HIV infections

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HIV infections

• Kevin Forward

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Characteristics of retroviruses

• Enveloped, positive-strand RNA virus
• It has an enzyme called reverse transcriptase
  that makes a DNA copy of its genome
• The DNA copy is integrated into the host
  chromosome to become a cellular gene
• Subfamilies of retroviruses
• Oncoviruses (HTLV-1, HTLV-2)
• Lentiviruses (HIV-1, HIV-2)
• AIDS
• HIV positive, less than 200 CD4 cells, or an
  AIDS indicator disease

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Retrovirus discovery

• Work had already begun on HTLV1 and 2
• HIV discovered in 1981 by Gallo and Montagnier in
  patients with early AIDS
• Subsequently, HIV-2 was isolated in West Africa

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Epidemiology

• Global Distribution
• Over 50 million infected with HIV world wide,
• 3 million deaths per year.
• 7 million new infections per year,
• 580,000 new infections in children per year.
• Two-thirds of world HIV infections in Sub-Saharan
  Africa where prevalence is 1 out of 13 people
  between 15-49 yo.
• One out of 100 sexually active adults in world
  infected with HIV

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Adults and Children Living with HIV/AIDS 2004
Eastern Europe Central Asia 1.4 million
Western Europe 610,000
N. America 1.0 million
S SE Asia 7.1 million
North Africa 540,000
Caribbean 440,000
Sub-Saharan Africa 25.4 million
Latin America 1.9 million
Total 39.4 (35.9 44.3) Million
Data from UNAIDS
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Global View of HIV infection
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In Canada

• Trends
• More people who use needles to inject drugs are
  being infected
• Half of all new HIV infections are in people
  under 25 years old
• Young rather than older gay men are especially at
  risk
• More women are becoming infected
• More people living with HIV and AIDS due to
  decline of deaths

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Transmission

• HIV is present in
• blood (or fluids contaminated by blood and serum)
• semen
• vaginal fluids
• Host related factors are biggest determinate
• Factors that increase infectiousness primary
  infection, late stage infection, genital tract
  infections
• Risk probabilities
• female to male 1 in 700-3000
• male to female 1 in 200-2000
• Male to male 1 in 10-1600
• Needle stick 1 in 200
• Mother to infant 1 in 4 (with treatment 1 in
  25)
• Transfusion of infected blood 1 in 450.000 per
  unit)

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The virus Structure

• Medium size virus with an envelope acquired from
  the host cell plasma membrane
• Each virus contains two copies of positive-strand
  RNA
• Each virus also contains 10-50 copies of reverse
  transcriptase and integrase enzymes

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Replication

• The mushroom shaped gp120 of HIV interacts with
  the CD4 surface molecule expressed on T-helper
  lymphocytes and cells of the macrophage lineage
• Macrophages
• Dendritic cells
• Microglial cells (brain cells)
• HIV enters the cell by fusion with the cellular
  envelope

Primary receptor CD4Co-receptor CXCR4 or CCR5
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Replication (contd)

• After release, the reverse transcriptase
  synthesizes a complementary DNA strand
• A copy of the DNA strand is then produced
• Once integrated, viral DNA is transcribed like
  other host genes
• Each copy contains approximately five errors or
  mutations

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Viral protease
RNA
RNA
Proteins
Reverse transcriptase
RT
RNA
RNA
DNA
Viral regulatory proteins
RT
DNA
DNA
Provirus
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Pathogenesis

• HIV infection of CD4 lymphocytes results in cell
  death by a direct effect or by triggering
  apoptosis (programmed cell death)
• Antibodies against gp120 may produce antibody
  dependent cytotoxicity
• Other cells are spared and may serve as important
  reservoirs of virus
• CD4s are primarily responsible for delayed type
  hypersensitivity and cell mediated immunity
• As CD4 cells are lost, opportunistic infections
  and malignancies occur

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Clinical syndromes

• Initial infection
• symptoms occur within weeks of infection
• many are asymptomatic but some develop infectious
  mononucleosis-like symptoms viral meningitis or
  rash
• Primary infection may be followed by a long
  symptom free period during which CD4 cells slowly
  reduce in number

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Progression of HIV Infection
Primary Infection
Possible acute HIV syndrome Wide dissemination of
virus Seeding of lymphoid organs

1200
1100
Death
1000
Opportunistic Diseases
1512
Intermediate stage
900
1256
800
1128
700
CD4 T-cells/mm3
164
Constitutional Symptoms
600
Plasma viremia titer
132
500
116
400
18
300
14
200
12
100
0
Weeks
Years
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Clinical syndromes
AIDS develops when any of a number of signs of
CD4 depletion occur

• opportunistic infections
• oral candidiasis
• toxoplasmosis
• cryptococcal meningitis
• severe herpes infections
• cytomegalovirus infections
• tuberculosis
• Pneumocystis pneumonia

• malignancies
• Kaposis sarcoma
• Lymphoma
• Cervical cancer
• AIDS related dementia
• wasting syndrome

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Major complications in the course of HIV
infection
Lymphoma
400
Tuberculosis
Herpes zoster, thrush, HSV
CNS disorders (HIV)
Bacterial infections, esophageal candidiasis
CD4/mm3
Pneumocystosis
200
Wasting
Toxoplasmosis
Atypical mycobacteriosis
100
CMV, cryptosporidiosis
microsporidiosis
20
PML
Time in years from infection
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Laboratory aspects

• Serology
• Screening tests for antibodies to a number of
  viral antigens by enzyme immunoassay
• Confirmation using Western blot
• Immunologic studies
• CD4 counts
• Viral load testing (PCR quantitation of RNA in
  plasma)
• Resistance genotyping (looking at the sequences
  of the genes in the HIV to see if the sequences
  have the mutations that cause resistance)

Cultures are seldom done anymore
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Positive HIV Western Blot
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Treatment of HIV/AIDS

• Three classes of anti retrovirals
• Nucleoside analogs
• Non nucleoside reverse transcriptase inhibitors
• Protease inhibitors
• Usually Highly Active Anti Retroviral Therapy
  (HAART) is used
• Problems include
• Side effects, compliance, resistance, cost
• Controversy exists on early or late initiation as
  all of these things need to be balanced.

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Suppression of plasma viremia by HAART
106 105 104 103 102 101
1,600 1,200 800 400 0
CD4 count (cells/mm³)
Plasma viral load (copies/mL)
0 5 10 15 20 25 30
Months after treatment
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Why Antiretroviral Therapy?
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Why Antiretroviral Therapy?
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Needle stick exposure

• Risk of infection depends on
• Stage of the patients disease
• How much blood (hollow vs solid, gauge of needle,
  aspiration vs injection)
• What to do
• Confirm patients status
• Document your status
• Begin antiviral prophylaxis

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Questions?