Intricacies of the virus (some of them)

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Intricacies of the virus(some of them)

• Rupert Kaul
• University of Toronto

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Overview

• Description of HIV and its life cycle
• Transmission of HIV
• Clinical events during HIV/AIDS
• The immune response against HIV - can it be
  effective?

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HIV virus and genetics

• RNA virus in the lentivirus family
• HIV-2
• RNA only 40-50 the same as HIV-1
• less common, spreads less easily, less virulent
• only common in West Africa, Portugal
• HIV-1 is divided into several strains (clades)
• clade B most common in Europe / NA
• clade C most common globally (SA)
• clades may have some differences (transmission,
  illness) and are beginning to mix together

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Kahn. IAVI Report - May / August 2003.
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HIV virus and genetics

• Within a clade - 85-90 homologous
• Within an individual - quasispecies gt95
  homologous
• About 109 viruses produced per day, error-prone
  reverse transcriptase (q 10-4-10-5)
• The virus is 10 Kb of proviral DNA long
• Most viruses are not able to infect a cell or
  reproduce only about 1/100 - 1/1000 can

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Outline of HIV life cycle
(1) HIV-1 attachment (2) Fusion (3) Cell entry
(4) Reverse transcription, formation of the
pre-integration complex (PIC) (5) Nuclear
transport (6) Chromosomal integration of DNA
provirus (7) Transcription of viral RNA (8)
Nuclear export of RNA (9) Translation and
processing (10) Membrane transport (11) Virion
assembly (12) Budding (13) Maturation.
Weiss RA. Trop Med Int Health. 2000.
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Global HIV rates

• WHO (2005) estimates 40 million HIV/AIDS
• worst affected is sub-Saharan Africa
• up to 30 of sexually-active adults (SA)
• 10 in east, west Africa, less in north
• may be lower in some rural areas (lt1)
• HIV rates low in some countries (Senegal lt1)
• in some countries rates (incidence and
  prevalence) falling (Uganda, Kenya)
• in some epidemic is escalating (SA, Botswana)
• in Kenya over 50 of inpatients are HIV

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HIV transmission

• Sex
• by far the most common method of transmission
  85-90 of global cases
• quite inefficient 0.3 (USA) - 3 (Thailand)
• increased via
• amount of virus in infected partners blood
• STDs (especially if ulcer)
• type of sex (anal gt vaginal gt oral)
• gender (male?female gt female?male)
• lack of male circumcision
• type (clade) of virus - clade C more infectious??

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Partner plasma viral load and transmission
Quinn et al. NEJM, 2000.
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Cohen, M. J Infect Dis, 2005.
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Core groups and HIV transmission
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Gender split in HIV/AIDS varies by region
Gender split among people withHIV infection, by
region
UNAIDS, 2002 www.unaids.org
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Genital herpes and HIV transmission
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Herpes rates in Kenya
Weiss (L), Wald (R.) Herpes, 2004.
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HIV transmission

• From a mother to her baby
• rate without antiviral drugs is 25 during
  delivery
• via baby swallowing virus during delivery
• risk during delivery increased by maternal STD
• transmission reduced via ARVs, C-section
• breast feeding also risky (10-15)
• Other methods less common globally
• blood transfusion / other blood products
• IV drug use
• contaminated needles / medical instruments
• occupational exposure

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Preventing transmission

• Sexual
• ABCs - especially Cs - especially core groups
• ARVs
• STD treatment, prevention?
• Microbicides, HIV vaccine?
• From mother to baby
• Screening followed by ARVs
• Caesarean section
• Through blood/needles
• Screening, needle exchange / needle provision

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Natural history of HIV infection

• (1) Acute HIV syndrome
• occurs within 1-2 weeks of HIV infection
• due to unchecked dissemination of virus (gut!)
• about 50 of infected persons will develop
• swollen lymph nodes
• flu-like illness with rash, fever, etc
• high levels of virus in the blood, very
  infectious
• HIV ELISA (antibody) test will be negative

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Natural history of HIV infection

• (2) Latent stage
• stage usually lasts for 5-10 years
• begins as body mounts partial immune response
• HIV-1 ELISA test now positive
• most people will have no symptoms
• amount of virus is low, people less infectious
• gradual decline in numbers of CD4 lymphocytes
  eventually immune system breaks down

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Natural history of HIV infection

• (3) Advanced HIV infection (AIDS)
• CD4 counts now low (usually under 200/mm3)
• immune system cannot function properly
• patients develop opportunistic diseases
• infections both common and uncommon
• cancers lymphoma and Kaposi sarcoma
• higher viremia, more infectious
• stage lasts 1-2 years, ends in death

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HIV course if untreated
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Clinical manifestations AIDS

• 1) Infections
• as the CD4 count falls under 200 cells/mm, prone
  to infections in lung (TB, PCP), brain (crypto,
  toxoplasmosis), gut (diarrhea), eyes (CMV)
• 2) Malignancies
• several are common, especially Kaposis sarcoma
  (skin), lymphoma
• 3) Direct virus effects
• neuropathy, nephropathy, etc

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Therapy for HIV

• Highly-Active AntiRetroviral Therapy has
  transformed HIV care
• combining 3-4 drugs can reduce virus to
  undetectable levels, restore CD4 counts
• major reduction in death rates from HIV
• BUT
• Expensive, needs infrastructure - still not
  available in most of the world
• high pill burden, significant side effects
• lt95 compliance leads to drug resistance

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HIV immune protection

• This is the goal of HIV vaccines
• But it has various possible meanings
• Sterile immunity no infection after contact
• Controlling immunity infected, but do not
  develop immunosuppression (therapeutic)
• Transmission immunity infected, but dont shed
  or transmit virus

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HIV and the immune system

• immune system has 3 main components
• nonspecific intact skin, body fluids, etc
• specific humoral (via antibodies)
• cellular (via lymphocytes)
• lymphocytes are divided into CD4 and CD8 cells
• CD8 cells do the killing, CD4 cells supervise
• HIV binds to CD4, infects these lymphocytes
• causes immune suppression

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Innate protection against HIV

• Hey, it works gt99 of the time
• Improving this could be important for a
  microbicide
• BUT what exactly is protecting against HIV?
• Mucus, pH, healthy bacteria (lactobacilli)
• Intact genital/rectal epithelium
• Several immune proteins (SLPI, lactoferrin, etc)
  and many unknown

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Good things about antibodies

• Some antibodies target conserved HIV regions
• Passive infusion of antibody cocktail ONLY
  model of sterilizing immunity in primates
• ? Pre-formed Ab applicable via microbicides
• Basically, any preventive HIV vaccine will
  probably neeed to induce good antibody responses

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How do cytotoxic T lymphocytes (CTL) work?
Sewell A, 2000.
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HIV escape from CTL control
Mutation
Other
And these CTL escape mutants can be transmitted
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HIV superinfection can occur

• Despite strong CTL, patients can be infected by a
  second strain of HIV-1
• Not good news for vaccines!

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Summary

• HIV is an enormous global problem
• Spread through sex gt blood, mother-child -
  several factors make this more/less likely
• Without therapy causes immune collapse (AIDS) and
  death in 10 years
• Several key parts of the life cycle can be
  targeted by drugs
• New combination therapy very effective, but faces
  problems of cost, side-effects, resistance
• Virus escape from immune responses is a problem
  for vaccines

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Small groups discussion points

• Why is it so hard to make an HIV vaccine?
• Why has HIV spread more in some parts of the
  world than others?
• What does a negative HIV test mean?