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BIOM30002 > lecture 13 > Flashcards

lecture 13 Flashcards

HIV-1 infection: virology, pathogenesis and treatment - epidemiology - virology: general, HIV entry - immunology

1
Q

Approximately how many adults and children are estimated to be living with HIV?

A
  • total: 35.3 million [32.2 - 38.8]
  • most in sub-saharan africa (~80%, 25.0 mil)
  • w/i our region about 5 mil
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2
Q

How has the epidemiology changed in recent years?

A
  • number of new infections declining, largely attributed to access to antiretroviral therapy
  • makes people better and live longer, reduces their infectiousness
  • since it’s been available in low income countries there’s been progressive decline in new HIV infections
  • also a decrease in AIDS deaths globally since the mid 2000s
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3
Q

What is the relationship between antiretroviral therapy and infection?

A
  • e.g. in Botswana
  • new infections peaked ~mid 90s
  • very significant decline in infections over the last 15 years which is associated at the same time with introduction of antiretroviral treatment
  • botswana has one of the best programmes in africa
  • close to 90% of people who need treatment in botswana are on treatment
  • antiretroviral therapy reduces how much virus in the body and reduces your infectiousness
  • this sort of pattern has been seen everywhere
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4
Q

What has happened to new HIV diagnoses in Australia?

A
  • about 1200 new infections in Australia in 2012
  • slight increase from previous years
  • concerning because slight, but steadily increasing curve in Australia, while the rest of the world is witnessing reductions
  • in context, 1200 infections/year in australia vs recent celebrations in south africa where they reach a point where they only had 1000 infections a day
  • (important to consider that they have a larger population, ~80 mil)
  • number of infections in Aus peaked in early 80s - this is when HIV test became available
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5
Q

Why do we keep track of newly diagnosed and newly acquired HIV infections in Australia?

A
  • may have HIV for 10 years and be completely well and then diagnosed with infection
  • very different to having recently acquired HIV
  • number of newly acquired infections in Aus ~300, pretty stable
  • there isn’t a big impact on the transmission of HIV
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6
Q

Who is generally getting infected by HIV?

A
  • newly diagnosed: mostly men who have sex with men (64%), heterosexual contact (25%), tiny numbers of people who inject drugs, always a number of people who have no identifiable risk factors
  • Australia has one of the lowest rates of HIV in people who inject drugs, largely because the government provided access to clean needles
  • many parts of the US still don’t have access to clean needles and so still have high rates of infection in people who inject drugs

newly acquired
- most in men who have sex with men, mostly young men (median age of 30) - 85%

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7
Q

What are risk factors for HIV globally?

A
  • heterosexual: 80-75% (largely the sort of transmission you see throughout Africa)
  • homosexual: 5 - 10%
  • IV drug use: 5 - 10% (mostly in countries that don’t have access to clean needles, strict bans)
  • blood transfusions: 3 - 5% (very rare in all parts of the world)
  • unknown: 0 - 17%
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8
Q

What are behavioural and social factors associated with a generalised epidemic?

A
  • little or no condom use
  • multiple partners
  • overlapping sexual partners
  • large sexual networks
  • age mixing; old men and young girls
  • women dependent on marriage/prostitution
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9
Q

What are biological factors associated with a generalised epidemic?

A
  • high STI rates: increases the likelihood of transmission of HIV, particularly ulcerative STI
  • low rate of male circumcision: protects men from acquiring HIV by about 70%
  • HIV subtype (possibly)
  • genetics of host
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10
Q

What is HIV?

A
  • a (complex) retrovirus

- of the Lentiviridae family

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11
Q

What are non-primate retroviruses?

A
  • CAEV/Visna: Caprine arthritis encephalitis/Visna virus
  • EIAV: equine infectious anaemia virus
  • BIV: bovine immunodeficiency virus
  • FIV: feline immunodeficiency virus
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12
Q

What are primate retroviruses?

A

Simian Immunodeficiency Virus

  • African Green Monkey SIV (agm)
  • Sooty Mangabey SIV(sm) (–> HIV-2)
  • Macaque SIV (mac)
  • Mandrills SIV (mnd)
  • Sykes monkeys SIV (syk)
  • Chimpanze SIV (CPZ) (–> HIV-1)

infect monkeys naturally in the wild
a lot of research into how some monkeys get infected with SIV and not get sick, while others get an AIDS-like illness

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13
Q

What is the origin of HIV?

