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M2M: Mod 1, 3 > 13-15. HIV > Flashcards

13-15. HIV Flashcards

1
Q

Approximately how many adults & children are estimated to be living with HIV (2012)?

A

Around 35.3 million (between 32.3 - 38.8 million)

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2
Q

What is attributed to the decrease in new HIV infections & AIDS related deaths globally?

A

Access to antiretroviral therapy, which reduces the infectiousness of HIV-infected individuals by reducing the amount of virus in body

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3
Q

What is the general trend of new HIV diagnoses in Australia?

A

1983 - HIV virus was discovered

1985 - virus testing became available, hence a peak in new diagnoses is observed before numbers decrease over time

Unlike the rest of the world, Australian cases are on a slow but generally steady incline (still comparatively very very low numbers of HIV infected compared w. South Africa)

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4
Q

What is the difference between newly diagnosed and newly acquired HIV infection?

A

Newly diagnosed: acquired more than 6 months ago and did not know about it until tested much later post-infection

Newly acquired: acquired within the last 6 months

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5
Q

What are the greatest risk factors for newly diagnosed vs newly acquired HIV infections? (AUS)

A

In Australia, men who have sex with men make up respectively 64% and 85% of those with HIV infection. *median age ~ 30yo.

Heterosexual contact is the next most common at 25% and 9%.

Low numbers due to injecting drug use due to introduction of access to clean needles.

Men who have sex with men and have injecting drug use 3% & 3%

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6
Q

What are the risk factors for HIV globally?

A

Heterosexual 80-85%

Homosexual 5-10%

Intravenous drug use 5-10%

Blood transfusions 3-5%

Unknown 0-17%

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7
Q

What are the factors associated with a generalised epidemic?

A

Behavioral and social factors

  • little or no condom use
  • multiple partners
  • overlapping sexual partners
  • large sexual networks
  • age mixing: old men & young girls
  • women dependent on marriage/prostitution

Biological factors

  • high STI rates
  • low rate of male circumcision
  • HIV subtype (possibly)
  • genetics of host
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8
Q

What family does HIV belong to and what are some examples of non-primate and primate retroviruses?

A

HIV is a retrovirus of the Lentiviridae family.

Non-primate retroviruses

  • CAEV/Visna: Caprine arthritis encephalitis/Visna virus
  • EIAV: Equine Infectious anaemia virus)
  • BIV: Bovine Immunodeficiency virus
  • FIV: Feline Immunodeficiency virus

Primate retroviruses:

  • African Green Monkey (SIVagm)
  • Sooty Mangabey (SIVsm) ——– HIV-2
  • Macaque (SIVmac)
  • Mandrills (SIVmnd)
  • