Identification of AIDS

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Identification of AIDS
1981 5 cases of a rare type of pneumonia,
Pneumocystis carinii, opportunistic infection in
people with immune system impaired by cancer or
immunosuppresents (only 2 cases observed between
1967 and 1979)
Over next 30 months 26 cases of Kaposi's
sarcoma generally only observed in older men and
individuals being treated with immunosuppresents.
Increase in occurrences of chronic
lymphadeonopathy (enlarged lymph nodes) and
non-Hodgkin's lymphoma
1982 the above collection of clinical conditions
recognized as a syndrome Acquired
immunodeficiency syndrome (AIDS). Underlying
cause not known
1984 HIV isolated by Luc Montagnier (Pasteur
Institute, Paris) and Robert Gallo (National
Cancer Institute). Leads to serological tests
allowing for the identification of the virus
(ELISA).

• by 2002
• Leading infectious cause of death worldwide,
  surpassing malaria and tuberculosis
• 30 million deaths worldwide
• 42 million HIV

        gt 25 million in sub-Saharan Africa    9
of population ages 15 - 49, 2 of every 5 15 year
olds will die from AIDS    Botswana 36 of
adult population infected    Swaziland,
Zimbabwe, Lesotho, Zambia, South Africa and
Namibia 19 to 25 of adult population infected
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Structure of HIV
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HIV is enveloped by a lipid bilayer containing
two glycoproteins gp41 spans the membrane and is
associated with gp120 located on the external
face (72 per virion)
gp120 is the viral receptor for CD4 on a host
cell The viral envelope derives from the host
cell and therefore contains some host-cell
membrane proteins including class I and class II
MHC molecules
HIV genome consists of two copies of
single-stranded RNA which are associated with two
molecules of reverse transcriptase (p64), with
nucleoid proteins p10 (a protease) and with p32
(an integrase)
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HIV is a retrovirus
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A retrovirus carry their genetic information in
the form of RNA
When the retrovirus enters a cell, the RNA is
reverse transcribed to DNA by a virally encoded
enzyme (reverse transcriptase) Reverse
transcriptase reverses the normal transcription
process and makes a DNA copy of the viral RNA
genome
The DNA acts as a template for the synthesis of
its complementary DNA This DNA (the provirus) is
integrated into the cell genome (via viral
integrase) and is replicated along with the cells
DNA
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Genetic organization of HIV
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gp120 molecules on the membrane of HIV bind to
CD4 molecules on the surface of the helper T cell
certain HIV strains will infect monocytes and
other cells that have CD4 on their cell surface
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A second receptor is necessary for entry and
infection of HIV

• The second receptor is a chemokine receptor
• CXCR4 on T cells
• CCR5 on monocytes/macrophages