A
  • 100% arose from these monkey viruses
  • SIV (CPZ) –> HIV-1
  • SIV (sm) –> HIV-2 (only seen in parts of Africa)
  • largely because of practices of eating monkey bush meat
  • bloody business –> transmission event
  • capacity to move from monkey host to human host
  • probably around the 1930s, though first documented cases was 50s
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14
Q

What family of virus is HIV?

A

retrovirus

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15
Q

What is the major human lentivirus?

A
  • HIV-1

- HIV-2

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16
Q

What is the size of the virus?

A

80-130 nm

17
Q

What is the capsid symmetry?

A

icosahedral

18
Q

Does the virus have an envelope?

A

yes

19
Q

What is the genome of the virus?

A

diploid linear 10kb and sense ssRNA

two strands of ssRNA

20
Q

Where is the genome of the virus replicated?

A

nucleus

21
Q

Where does virus assembly occur?

A

cytoplasm - plasma membrane

22
Q

What are common features of lentiviruses?

A

slow disease

23
Q

What diseases are caused by lentiviruses?

A
  • AIDS
  • neurologic
  • arthritis
  • pneumonia
24
Q

What does the HIV genome look like?

A
  • a high degree of variability exists for gag and env proteins
  • m7G cap, gag (structural proteins), pol (viral enzymes), env (envelope glycoproteins), poly A tail
  • regulatory proteins: tat, rev, vpr, vpu, vif, nef
  • pol and env same ‘side’
  • all retroviruses have the three main genes, differ by their regulatory genes (control viral life cycle)
  • evolved to do some really interesting things to evade the immune response
25
Q

What is the structure of a retrovirus?

A
  • two single strands of RNA
  • lipid bilayer on outside
  • proteins in lipid bilayer = envelope proteins
  • sitting out on lipid bilayer is the gp120 = glycoprotein responsible for latching onto a human cell
  • embedded in the lipid bilayer by another glycoprotein: gp41
  • env responsible for attachment to cell and fusion of the viral membrane to the plasma membrane (SU-surface; cell attachment, TM-transmembrane; fusion domain)
  • gag: MA-matrix, structural protein under envelope; CA-capsid, another protective layer for RNA; NC-nucleocapsid, sit along two strands of RNA
  • pol: enzyme that the virus needs to replicate; RT-reverse transcriptase, allows virus to copy from RNA to DNA; IN-integrase, allows virus to integrate into the host genome; PR-protease, allows virus to make the proteins it needs (important in drug development)
26
Q

What is the global distribution of HIV clades? How are they defined?

A
  • clade B is dominant virus that we see in Australia, US, Canada, parts of south america and parts of europe
  • clade C is the predominant virus seen in Africa and India,
  • important for understanding the epidemiology and origins of HIV and how it is spread
  • important for vaccine development
  • defined by their genetic diversity from each other
  • within HIV-1 M group: sit separate to each other on a phylogenetic tree
27
Q

How is HIV-M group phylogenetically related to the SIVs?

A
  • sits very closely to SIV-CPZ
  • this is what suggests the link
  • SIV-SM sits on the same branch as HIV-2
28
Q

What is the HIV life cycle?

A
  1. CD4 binding
    - gp120
  2. Co-receptor binding
    - chemokine co-receptor (CCR5 or CXCR4)
  3. fusion
    - reverse transcription of viral RNA genome
    - proviral DNA
    - integration
    - transcription
    - viral RNAs
    - translation
    - assembly
  4. budding
  5. maturation
  6. new HIV virion
29
Q

What are key replication features of HIV?

A
  • rapid
  • error prone RT leads to rapid evolution of multiple quasispecies
  • 10 billion particles produced per day
  • impact on host cells
    • CD4+ T-cells: activated = death, resting = latent
    • monocyte/macrophages: long lived slow release of virus
30
Q

What occurs during host-cell entry?

A
  • gp120 binds CD4 and a chemokine co-receptor
  • Attachment: viral gp120 protein binds to CD4 on host cell
  • results in a conformational change
  • Co-receptor binding: gp120-CD4 complex binds to CCR5 or CXCR4 on host cell
  • Fusion: virus fuses with host cell membrane, facilitating viral entry
31
Q

What are the main HIV chemokine receptors?

A
  • CCR5 and CXCR4
  • different strains of the virus use different coreceptors
  • viruses that use CCR5 are called R5
  • viruses that use CXCR4 are called X4 viruses
  • in some patients over time the develops the capacity to use both and is known as D/M - dual tropic
  • this is important because it determines which cells the virus predominantly enters
  • big impact on the natural history of the infection
  • most people are infected with R5, about 95%
  • virus populations containing a mixture of R5-tropic, X4-tropic, and/or dual-tropic HIV are called mixed tropic (D/M)
32
Q

What is the co-receptor usage and natural history?

