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University
of Washington School
of Medicine, Department
of Microbiology
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Mullins laboratory uses the techniques of molecular,
computational and virus biology to provide basic
insights into the HIV-human host relationship. Our goals are to
assist the fight against AIDS by gaining insight into the
development of the disease and thereby refine therapies and create
effective vaccines.
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In
the early 1980's a new infectious disease emerged that
changed the world's attitude towards sex and towards
blood and blood products. This disease, acquired
immunodeficiency syndrome (AIDS), results from
progressive destruction of the immune system and
typically develops about 10 years following infection
with human immunodeficiency virus (HIV). AIDS is now a
global pandemic, though by far the largest burden falls
on the developing world.
AIDS results from the immune destruction caused by human
immunodeficiency virus (HIV). In two decades our
knowledge of HIV and AIDS has grown exponentially. More
importantly, in the last few years, insights as to how
the disease process may be halted or potentially
reversed have emerged, and effective therapies are in
use. However, neither a cure nor a preventive vaccine
has been found.
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of the most striking features of HIV is the speed at
which its genome evolves. In a single year, an HIV
strain within one patient can evolve viruses that are as
genetically different from one another as human genes
now differ from a chimpanzee's. Rapid mutation, natural
selection, and other evolutionary forces contribute to
this astonishing in vivo diversification. The
relationship of viral diversity to the length and
severity of the disease, and its contribution to the
ultimate breakdown of the immune system, remain unclear.
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We
use a variety of techniques to understand the
implications of HIV's extraordinary genetic diversity
for the pathogenesis of AIDS and with the intention of
applying this information to the development of more
effective therapies and vaccines. These techniques
include virology, molecular biological and statistical
analysis of nucleotide sequences, and high-throughput
array analysis of cellular transcription.
We are investigating the molecular evolution of HIV-1
and HIV-2 from two viewpoints: From within individual
patients and between patients from the human population
at large. By examining the evolution of HIV within a
host we can determine compartments or cell types within
the body that have unique signatures of virus evolution.
One way of capitalizing on these signatures is to
identify anatomical compartments that are in a therapy
shadow, i.e., compartments in which drugs are
ineffective against the virus. The identification of
such compartments should assist development of more
potent and highly targeted therapies that prevent HIV
from replicating within these shadows. Evolution of HIV
is also being studied between different hosts, where we
identify viral lineages or ancestral states with the
potential for providing us with promising sequences for
vaccine development. In addition, this line of research
can lead to a better understanding of the epidemiology
of HIV transmission and spread.
We are using expression array technology to understand
the cellular response to infection and expression of
viral proteins. We are also using cell culture tools to
understand the relationship between viral genotype and
phenotype and to assess kinetic parameters of infection
and treatment.
In all cases, molecular, computational and biological
analyses conducted in the Mullins laboratory merge with
in vivo analyses of biological activity conducted by
collaborating laboratories and clinical investigators,
in order to ensure that our research program remains
focused on the primary goal--improving our ability to
fight AIDS.
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