Infectious Diseases

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Infectious Diseases

• Gene-Environment Interaction
• by
• Vidya Maharaj

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Infectious Diseases

• In medicine, infectious disease or communicable
  disease is disease caused by a biological agent
  such as by a virus, bacterium or parasite. While
  the word "infectious" can cause alarm, it is
  simply a term for a whole class of diseases.
  Infectious diseases need not be dangerous, and
  may not spread from person to person at all.

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Viruses Parasites

• Viruses are tiny geometric structures that can
  only reproduce inside a living cell. They range
  in size from 20 to 250 nanometers (one nanometer
  is one billionth of a meter). Outside of a living
  cell, a virus is dormant, but once inside, it
  takes over the resources of the host cell and
  begins the production of more virus particles.
  Viruses are more similar to mechanized bits of
  information, or robots, than to animal life.
• Parasites are organisms that live or coexist off
  another organism.

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Bacteria

• Bacteria are one-celled living organisms. The
  average bacterium is 1,000 nanometers long. (If a
  bacterium were my size, a typical virus particle
  would look like a tiny mouse-robot. If an average
  virus were my size, a bacterium would be the size
  of a dinosaur over ten stories tall. Bacteria and
  viruses are not peers!) All bacteria are
  surrounded by a cell wall. They can reproduce
  independently, and inhabit virtually every
  environment on earth, including soil, water, hot
  springs, ice packs, and the bodies of plants and
  animals.

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Top Ten Infectious Diseases Reported

• HIV/AIDS
• Diarrheal Diseases
• Tuberculosis
• Malaria
• Measles
• Pertussis
• Tetanus
• Meningitis
• Syphilis
• Hepatitis B

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Prevalence of Infectious Diseases (2002)

• 57 million people were infected with infectious
  diseases in 2002 compared to 51 million in 1993.
• The top three single agent disease killers are
  HIV/AIDS, TB and malaria. From 1993 to 2002, the
  death ranking for AIDS went up while Hepatitis B
  went down. While the number of deaths has
  decreased in almost every disease, it has
  increased four-fold in AIDS.

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What is HIV?

• HIV is the virus that causes AIDS.
• H-Human because this virus can only infect human
  beings.
• I-Immuno-deficiency because the effect of the
  virus is to create a deficiency, a failure to
  work properly, within the body's immune system.
• V-Virus because this organism is a virus, which
  means one of its characteristics is that it is
  incapable of reproducing by itself. It reproduces
  by taking over the machinery of the human cell.  

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What is AIDS?

• A-Acquired because it's a condition one must
  acquire or get infected with not something
  transmitted through the genes
• I-Immune because it affects the body's immune
  system, the part of the body which usually works
  to fight off germs such as bacteria and viruses
• D-Deficiency because it makes the immune system
  deficient (makes it not work properly)
• S-Syndrome because someone with AIDS may
  experience a wide range of different diseases and
  opportunistic infections.

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HIV/AIDS

• First cases identified June 1981.
• gt900,000 cases in US with gt500,00 deaths
• - About 40,000 new cases 15,000 deaths per yr
• - Heavily disproportionate for minority
  populations
• - Perhaps as many as 300,000 undiagonsed HIV
• World Estimates (as of 2005)
• - gt40 million living with HIV
• - gt25 million deaths
• - In 2005 estimated 5 millioin new infections
  and 3 million dealths
• - Areas of the world with up to 25 of adults
  infected
• - Prediction of an additional 45 million by 2010

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Risk Factors

• Those who have multiple sex partners.
• Those who have sexually transmitted diseases
  (STDs) and opportunistic infections.
• Those who inject drugs, especially if they share
  needles.
• Those who handle blood or body fluids as a
  routine part of their job, such as doctors,
  dentists, nurses, lab technicians, and funeral
  workers.
• Those who have hemophilia.
• Those who received transfused blood or other
  blood products before 1985. Since all blood is
  now screened for HIV and all blood products are
  now heat treated to destroy HIV, the risk of
  getting HIV from transfused blood or blood
  products is low.
• Those who have their ears or other body parts
  pierced with needles that have not been properly
  cleaned and sterilized.
• Those who have tattoos inked with needles that
  have not been properly cleaned and sterilized.
• Infants whose mothers are infected with HIV.
• Those with active tuberculosis (TB).

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Screening for HIV/Aids

• When HIV enters the body, it begins to attack
  certain white blood cells called T4 lymphocyte
  cells (helper cells). Your doctor may also call
  them CD4 cells. The immune system then produces
  antibodies to fight off the infection. Although
  these antibodies are ineffective in destroying
  HIV, their presence is used to confirm HIV
  infection. Therefore, the presence of antibodies
  to HIV result from HIV infection. HIV tests look
  for the presence of HIV antibodies they do not
  test for the virus itself.
• The most commonly used initial test is an enzyme
  immune assay (EIA) or the enzyme-linked
  immunosorbent assay (ELISA). If EIA test results
  show a reaction, the test is repeated on the same
  blood sample. If the sample is repeatedly the
  same result or either duplicate test is reactive,
  the results are "confirmed" using a second test
  such as the Western blot. This more specific (and
  more expensive) test can tell the difference
  between HIV antibodies and other antibodies that
  can react to the EIA and cause false positive
  results. False positive EIA results are uncommon,
  but can occur. A person is considered infected
  following a repeatedly reactive result from the
  EIA, confirmed by the Western blot test.