gp41 inserts its amino terminal head into the
host cell membrane
The viral membrane and the helper T cell membrane
fuse and the viral core is released into the
cytosol
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viral encoded RNA is exported to the cytoplasm
where host cell ribosomes catalyze synthesis of
viral proteins which, along with HIV ssRNA,
assemble beneath the host cell membrane (into
which gp120 and gp140 have been
inserted membrane buds out and off
Assembly, budding and maturation of HIV-1
SU surface glycoprotein gp120 TM
transmembrane glycoprotein gp41
Does HIV kill the cells it buds off from?
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What are the consequences of a depleted
population of CD4 positive helper T cells?
When CD4 T cells numbers decline below a critical
level, cell-mediated immunity is lost and
infections with a variety of microorganisms appear
Infections are the major cause of death in AIDS
with respiratory infection with pneumocysitis
carinii and mycobacterium the most
prominent Most of these pathogens require
effective macrophage activation by CD4 T cells or
effective cytotoxic T cells for host
defense Opportunistic pathogens are present in
the normal environment but cause severe disease
in immunocompromised hosts such as HIV and cancer
patients HIV patients are also susceptible to
several rare cancers
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An immune response controls but does not
eliminate HIV
Soon after infection, viral RNA is detectable in
the serum HIV infection is most commonly
detected by the presence of anti-HIV antibodies
after seroconversion (which normally occurs a few
months after infection) seroconversion the
phase in an infection when antibodies against the
infecting agent are first detectable in the
blood The appearance of clinical symptoms
varies, but often do not appear for at least 8
years after infection The onset of clinical AIDS
is usually signalled by a decrease in T cell
numbers and an increase in viral load
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Therapeutic Agents for HIV Reverse Transcriptase
Inhibitors
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Nucleoside analogs and nonnucleoside analogs
Nucleoside analogs act by conversion to the
corresponding triphosphate, which is then
incorporated into DNA but further chain
elongation is prevented because of the absence
of a 3 hydroxyl
Along with AZT, are all approved for treatment of
human HIV infection
These compounds slow the progression of an HIV
infection but do not stop it They are toxic
particularly to hematopoetic cells in the bone
marrow and nonspecific (these nucleoside analogs
are also used by human DNA polymerase) so
cannot be taken in large doses RT has no
proofreading function and therefore generates
mutations on average of one new mutation per one
replication of the viral genome Selective
pressure of an anti-HIV drug such as AZT results
in rapidly evolving drug resistant forms of HIV
(RT rapidly evolves to a drug resistant form it
has
Nonnucleoside analogs such as Nevirapine
specifically inhibit reverse transcriptase
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Therapeutic Agents for HIV HIV protease
Inhibitors
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HIV-1 protease inhibitors
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uncomplexed HIV-1 protease (resembles eukaryotic
aspartic proteases) crystal structure solved in
1989 a homodimer of 99-residue subunits with a
single active site formed by the two subunits
HIV-1 protease complexed with an inhibitor upon
binding inhibitor, the hairpin flaps move down
Effectiveness of protease inhibitors are
subject to the same mutation pressure that
reverse transcriptase inhibitors are subject to
This has led to the use of combination therapies
or cocktails so that when a virus gains
resistance to one of the drugs in the cocktail
will still be suppressed by the other drugs
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Current state of HIV therapy
Although plasma levels of HIV-1 in many patients
on combination therapy become undetectable, this
does not constitute a cure If drug therapy is
interrupted, the virus will reappear in the
plasma because certain tissues will harbor latent
viruses therefore these drugs must
be taken for the life of the individual Problems
associated with taking these drugs different
drugs must be taken at different times and under
different conditions in order to maximize their
bioavailability (example before, during or
after a meal) the bioavailability of each drug
must be maintained at a certain level to
minimize the emergence of resistance forms of
HIV (therefore a rigid schedule must be
maintained) significant side effects fatigue,
nausea, diarrhea, numbness, kidney stones HIV
protease inhibitors are difficult to synthesize
and therefore expensive (in developing
countries where AIDS is most prevalent there is a
problem with purchasing these drugs)
HIV vaccine
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Emerging Viruses
Arent really new viruses but rather variants
of pre-existing viruses or existing viruses that
become detectable through technological advances
example hepatitis A and hepatitis B were known
viruses by the 1970s Some forms of hepatitis
could not be attributed to hep A or hep B but no
separate virus was identifiable so the disease
was called nonA, nonB hepatitis until hepatitis
C was identified in the 1980s
example HIV-1 probably existed in chimpanzees
