Are you HIV Resistant?
By: Ashley Arnett
Advisor: Dr. Grimes
Introduction
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Since the 1980’s many people have been infected
with HIV.
However, not everyone who is exposed to the virus
gets sick.
Scientists have carefully studied people who seem
resistant to the HIV infection.
The very rapid evolution of the HIV virus makes it
extremely difficult to treat. But, scientist are pursuing
all avenues to learn methods to impede the infection.
HIV/AIDS
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In June 1981, the first cases of what was
later called acquired immunodeficiency
syndrome (AIDS) in the United States were
reported.
Since 1981, the HIV epidemic has continued
to expand in the US.
Approximately 1 million people are living with
HIV/AIDS in US. An estimated 25% of whom
are unaware of their infection.
Background
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Two incidents have indicated that the natural
resistance to HIV-1 infection, while rare, does exist.
First there are individuals who have been exposed to
HIV, sometimes repeatedly and over long periods of
time who have remained HIV-negative.
These people were commerical sex workers, infants
born to positive mothers, health care workers and IV
drug users.
Background
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Second, there are
individuals who have
been infected with HIV
but whose disease has
not progressed or has
progressed extremely
slowly compared to the
average experience.
What is different about
these people???
What’s different about these People?
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The individuals who seem to have complete
natural resistance to the HIV virus are
homozygous for the CCR5-delta32 gene.
The individuals who are termed “slow
progressors” are heterozygous for the CCR5delta32 gene.
CCR5
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HIV-1 needs two receptors to gain entry into
human cells; the CD4 receptor found on
some cells of the immune system, and the
chemokine co receptor used by most
circulation strains of HIV-1 (CCR5).
Once HIV has bound to CD4 and CCR5 and
the area of the virus is exposed that can fuse
with the human cell, it permits entry of the
viral genetic material into the cell.
CCR5-delta32
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CCR5-delta32 is a polymorphism in the gene
encoding CCR5 in which a 32 base pair has been
deleted.
The distribution of CCR5-delta32 varies
geographically.
The frequency of the mutation is about 10% in
Europe and nearly absent in Africans and East
Asians.
In the United States, about 1% of Caucasians have
at least one copy of the gene.
HIV resistance?
Why is the CCR5-delta32 mutation so frequent
in Northern Europe?
It is possible that this gene provided resistance
to previous epidemics.
If true, people with CCR5-delta32 mutation
would have been more likely to survive and
pass it down to their offspring.
HIV Resistance
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Two different diseases were widespread in
Europe when this mutation is believed to
have arisen.
Resistance to bubonic plague )also called
the Black Death) might have influenced
CCR5-delta32 distribution.
Recent findings name smallpox immunity as
another strong possibility.
The Black Death
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In 1665, the black plague hot a small village in
England called Eyam. The town quarantined itself to
keep the Black Death from spreading,
A year later half of the townspeople were dead.
In 1996, researchers tracked down rhw descendants
of the half that lived.
They found the mutation called CCR5-delta32.
The mutation was already known to be the special
component in mysteriously HIV resistant individuals.
The Black Death
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The Black Death was one of the most deadly pandemics in
human history, killing about 40% of the European population.
Today, what we call the Bubonic plague is caused by the
bacterium, Yersinia pestis.
Scientist now suggest the actualy cause to be mixed with a
virally borne hemorrhagic fever.
This may be different from what you have learned about the
Black Death because in Europe the graves are crawling with
Yersinia pestis. Both diseases probably co-existed, but the
virus being the one to cause most of the deaths and the CCR5
mutation.
The Bubonic Plague
Smallpox
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An acute infectious disease caused by a virus. No
one has contracted smallpox since 1977 and was
declared ericated from the Earth in 1980.
It was estimated that the official figures reported to
WHO represently only 2% of the true incidence.
Poxviruses infect lymphocytes via a close relative to
CCR5, so cross-resistance could have occurred.
Smallpox
Smallpox vs. Black Death
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Smallpox was not as catastrophic as the Black
Death, but it did primarily kill children which usually
do not make it into historical accounts.
The Cumulative effect of small scale smallpox
epidemics over 700 years killed far more than the
Black Death Pandemic
The intermittent nature of the plague was caused at
least in part by indirect transmitting between rodent
reservoirs via fleas.
Smallpox was transmitted directly between humans
resulting in a more contagious transmitting.
