Viral Pathogens
Part one: HIV
Learning outcomes
After this lecture, you should be able to:
• Describe the structure of HIV.
• Describe the replication of the HIV virus
• Explain the disease progression following
HIV infection.
• Describe the mechanisms for prevention
of infection.
• Discuss treatment methods for HIV
infected individuals.
HIV Infections and AIDS
• HIV
– Human immunodeficiency virus
• AIDS
– Acquired immunodeficiency syndrome
• First noted in late 1970’s, early 1980’s
• Two types of virus HIV-1 and 2
• HIV-2 prevalent in West Africa (less severe)
• HIV viruses have evolved from simian viruses.
• 1959 first documented case of AIDS although initial
infection thought to have passed to human much earlier
but due to rural location went unnoticed
HIV in Sri Lanka
• Sri Lanka considered to be a low HIV
prevalence country
People Living with HIV/AIDS (January 2014)
Adults 3000
(>15 Years) (range 2000-5000)
Children
75
(<15 Years)
New Cases in 2012 280
Adult Prevalence
<0.1%
(>15 Years)
http://www.aidscontrol.gov.lk/web/index.php/en/statistics/hiv
Surveillance in Sri Lanka
• A well organised, surveillance & control
programme
http://www.aidscontrol.gov.lk/web/index.php/en
But why worry about HIV?
http://www.ipsnews.net/2014/02/hiv-dangerous-threshhold-sri-lanka/
Global prevalence
Global situation and trends
• Since the beginning of the HIV epidemic,
almost 75 million people have been
infected with the HIV virus.
• Approx 36 million people have died of HIV.
• Globally, 35.3 million [32.2–38.8 million]
people were living with HIV at the end of
2012.
HIV
• Retrovirus, genus Lentivirus
• Encodes reverse transcriptase which makes a
dsDNA from the ssRNA genome
• Enveloped virus
• Viral genes can permanently integrate into host
DNA
• HIV positive
– Have the virus within the body
• AIDS
– Have the virus and an immunosuppressive disease
• HIV can only infect host cells that have the
required CD4 marker plus a co-receptor.
Reverse transcriptase
• RNA dependant DNA polymerase, i.e. makes a
DNA copy of an RNA molecule
• Discovery of retroviruses and associated
enzymes have allowed great advances in
molecular biology. Reverse transcriptases now
produced and used routinely in the lab
• First retrovirus to be isolated was HTLV-1 from a
patient with Human T-cell leukaemia
• Reverse transcriptase of HIV very error prone,
leads to genetic instability and generation of new
strains of virus over the course of infection.
Evolution of HIV viruses
HIV virus genes
• env -encodes gp160 which is cleaved into gp120 and
gp41
– Cleavage is essential for infectivity
• gag -group specific antigen (core/capsid protein)
• pol -encodes RT polymerase, integrase, protease
• rev - protects mRNA from nucleus to cytoplasm
• nef -alteration of cell signals, progression to AIDS,
reduces the number of cell surface CD4 molecules
• vif -promotes virus assembly
• vpu -facilitates release of virus
• vpr -transport of DNA to nucleus for integration
• tat - transactivator or regulatory gene; recruits cellular co-
factors for DNA transcription
Co-receptors for HIV infection
•Two chemokine receptors – CCR5 and CXCR4 have been identified as co-
receptors for entry of HIV.
•Macrophage tropic (M-tropic) strains of HIV replicate in macrophages and CD4 T
cells
•use the chemokine receptor CCR5 (deficient individuals more resistant to
infection)
•T-Tropic isolates replicate in CD4 T cells and macrophages
• use the chemokine receptor CXCR4
• some viruses use both CXCR4 or CCR5
•Mutation in gp120 results in the shift of M to T occurs late, correlates with
progression
•Genetic mutations in the genes coding for co-receptors have been identified.
Such mutations result in increased protection against, or a delay in, HIV infection.
•New therapies may be developed based on the chemokine receptor network .
Epidemiology of HIV Infections
• Transmission occurs by direct and specific
routes:
• Through sexual intercourse
– Virus present in semen and vaginal secretions
• Transfer of blood or blood products
– Blood transfusions, intravenous drug users
• Babies can be infected before or during
birth, and from breast feeding.