A

CCR5-using viruses (R5)

  • nearly all infections are caused by R5 viruses
  • R5 viruses cause less T-cell destruction
  • more easily transmitted but cause less T-cell destruction - probably an advantage for the virus

CXCR4-using viruses (X4)

  • rarely transmitted (don’t cross mucosal membranes as efficiently)
  • emerge late in the course of infection
  • 50% of patients with AIDS carry an X4 virus
33
Q

What is natural resistance to HIV?

A
  • CCR5 mutations
  • the delta32 mutation leads to a deletion of 32bp and no expression of CCR5
  • about 1% of people in the room will be CCR5 negative meaning they carry this delta 32 mutation
  • don’t make CCR5 to be presented on the surface of their cells
  • 5 - 10% of people are heterozygous
  • discovered because some people who were very high risk (gay men in new york) just weren’t getting it
  • rare

normal wt/wt

  • normal CCR5 expression
  • progression of HIV over about 10 years
  • normal immune function

heterozygotes

  • decreased CCR5 expression
  • delayed progression to AIDS/death
  • normal immune function

homozygotes

  • no CCR5 expression
  • rare infection with X4
  • normal immune function (v. rare infections that are worse because of it, but normally redundant)
34
Q

What is the global prevalence of the CCR5 delta 32 mutation?

A
  • 5 - 14% of caucasians of european descent carry the mutation (1% are homozygous)
  • the origin the mutated allele has been traced to European geography ~1,000 years ago
  • possible selection by pandemic pathogen, likely smallpox or bubonic plague
  • rare in south america, africa, asia
  • up to around 14% in scandinavian countries
  • HIV probably kills you too efficiently to create a selection advantage in the host for a particular mutation
35
Q

What kinds of cells does HIV infect?

A

CD4+ T lymphocytes

  • activated T-cells
  • massive and early depletion in the GIT

monocytes and macrophages

  • express CD4, CCR5 and low level CXCR4
  • tissue macrophages in brain (glial cells), lung, gut, bone marrow monocyte precursors, lymphoid tissue macrophages
  • macrophages are chronically infected and serve as a reservoir

Dendritic cells
- allow HIV entry, but productive infection is rare

Other cells

  • thymocytes
  • CD34+ progenitor cells
36
Q

What are some ways in HIV has evolved to overcome some antiviral factors that we have?

A
  • APOBEC3G host protein has a function in editing RNA, inhibited by vif (HIV protein)
  • TRIM 5-alpha blocks uncoating of retroviruses, inactive against HIV because of capsid HIV protein
  • Tetherin normally blocks release of virus, vpu inhibits
  • LEDGF tethers HIV to host chromatin, integrase takes advantage of this to facilitate integration
  • intracellular evolution
  • HIV has evolved to overcome some of out natural defences to other retroviruses
37
Q

What are the very first steps of HIV following infection?

A
  • within hours: penetrates mucosal surface (e.g. vagina or rectum)
  • enters via a break in the epithelium (why it is transmitted more easily in people with previous STI)
  • first cell it comes in contact with is the dendritic cell
  • DCs pass on to activated T cells
  • within days you start to get release and infection of both activated CD4+ T cells (productive infection) and latent CD4+ T cells (latent infection)
  • virus carried to local lymphnode
  • replicates like mad
  • within 1 - 2 weeks start to see virus within plasma
  • weeks/months/years you see immune response
38
Q

What is cell-mediated immunity to HIV?

A
  • we make a really good immune response to HIV, we just can never clear it
  • T and B cell response
  • CD4 presented antigen on MHC II
  • CD8/MHC I
  • w/i weeks start to measure virus in blood
  • w/o any treatment at all viral load declines because you are making an effective HIV-specific CD8+ t cell response
  • brings it down to set point
  • some people are able to really control the virus well and can bring it down by themselves without drugs to extremely low levels while others have very limited capability to control the virus
  • w/i about a month you start making antibodies
  • less effective
    doesn’t seem to do much
    basically makes Abs that are non-neutralising or if they are neutralising, the virus rapidly escapes
39
Q

What is evasion of the immune response by HIV?

A

Sequence variation

  • lack of recognition (both CTL and antibody)
  • antagonism
altered antigen presentation 
- down regulation of MHC class I molecules by Tat, Vpu and Nef

loss of effector cells

  • clonal exhaustion
  • loss of CD4 T cell help
  • replicative senescence

latency
- particularly in resting T-cells, macrophages and astrocytes

privileged sites of viral replication
- brain, testis, gastrointestinal tract

BIOM30002 (36 decks)

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