to perform pre-clinical studies for prostratin.
AIDS Research Alliance also established collaborations with
multiple laboratories to examine in more detail the latent
virus-activating property of prostratin. Results from
these experiments have been encouraging. In July 2005,
AIDS Research Alliance signed an agreement with a major contract
research organization to conduct the remaining pharmacokinetic
and toxicology studies of prostratin. The results of these
experiments are pending.
- Prostratin
Review
- Prostratin
Update - 2006
- Prostratin FAQ
- Korin et al., J. Virology, 76 (16), 8118-23, 2002
- Witvrouw et al., Antiviral Chemistry & Chemotherapy,
14:321-328, 2003
- Brooks et al., Immunity, 19 (3), 413-23, 2003
- Biancotto et al, J Virology, 78:10507-15, 2004
- Rullas et al., J Antiviral Chemistry & Chemotherapy 9:545-54,
2004
- (PKC) in response to prostratin or PMA. A paper was
published in the journal Antiviral Chemistry & Chemotherapy (Hezareh et
al., Antiviral Chemistry & Chemotherapy, 15:207-22.,
2004).
Microbicides: An essential HIV prevention strategy
There is an urgent need for more methods to prevent HIV infection,
especially those that put women in control. Microbicides
are synthetic or natural substances – manufactured in
the form of a gel, cream, suppository or film – that
can neutralize or kill a microbe. Unlike condoms, an
HIV microbicide could be used without the cooperation or
knowledge of one’s sexual partner, offering women (and
men) who lack the power to avoid sex with partners who may
be HIV-infected.
Sexual contact now accounts for 95% of all HIV infections
worldwide. In North America the most common sexual practice
that leads to HIV infection remains anal sex. Far from
being limited to men who have sex with men (MSM), more scientific
reports and popular media coverage suggest that it is also
a widely practiced sexual behavior in the general heterosexual
population, particularly in younger people. It is well
established that unprotected anal intercourse (UAI) is a risk
for the development of Sexually Transmitted Disease (STD) and
HIV infection in men. However, much less is known about
the contribution of anal sex, and unprotected intercourse (UI)
in particular, to HIV infection in women.
Vaginal microbicide development is already advanced both in
the United States and abroad with several Phase III efficacy
trials currently underway in Africa. Rectal microbicide
development, by comparison, is in its infancy. There
are critical basic questions about anal intercourse that need
to be answered first. These questions relate to the behavior
before, during and after anal sex, and what happens physically
to the anal canal and rectum with penetration. Investigators
at AIDS Research Alliance, in collaboration with UCLA, are
planning studies to address these important questions. The
UCLA/ARA study proposes to investigate how anal sex is commonly
practiced, what symptoms individuals who have anal sex experience
and how they would prefer to apply a potential rectal microbicide.
The study will recruit approximately 900 subjects in Baltimore
and Los Angeles with the aim of reaching a wide range of ethnic
groups and age ranges of HIV-positive and HIV-negative men
and women.
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