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22 Mar 2011
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LECTURE โ€“ March 22, 2011
Antibodies neutralize pathogens
๎€Using HIV as example of a pathogenic infection
๎€Vaccinate in order to induce antibodies that neutralize infection, prevent
infection from becoming established
1981 โ€“ when HIV was first noticeable
๎€At then, not considered viral infection, but a bacterial infection
๎€This is not normally dangerous in immunocompetent people
๎€So unusual
Kaposiโ€™s sarcoma โ€“ type of cancer โ€“ seen rarely
1982 โ€“ symptoms not restricted to homosexual groups
๎€Clear at that time that individuals suffering from this disease had lack of
immune function, acquired because this was not inherited
๎€Looking at the history of the disease, AIDS was seen as infectious
start of HIV epidemic
AIDS โ€“ description of symptoms
Type 3 because there were already two other viruses known to infect human T cells
1986 โ€“ causal agent of AIDS as a disease is the HIV virus
Short time btw identifying new disease and epidemiological studies proving the disease was
caused by infectious agent โ€“ to discovering and characterizing the retrovirus called HIV โ€“
all happened within 5 year span, at which point it was clear that AIDS was a new disease
caused by a novel retrovirus called HIV
Retroviruses
๎€Viruses do not contain all genetic material required for their lifecycle
๎€Retroviruses โ€“ genetic information is RNA
oRNA contains genetic information that allows for transmission of RNA
retrovirus from one cell to next
oFirst stage of process is reverse transcription of RNA back into DNA
oThen DNA transcribed into RNA, then translated into protein โ€“ to create
new retroviral particles
๎€Extra stage: RNA reverse transcribed into DNA
๎€Unique opportunity to interfere with lifecyle of retroviruses
๎€Because no normal stage in higher organisms where RNA is
required to be transcribed into DNA
โ€ขPotential place for drug targeting
๎€HIV is a retrovirus
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oSeveral families โ€“ alpha, beta, gamma, delta, epsilon, spumaviruses,
lentiviruses
oHIV is part of Lentiviruses
๎€Lentiviruses named because they are slow-acting
๎€Each will infect target cell and long period of time, before
symptoms are apparent
Lentiviruses
๎€HIV-1 is most prevalent in humans
๎€SIVmac โ€“ causes similar disease in monkeys, especially macacs
๎€EIAV โ€“ not as closely related โ€“ also like MVV โ€“ not as closely related as the inner
cluster
oInteresting because there are related viruses that infect different species
and in many causes, similar types of disease
oSuggesting FIV, HIV2, SIV, HIV may be evolved from one another by
crossing species
๎€THIS IS CALLED ZOONOSIS
oClear that HIV as a human virus has evolved from related viruses that
were present in monkeys
oChimpanzees have simian immunodeficiency virus, related to HIV,
around for longer than HIV
oHIV-2 less virulent โ€“ west Africa โ€“ came from different species of monkey
oTwo independent examples of a disease of primates (non-human) that
have crossed over into humans and ended up causing a disease
oWhen viruses are established in non-human species, viruses may not be
as pathogenic as in humans after crossing over
๎€EX. influenza carried in many birds, ex. ducks โ€“ many strains
replicate but cause virtually no symptoms
๎€Innocuous in natural host
๎€But when transferred into new host โ€“ viruses like influenza cause
severe symptoms
๎€ZOONOSIS has huge impact on ability to control infectious disease
๎€Smallpox โ€“ arguably the most important success of the immune system โ€“ because
now eradicated
oNo animal host for smallpox
oBecause if can wipe out in humans, can wipe out globally
oBUT it wouldnโ€™t matter if can vaccinate all against influenza, since it
exists naturally in the world โ€“ can return
๎€Zoonosis โ€“ diseases infect non-humans and subsequently transfer
disease to humans โ€“ profound impact on ability to control disease
HIV virus
๎€Genetic material is RNA
๎€One particle contains two RNA genomes, coated by capsid and matrix proteins
that form the HIV core
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๎€Reverse transcriptase also embedded in the core โ€“ enzyme responsible for
transcribing RNA of virus into DNA once the cell is infected
๎€Surrounding matrix is lipid membrane, which comes from host cells that have
been infected
๎€Embedded in lipid membrane are gp120 and gp41 โ€“ produced as single protein
gp160 that is subsequently cleaved to form the two proteins, which are essential
to lifecyle of HIV
oThese proteins allow the virus particle to bind to target cell
๎€Lifecyle starts with infectious HIV particles that are circulating outside the cell,
bind to target cell, virus undergo fusion with target cell to inject contents of
capsid into target cell that is now infected
oRNA of virus is reverse transcribed to generate DNA
oDNA can translocate from cytoplasm to nucleus, integrating itself into the
DNA of the target cell
๎€At this stage, viral DNA is double-stranded DNA
๎€Viral DNA known as provirus โ€“ not in viral stage yet
๎€Normal host machinery allows for transcription of genes encoded
by provirus, and for generation of new RNA strands that will form
core of newly generated c
๎€Transcription and translation generate HIV protein
๎€Transcription โ€“ RNA generated
๎€RNA and retroviral proteins assemble in cell to generate new virus
that buds off from infected cell
๎€Series of stages in lifecycle
โ€ขFusion, reverse transcription, integration of provirus,
transcription of provirus, and formation of new viral
particles and budding of them from plasma membrane of
infected cell
HIV infection of target cell
๎€First stage โ€“ viral particle must have capacity to bind to target cell
oGP120 of virus bind to molecule expressed on some T lymphyoctes โ€“ CD4
oCD4 is cellular receptor for HIV
oOnce interaction btw GP120 and CD4 takes place, conformation change in
GP120, so it can bind to second cell surface receptor on CD4+ T cell, either
CCR5 or CXCR4
๎€Different strains of HIV prefer different receptor
๎€CCR5 and CXCR4 are chemokine receptors that allow for normal
migration of T cells to different sites in lymphoid tissues
โ€ขSo required for normal function of CD4+ T cells
oGP120 binds to either CCR5 or other, allows for conformational change in
GP41 that allows GP41 to penetrate membrane, allowing fusion of viral
membrane to cellular membrane, to deliver viral core into cell
๎€This process explains why target cell of infection are helper T โ€“
cells
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Document Summary

using h iv as example of a pathogenic infection. vaccinate in order to induce antibodies that neutralize infection, prevent infection from becoming established. at then, not considered viral infection, but a bacterial infection. This is not normally dangerous in immunocompetent people. Kaposi"s sarcoma type of cancer seen rarely. 1982 symptoms not restricted to homosexual groups. clear at that time that individuals suffering from this disease had lack of immune function, acquired because this was not inherited. Looking at the history of the disease, aids was seen as infectious start of hiv epidemic. Type 3 because there were already two other viruses known to infect human t cells. 1986 causal agent of aids as a disease is the hiv virus. viruses do not contain all genetic material required for their lifecycle. extra stage: rna reverse transcribed into dna. unique opportunity to interfere with lifecyle of retroviruses.

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