for a long time, then jumped to humans and
only became noticeable in human populations in
the middle of the last century
example Ebola first emerged from an unknown,
probably animal host-but host animal has not yet
been identified- in the African rainforests in
1976 (when humans were clearing the rainforest
and came in contact with animal species not
previously encountered)
example hanta virus (Sin Nombre virus) 1993 in
Northwestern New Mexico natural host is the deer
mouse and infects humans that come in contact
with virus that has been shed in mouse droppings
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Zoonoses infection of humans with viruses
which have birds or animals as
their natural host
Zoonotic viruses infect, reproduce, spread and
evade their bird or animal hosts and therefore
humans are irrelevant for their survival 1999
West Nile virus killed seven people in the NYC
area This virus is common in other parts of the
world but only recently emerged in North
America Birds are the natural hosts for West
Nile Virus and mosquitoes transmit the virus from
birds to humans (but humans are a dead end for
this virus because the amount of virus in the
blood stream of a human is usually too small to
be effectively transmitted by a mosquito to
another host West Nile probably arrived in North
America by the transport of infected mosquitoes
or infected birds from another part of the
world (West Nile can infect 60 bird species)
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SARS Severe Acute Respiratory Syndrome
SARS is a type of viral pneumonia, with symptoms
including fever, a dry cough, dyspnea (shortness
of breath), headache, and hypoxaemia (low blood
oxygen concentration). Typical laboratory
findings include lymphopaenia (reduced lymphocyte
numbers) and mildly elevated aminotransferase
levels (indicating liver damage). Death may
result from progressive respiratory failure due
to alveolar damage. The typical clinical course
of SARS involves an improvement in symptoms
during the first week of infection, followed by a
worsening during the second week. Studies
indicate that this worsening may be related to
patient's immune responses rather than
uncontrolled viral replication
CORONAVIRUSES AND SARS A new type of
coronavirus has been identified as the cause of
the emergent disease called Severe Acute
Respiratory Syndrome or SARS. The "SARS Virus"
was officially declared the causative agent on
16th April 2003 by the WHO. The genome for this
novel virus was sequenced by various groups just
prior to this announcement.
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Feb 7-2005 First SARS vaccine trials look
promising A SARS vaccine could be used among
high-risk groups in China in the event of a
large-scale outbreak again this spring, say
experts.  The inactivated vaccine was produced
last May following a year of intense research to
find a vaccine for the virus which sparked a
global health scare when it emerged in early
2003.   Trials among 36 volunteers have proven
effective and safe in the first-phase human tests
begun on May 22, 2004, said Yin Weiping, managing
director of Beijing-based Sinovac Biotech Co Ltd
which produces the vaccine.   Yin heads China's
SARS vaccine development group, working with
experts from Beijing Sinovac, the Chinese Centre
for Disease Control and Prevention and the
Chinese Academy of Medical Science.   Before last
month, antibodies had been found in all
volunteers, who had the test vaccine, said Yin,
adding that they did not sustain any obvious side
effects,  His laboratory currently has a number
of batches of inactivated vaccine and can produce
more if necessary.   Only after a vaccine has
passed the third round of human trials in
fighting an active virus that breaks out
naturally will it be provided to the public, he
said.   However, in the event of a sudden and
widespread SARS outbreak, some high-risk groups,
such as doctors might be immunised ahead of
completion of the second and third-round trials,
said Dr Lin Jiangtao of Beijing's Sino-Japanese
Friendship Hospital, where the first tests were
conducted. China Daily
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News_at_Nature.com Published online 10 January
2005 doi10.1038/news050110-3
Caution raised over SARS vaccine
Vaccinating against one strain of SARS might
aggravate infection with other strains.. A
cautionary note has been sounded for those
developing vaccines against severe acute
respiratory syndrome (SARS). Some vaccines could
prove useless against certain strains, or even
worsen the infection, a preliminary study suggests
In the new study, Gary Nabel of the National
Institute of Allergy and Infectious Diseases in
Bethesda, Maryland, and his co-workers injected
mice with spike protein from a SARS virus taken
from a human patient infected in early 2003. They
then collected the antibodies the animals
produced.In lab experiments, they showed that
these antibodies were unable to attack spike
protein from a different strain of SARS, isolated
from a patient infected in late 2003.The team
next tested whether the antibodies would attack
spike proteins from two SARS strains isolated
from civets, from which the virus is thought to
have originally jumped into humans. In this case,
they found hints that the antibodies actually
boosted the ability of the virus to infect cells.
The study is published in the Proceedings of the
National Academy of Science
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