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Screening for HIV/Aids

• In addition to the EIA or ELISA and Western blot,
  other tests now available include
• Radioimmunoprecipitation assay (RIPA) A
  confirmatory blood test that may be used when
  antibody levels are very low or difficult to
  detect, or when Western blot test results are
  uncertain. An expensive test, the RIPA requires
  time and expertise to perform.
• Dot-blot immunobinding assay A rapid-screening
  blood test that is cost-effective and that may
  become an alternative to standard EIA and Western
  blot testing.
• Immunoflourescence assay A less commonly used
  confirmatory blood test used on reactive ELISA
  samples or when Western blot test results are
  uncertain.
• Nucleic acid testing (e.g., viral RNA or proviral
  DNA amplification method) A less available blood
  test that can be used to resolve an initial
  indeterminate Western blot result in certain
  situations.
• Polymerase chain reaction (PCR) A specialized
  blood test that looks for HIV genetic
  information. Although expensive and
  labor-intensive, the test can detect the virus
  even in someone only recently infected.

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Structure of HIV

• HIV has just nine genes (compared to more than
  500 genes in a bacterium, and around
  20,000-25,000 in a human). Three of the HIV
  genes, called gag, pol and env, contain
  information needed to make structural proteins
  for new virus particles. The other six genes,
  known as tat, rev, nef, vif, vpr and vpu, code
  for proteins that control the ability of HIV to
  infect a cell, produce new copies of virus, or
  cause disease.
• At either end of each strand of RNA is a
  sequence called the long terminal repeat, which
  helps to control HIV replication.

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How HIV works!
CD4 antigen
CD4 cell
Co-receptor
HIV gp120 binds to CD4/co-receptor
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CD4 antigen
Co-receptor
CD4 cell
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T4 cell
HIV
gp41
Co-receptor
gp41
CD4 antigen
gp120
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Matrix
Gp120 binds to CD4/co-receptor
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Reverse transcriptase
Protease
Integrase
tRNA
Binding causes a conformational change in the
gp120 molecules
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Gp41 is exposed and embeds in the membrane of the
CD4 cell
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Membranes begin to fuse
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Membranes fuse
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Nucleocapsid enters CD4 cell
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Nucleocapsid in cytoplasm
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Cell membrane
Nuclear membrane
Nuclear pore
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Nuclear membrane
Targeting signal interacts with nuclear protein
(nuclear pore?)
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Reverse transcriptase
protease
Surface membrane
integrase
Nuclear membrane
RNA
Components of HIV enter the nucleus
tRNA
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Genetic factors associated with HIV.

• CCR5-?32
• CCR5 Promoter
• CCR2-641
• RANTES-28G
• RANTES-403A
• SDF-1 3A
• CX3CR1-I249M280

• CXCR4
• CCR2b
• CCR3
• HLA-A
• HLA-B
• HLA-C
• CCR1

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Classification of HIV-1 Strains

• R5 strain
• Uses CCR5 as coreceptor
• Replicates slowly and is minimally cytopathic
• Strain primarily transmitted
• Prevalent in the early stage of disease
• X4 strain
• Uses CXCR4 as coreceptor
• Replicates fast and is highly cytopathic
• Is rarely transmitted
• Appears in approximately 50 of patients in the
  late stage of disease
• R5X4 strain
• Uses both CCR5 and CXCR4 as coreceptor with
  comparable efficiency
• Has similar properties to the X4 strain

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Chemokines and Chemokine Receptors

• Chemokines
• Chemotatic cytokines that attract leukocytes to
  the site of inflammatory reaction
• more than 40 have been identified and classified
  into 4 groups, CXC(a), CC(b), C(g), CX3C(d)
• Chemokine receptors
• 18 known human chemokine receptors
• CXCR1-5, CCR1-11, XCR1, CX3CR1
• Some are highly specific for each other, but
  redundancy is the norm among the
  chemokine-chemokine receptor interaction

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Dual Effects of Chemokines on HIV-1 Infection

• Pros
• Block HIV-1 entry by competing with HIV-1 for the
  same chemokine receptor
• Down-regulate chemokine receptor from the host
  cell surface
• Cons
• Induce an inflammatory response attracting
  non-infected target cells to the site of active
  viral replication
• Induce intracellular signaling that enhances
  HIV-1 replication

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Drugs

• Antiretroviral Agents Currently Available
  (generic name/Trade name)
• Nucleoside Analogs
• zidovudine/Retrovir (AZT, ZDV)
• didanosine/Videx, Videx EC (ddI)
• zalcitabine/HIVID (ddC)
• stavudine/Zerit (d4T)
• lamivudine/Epivir (3TC)
• abacavir/Ziagen (ABC)
• Non-Nucleoside Reverse Transcriptase Inhibitors
• nevirapine/Viramune (NVP)
• delavirdine/Rescriptor (DLV)
• efavirenz/Sustiva (EFV)
• Nucleotide Analogue
• tenofovir DF/Viread (TDF)
• Protease Inhibitors
• indinavir/Crixivan
• ritonavir/Norvir
• saquinavir/Invirase, Fortovase
• nelfinavir/Viracept