BTY328: Virology [e-mail]

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BTY328 Virology wstafford_at_uwc.ac.za

• 18th Aug 10.50- AIDS
• 19th Aug 9.40- HIV molecular biology
• 20th Aug 8.30HIV prevention
  treatment
  
  

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Acquired immune deficiency syndrome

• AIDS patients have many diseases, most having
  more than one disease at any given time.
• Collectively the diseases that are expressed in
  an AIDS patient are referred to as a syndrome.
• The number of diseases an AIDS patient has, and
  the severity of their expression reflects the
  functioning of that persons immune system.

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Chronicle of the onset of AIDS epidemic in the
U.S.A.
1981 June, LA 5 cases of an unusual pneumonia,
pneumocystis (CDC)? July 41 cases of Kaposis
Sarcoma, a rare skin cancer August 100 cases of
homosexual men dying of rare diseases End of
1981 121 deaths 1982 May immune system
disorder known to doctors around 335 people
affected July 34 cases of a serious immune
disorder among Haitians. December infant dies
of AIDS after multiple blood transfusions
1983 Pasteur Institute - new virus in
patient with symptoms preceding AIDS named it
lymphadenopathy-associated virus, or LAV
Women can catch it too 1476 deaths
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AIDS chronicle
1984 Robert Gallo (US) CDC reports that
HTLV may cause AIDS 3500 deaths Drug
users are getting AIDS 1985 Blood test made
available to blood banks Rock Hudson admits
to having AIDS. Dies in October Blood supply
declared free of HIV virus Pentagon starts
screening recruits- Will reject positives
6850 deaths 1986 Women may transmit HIV to
men 12,000 deaths 1987 Insurers want to
test for HIV WHO makes global map of AIDS
cases 17,000 deaths
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AIDS an infectious agent?

• Koch's postulates
• 1. Epidemiological association the suspected
  cause must be strongly associated with the
  disease.
• 2. Isolation the suspected pathogen can be
  isolated - and propagated - outside the host.
• 3. Transmission pathogenesis transfer of the
  suspected pathogen to an uninfected host, man or
  animal, produces the disease in that host.

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HIV causes AIDS

• Previously rare diseases (Pneumocystis carinii
  pneumonia) opportunistic infections have become
  more common. In the rural Hlabisa District of
  South Africa, TB increased 360 percent from 1992
  to 1998, concomitant with a steep rise in HIV
  seroprevalence.
• Death rates are markedly higher among
  HIV-seropositive individuals than among
  HIV-seronegative individuals. Masaka District of
  Uganda (8,833 individuals). Among individuals
  ages 25-34, HIV-seropositive people were 27 times
  more likely to die than HIV-seronegative people.
• AIDS and HIV infection are invariably linked in
  time, place and population group. Virtually all
  patients with AIDS are HIV seropositive

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• Individuals from diverse backgrounds-
  heterosexual and homosexual men and women,
  haemophiliacs, blood transfusion recipients and
  injection-drug users and infants have all
  developed AIDS- the only common denominator
  being their infection with HIV (NIAID, 1995)?
• The development of AIDS following known HIV
  seroconversion observed in blood transfusion
  cases, in mother-to-child transmission and
  accidents to heath workers (needle injury from
  HIV patient).
• More than a dozen strains of simian
  immunodeficiency virus (SIV) cause AIDS in
  macaques (old world monkey).
• Isolation of HIV from AIDS patients, and culture
  in the laboratory. Detection by antibodies
  (ELISA, Western Blot) and PCR to trace the viral
  load o finfected patients

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AIDS pandemic

• In 2007, an estimated 33.2 million people lived
  with the disease worldwide, and it killed an
  estimated 2.1 million people, including 330,000
  children.
• Three-quarters of these deaths occurred in
  sub-Saharan Africa, retarding economic growth and
  destroying human capital.

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Global HIV infection
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Affected groups
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AIDS and immune function
T-cells and B-cells Thymus and Bone B-cells
produce antibodies T-cells help B-cells make
antibodies (helper T-cells)? kill damaged or
foreign cells (cytotoxic T-cells)? 2 kinds of
helper T-cells (biochemical messengers)? Th2
help B-cells Th1 help cytotoxic T-cells HIV
gradually eliminates Th1 Th2 cells HIV has a
surface protein gp120 which binds to CD4
receptor Th1 Th2 Immune system keeps
producing T-cells, but after 10-15years, the body
cant keep up with the rate of cell death No
immune response to infection AIDS begins......
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Typical progression of AIDS
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Rapid progressors

• A small percentage of HIV-infected individuals
  rapidly progress to AIDS within four years after
  primary HIV-infection and are termed Rapid
  Progressors (RP) (Anzala et al., 1995)?
• Rapid progression was originally thought to be
  continent specific, as some studies reported that
  disease progression is more rapid in Africa
  (N'Galy et al., 1988 Anzala et al., 1995
  Whittle et al., 1992), but others have contested
  this view (Marlink et a., 1994 French et al.,
  1999 Morgan et al., 2002).