• HIV does not survive long outside of the
body so not transmitted by touch, insect
bites, toilets etc
Infection
• HIV enters through mucous membrane
infects MALT (mucosal associated
lymphoid tissue)
• Virus taken up and amplified by
macrophages, can act as a reservoir and
also transport virus
• Other cells of the macrophage lineage
also infected
• Infects CD4 cells, results in increased
viral load
• Lytic infection of CD4 cells results in
destruction of cells
Primary effects of HIV infection:
– extreme leukopenia – lymphocytes in
particular
– formation of giant T cells and other syncytia
allowing the virus to spread directly from cell
to cell
– Infected macrophages release the virus in
central nervous system, with toxic effect,
inflammation.
Secondary effects of HIV:
– Destruction on CD4 lymphocytes allows for
opportunistic infections and malignancies.
Viral production latency and
reactivation
Signs and Symptoms of HIV
Infections and AIDS
• Symptoms of HIV are directly related to viral blood level
and level of T cells.
• The primary infection with HIV may go unnoticed, or is
typified by an acute flu-like illness
• A specific immune response follows with CD8 T cells vital
in controlling the virus.
• This control largely restores CD4 T cell levels but does
not eradicate HIV.
• Antibodies are detectable 8-16 weeks after infection.
• Asymptomatic phase 2-15 years (avg. 10)
• HIV gradually destroys the immune system.
• When T4 cell levels fall below 200/mL AIDS symptoms
appear including fever, swollen lymph nodes, diarrhea,
weight loss, neurological symptoms, opportunistic
infections and cancers.
Progression of infection
Diagnosis of HIV Infection
• Antibody tests
– ELISA, latex agglutination and rapid antibody tests
– rapid results but may result in false positives
– Sometimes antibodies can take some time to appear so not
always immediate
– Follow up with Western blot analysis to rule out false positives
persons who may have been exposed should be tested a second
time 3-6 months later.
• Molecular based tests
– Checking for viral genomic material (RT PCR)
– Can be used to gain an indication of viral load
– May help diagnose early infection before antibody production
Progression to AIDS
Diagnosis of AIDS is made when a person
meets the criteria:
1. Positive for the virus, and
2. They fulfill one of the additional criteria:
• They have a CD4 count of fewer than 200
cells/µl of blood.
• Their CD4 cells account for fewer than14% of all
lymphocytes.
• They experience one or more of a CDC-provided
list of AIDS-defining illnesses.
Insert Table 25.A page 776
AIDS-defining illnesses
Preventing and Treating HIV
• No widely available vaccine but this is an area of
active research
– monogamous sexual relationships
– condoms
– universal precautions for blood to prevent
transmission
– education about methods of transmission
• No cure; therapies slow down the progress of the
disease or diminish the symptoms
– inhibit viral enzymes: reverse transcriptase, protease,
integrase
– inhibit fusion
– inhibit viral translation
– highly active anti-retroviral therapy
The search for
a vaccine
Treatment strategies
Long Term Nonprogressors
• HIV-infected people who
– maintain CD+ T cell counts of at least 600 cells/ml of
blood
– have <5,000 copies of HIV RNA/ml of blood
– have remained this way for > 10 years after
documented infection
• Explanations of phenomena
– effective immune response to relatively conserved
proteins
– initial infection was with attenuated strain
– predisposing genetic differences
Directed learning
• What are the main issues around HIV vaccine
development? Do some additional reading and
make some additional notes on this subject.
• Identify some current research which is
attempting to identify additional means of
curing/preventing HIV infection other than the
vaccine strategy and make some notes on this.
What are the 3 main points to
take from this lecture?
1.
2.
3.
Suggested reading material
http://www.sciencedirect.com/science/article/pii/S01406736
11608775
http://onlinelibrary.wiley.com/doi/10.1002/9780470015902.
a0021550.pub2/full
http://onlinelibrary.wiley.com/doi/10.1002/9780470015902.
a0000410.pub2/full
http://onlinelibrary.wiley.com/doi/10.1038/npg.els.0003998/
full
