Virus Mutes the Effects of HIV
BY LYNN YARRIS, LBNL
engineering professor David Schaffer is developing a virus
to help prevent HIV infections from developing into AIDS.
a biological version of fighting fire with fire, researchers at
Berkeley Lab and UC Berkeley are designing a genetically modified
form of the HIV virus to prevent HIV infections from developing
into AIDS. While their model of an HIV parasite, called crHIV-1
(for conditionally replicating HIV-1) is yet to be synthesized,
it has performed well in computer simulations.
this time we are nowhere near an AIDS therapy, but our model does
show great promise in simulations and were very excited
about this line of research, says Adam Arkin, professor
in Bioengineering, who is leading this research. Collaborating
with him are David Schaffer, with UC Berkeleys Department
of Chemical Engineering, and Leor Weinberger, a UC Berkeley
graduate student who was instrumental in formulating the initial
concept and subsequent development of this crHIV-1 model.
in the public still equate HIV (Human Immunodeficency Virus) with
AIDS (Aquired Immune Deficiency Syndrome). Persons infected with
the HIV parasite gradually lose their ability to fight off disease
and infection. AIDS is declared only when the victims immune
system becomes depleted beyond a critical level and opportunistic
infections and other diseases arise as a result.
characteristics of an HIV infection, specifically the presence
of long lived, latently infected cell populations, make it unlikely
that it can be completely eradicated through the use of antiviral
drugs. An alternative approach is to manage the infection so that
it is no longer life-threatening.
idea is to reduce the virus population and thereby delay or even
prevent the onset of AIDS, says Arkin. This could
be done by creating a parasite of HIV, crHIV, that would suppress
production of the HIV parasite by converting latently infected
cells into a pseudolatent state.
an individual is first infected with HIV, theres a period
before the bodys immune system kicks in, usually about two
months, during which the HIV parasite rapidly reproduces and spreads
to other cells. The parasites primary target is a type of
cell in the immune system called a CD4 T lymphocyte. Following
this initial unchecked replication, the virus population stabilizes
at the HIV set point. A victims set point level is inversely
correlated with the time to AIDS onset. For a typical HIV positive
patient, the set point is maintained for about 10 years. When
the number of uninfected CD4 T cells drops below a critical threshold,
the HIV parasite population increases and the HIV infection develops
evidence suggests that reducing the HIV set point below some absolute
value may not be necessary, says Arkin. Rather, the
relative extent of the HIV set point reduction in a patient appears
to be a significant predictor of patient health and immune recovery.
Currently, the only effective means of reducing the HIV set point
is called HAART (for highly active anti-retroviral therapy). HAART
drugs are highly toxic, expensive and can be quickly overcome
by resistant HIV mutants. To find something better, Arkin, Schaffer
and Weinberger turned to synthetic biology. One of the hottest
new fields in the life sciences, the goal of synthetic biology
is to design and construct novel organisms and biologically-inspired
systems that can solve problems natural biological systems cannot.
researchers have done preliminary in vitro observationsof
crHIV-1 viruses, but Arkin, Schaffer and Weinberger are the first
to explore what would be needed for a crHIV-1 virus to infect
an HIV virus in an organism, then proliferate and persist enough
to reduce the HIV set point. To design their version of a crHIV-1
therapy, they worked with a widely accepted mathematical model
of HIV in vivo, called the Basic Model of HIV-1. Criteria for
their crHIV-1 virus were kept relatively simple.
Schaffer, Our design introduces only two new parameters.
The first is the ability of the parasitic virus to suppress HIV
production. Weve designed antiviral cargos that target the
host cell functions that HIV needs to replicate, rather than HIV
viral functions that can be rapidly evolved around. The second
parameter is the ability of the parasite virus to propagate in
parallel with HIV. If our parasite suppresses HIV too much in
its host cell, then it cant propagate and spread to other
cells to prevent further HIV infection.
says that when computational modeling of both parameters is complete,
this therapy virus will be created in the laboratory and in vitro
studies will begin. One of the critical questions to be resolved
is the potential for crHIV-1 to be transmitted from one individual
to another. This could be a problem or a benefit. As he and his
collegues explained in an earlier paper on this research, which
was published in the September 2003 issue of the Journal of
Virology, the spread of crHIV-1 through the population might
to act to mitigate the spread of HIV and AIDS.