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Long term non-progressors

• Individuals who are persistently infected with
  HIV-1, but show no signs of disease progression
  for over 10 years and remain asymptomatic are
  classified as Long Term Non-Progressors (LTNP).
  (Buchbinder et al., 1994 Cao et al., 1995
  Easterbrook, 1994 Levy, 1993).
• However, the term LTNP is a misnomer as
  progression towards AIDS can occur even after 15
  years of stable infection (Harrer et al., 1996).
• LTNP are not a homogeneous group regarding both
  viral load and specific immune responses against
  HIV-1. Some LTNPs are infected with HIV that
  inefficiently replicates (Deacon et al., 1995
  Kirchhoff et al., 1995) whilst others that are
  infected hav strong and broad set of HIV-specific
  humoral and cell-mediated responses that seems to
  delay the progression to AIDS.

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Highly exposed persistently seronegative

• A small group of individuals prostitutes in Kenya
  and in The Gambia) are HIV-negative despite
  being persistently exposed to HIV
• Continual transient infection may have occurred
  (Clerici et al., 1994 Pinto et al., 1995
  Rowland-Jones et al., 1995 Fowke et al., 1996).
  The CTL epitope specificity differs between
  Highly exposed persistently seronegative and HIV
  positive individuals (Kaul et al., 2001).The
  appearance of HIV-1-specific CD8 cytotoxic T
  cells (CTLs) early after primo-infection has been
  correlated with the control of HIV-1 viremia
  (Koup et al., 1994 Borrow et al., 1994).

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Prediction of progression rates

• Individuals with a broad expansion of the T cell
  receptor of CD8 T cells during primo-infection
  seem to have low levels of virus six to twelve
  months later, which is predictive of relatively
  slow disease progression. (Pantaleo et al.,
  1997).
• However, a few reports have correlated the
  presence of antibodies against Tat in long term
  non-pogressors.

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HIV subtype variation and effect on progression
rates

• The HIV-1 subtype that an individual becomes
  infected with can be a major factor in the rate
  of progression from sero-conversion to AIDS.
  Individuals infected with subtypes C, D and G are
  8 times more likely to develop AIDS than
  individuals infected with subtype A (Kanki et
  al., 1999). In Uganda, where subtypes A and D
  are most prevalent (Kaleebu et al., 2000),
  subtype D is associated with faster disease
  progression compared with subtype A (Kaleebu et
  al., 2002). ?

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Host genetic susceptibility

• HIV enters cells through an interaction with both
  CD4 and a chemokine receptor.
• While CCR5 has multiple variants in its coding
  region, the deletion of a 32-bp segment results
  in a nonfunctional receptor, thus preventing HIV
  entry. This gene is found in up to 20 of
  Europeans but is rare in Africans and Asians.
• Multiple studies of HIV-infected persons have
  shown that presence of one copy of this gene
  delays progression to the condition of AIDS by
  about 2 years. (Gonzalez et al).

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Co-infection and AIDS progression

• Coinfections or immunizations may enhance viral
  replication (entry to the cell reverse
  transcription and proviral transcription) (Lawn
  et al., 2001).
• The expression of Chemokine receptors is
  inducible by immune activation caused by
  infection or immunization, thus increasing the
  number of cells that are able to be infected by
  HIV-1 (Wahl et al., 1998 Juffermans et al.,
  2001).
• Co-infection with DNA viruses such as HTLV-1,
  herpes simplex virus-2, varicella zoster virus
  and cytomegalovirus may enhance proviral DNA
  transcription and thus viral load as they may
  encode proteins that are able to trans-activate
  the expression of the HIV-1 pro-viral DNA
  (Gendelman et al., 1986).

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The effect of co-infections on progression rates

• The impact of co-infections by micro-organisms
  such as Mycobacterium tuberculosis can be
  important in disease progression, particularly
  with those with poor access to medical care
  (Blanchard et al., 1997).
• Frequent exposure to helminth infections,
  (endemic in Africa) shifts the cytokine balance
  away from an initial Th1 cell response against
  viruses and bacteria which would occur in the
  uninfected person to a less protective T helper
  0/2-type response (Bentwich et al., 1995). This
  makes the host more susceptible to and less able
  to cope with infection with HIV-1.