Research
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Scientist studying HIV first learned about the
gateway blocking capacity of the CCR5
mutation in 1996.
Several drug companies, then quickly began
exploring the possibility of developing
pharmaceuticals that would mimic delta32 by
binding to CCR5 and blocking the
attachment of HIV.
Research
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Previous methods of treatment interfered with HIV’s
ability to replicate after the virus has already entered
the cell.
This new class of HIV treatment, called the early
inhibitor or fusion inhibitor drugs seeks to prevent the
virus from ever attaching at all.
These pharmaceuticals are still in relatively early
stages of development, but certainly stand as a
hopeful new method of approaching HIV treatment.
HIV Therapy
Early Inhibitors/ CCR5 antagonist
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Maraviroc is an entry inhibitor. Specifically, maraviroc
blocks the chemokine receptor CCR5 which HIV
uses as a co-receptor to bind and enter a human
helper T cell.
Maraviroc was developed by the drug company
Pfizer. On April 24, 2007 the U.S. FDA
recommended approval for the new drug, and the
drug received full FDA approval on August 6, 2007
for use in treatment experienced patients.
Summary
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CCR5-delta32 has a specific impact on the function
of T-cells. The mutation is widely dispersed
throughout Northern Europe and in those of
European descent.
It has been hypothesized that this allele was favored
by natural selection during the Black Death or during
small pox outbreaks.
The allele has a negative effect on T cell function,
but appears to protect against smallpox. Plague and
HIV.
Research
For Up-to-date information about current clinical trails
and research information.
 http://www.aidsresearch.org/?gclid=CNqaufbE4pICF
R_NIgodak486Q
WARNING:
Please do not partake in risky behavior and assume
that you can not contract HIV just because your
grandmother is British…You may be disappointed 
References
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Cohn, SK., Weaver, LT. “The Black Death and AIDS: CCR5- Delta 32 in genetics and history.” QJM, 2006
Aug; 99(8) 497-503
Duncan, CJ. et. al. “Reappraisal of the historical selective pressures for the CCR5 Delta 32 mutation.”
Journal of Medical Genetics, 2005 Mar; 42(3):205-8
Duncan, CJ. et. al. “What caused the Black Death?” Postgraduate Medical Journal, 2005 May;
81(955):315-20
Duncan, CJ., et. al. “Frequency analysis of the delta 32 CCR5 HIV resistance allele in a medieval plague
mass grave.” 2006.
Galvani, AP., Staltkin, M. “Evaluating plague and smallpox as historical selective pressures for the CCR5Delta 32 HIV resistance allele.” Proceedings of the National Academy of Sciences of the United States of
America, 2003 Dec; 100 (25):15276-9
Guilherme, A., et. al. “CCR5 receptor gene and HIV infection.” National office of Public Health Genomics,
2002.
Hedrick, PW. Verrelli, BC. “Ground Truth” for selection on CCR5 Delta 32,” Trends in Genetics. 2006 Jun;
22(6):293-6
Hummel, S., et al. “Detection of the CCR5 delta 32 HIV resistance gene in Bronze Age skeletons.” Genes
and Immunity, 2005; 6, 371-374
Lu, Y., “Genotype and allele frequency of a 32 base pair deletion mutation in the CCR5 gene in various
ethnic groups: absence of mutation among Asians and Pacific Islanders.” International Journal of
Infectious Disease. 1999 Summer; 3(4):186-91
References
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Nelson, M., et. al “The role of CCR5 and CCR2 polymorphisms in HIV-1
transmission and disease progression.” Nature and Medicine, 1997; 3, 11601162
Quillent, C., et. al. “HIV-1 resistance phenotype conferred by combination of
two separate inherited mutations of CCR5 gene.” Lancet, 1998 Jan;
351(9095):14-8
Silva, E., et. al. “HIV and the CCR5 delta 32 resistance allele.” FEMS
Microbiology Letters, 2004 Dec; 241(1)1-12
Smoljanovic, M. et. al. “Historic exposure to plague and present day frequency
of CCRdde32 in two isolated island communities of Dalmatia, Croatia.” Croat
Med J. 2006, Aug; 47(4):579-84
Styer, KL. et. al. “Study of the role of CCR5 in a mouse model of intranasal
challenge with Yersinia pestis.” Microbes and Infection, 2007; 9 (9):1135-9
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