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Defining AIDS

• Category A Acute phase (few weeks). The virus
  is produced in large quantities by the activated
  lymphocytes in the lymph nodes, sometimes causing
  the nodes to swell (lymphadenopathy), or
  generating flu-like symptoms, or can be
  asymptomatic. The viral load is greatly curtailed
  within a few weeks by cell mediated response to
  HIV-1 as the number of CD8 cytotoxic lymphocytes
  and Ab increases.The virus population at this
  stage fairly homogeneous
• Category B Asymptomatic Stage (several years).
  CD4 numbers decrease at a steady rate (approx 60
  cells/year) to around 200-500/ul and immune
  system weakens due to direct cytopathogenicity by
  the virus, or apoptosis. The virus population
  becomes more heterogeneous because of continual
  selection for specific mutants as a result of
  immunological pressure.

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Defining AIDS

• Category C Symptomatic Phase and AIDS. End
  stage when infected individual develops AIDS
  symptoms characterised by a CD4 count below
  200/ul blood and increased quantities of virus.
  Virus population becomes homogenous with
  increased virulence, expanded cellular host
  range, ability to cause syncytia. AIDS indicator
  conditions present Candida albicans esophagus
  and lungs, cytomegalovirus infection of eyes,
  tuberculosis, pneumocystis pneumonia,
  toxoplasmosis of the brain, Kaposis sacoma

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Common infection in AIDS
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AIDS summary

• Patients with acquired immune deficiency
  syndrome, regardless of where they live, are
  infected with HIV.
• If not treated, most people with HIV
  infection show signs of AIDS within 5-10 years.
• HIV infection is identified in blood by
  detecting antibodies, gene sequences or viral
  isolation.
• Persons who have exchanged bodily flids
  with HIV positive individual or contaminated
  blood (sex, intravenous drug use, vaccintions
  with repeated needle usage, heamophiliacs) become
  HIV positive and develop AIDS. Most children who
  develop AIDS are born to HIV-infected mothers.
• Monkeys inoculated with cloned SIV DNA
  become infected and develop AIDS.

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Origin of HIV ?
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Tracing the origin of the epidemic....to Africa

• 1959 Congolese man. Preserved blood sample taken
  in 1959 from a man from Leopoldville, Belgian
  Congo (now Kinshasa, Democratic Republic of the
  Congo). However, it is unknown whether this
  anonymous person ever developed AIDS and died of
  its complications. . Another early case was
  detected that same year, 1959, in a 48-year-old
  Haitian, who had immigrated to the United States
  30 years beforehand. He died the same year,
  apparently of the same very rare kind of
  pneumonia.
• HIV arrived in Haiti, probably in one person, in
  about 1966, at a time when many Haitians were
  working in newly independent Congo. Then in 1969
  HIV spread to the US - again in one person -
  where it circulated, unrecognised, for 12 years.
  The team thinks it may have remained invisible
  until it reached gay communities - compact groups
  that spread the virus efficiently - which led to
  visible clusters of the disease.

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HIV Origin in Africa..?

• Cameroon chimpanzees and Hunter theory
• A human was bitten by an ape or was cut while
  hunting one, and the human became infected. HIV
  most likely originated in wild chimpanzees in the
  southeastern rain forests of Cameroon or,
  Democratic Republic of Congo.
• Immunisation programmes with needle re-use
• The jump from chimpanzee to human likely occurred
  during the French colonial period (19191960).
  Systems of poor conditions (forced labour and
  poor nutrition) and mass immunisations using one
  needle on many patients enabled zoonosis and
  transmission the virus spread.

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HIV and its origin in Africa

• Iatrogenic event
• (1) Oral polio vaccine hypothesis. Late 1950s
  research into a polio vaccine in the Belgian
  Congo prepared using chimpanzee kidney tissue
  enabling the SIV to infect and adapt to humans.
  The hypothesis that oral polio vaccine was
  involved in the origin of AIDS has been
  investigated and generally rejected by the
  scientific community.
• (2)Hepatitis B (HB) vaccine hypothesis. African
  chimpanzees were used in the manufacture of the
  HB vaccines during the early 1970s. Human HB
  viruses cultured in chimpanzees were returned to
  humans whose infected blood serum was then pooled
  to develop four different strains of experimental
  HB vaccine pilot tested between 1970 and 1975 in
  New York City and Africa.

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HIV Origin in Africa.

• Hepatitis B vaccine
• and HIV zoonosis?

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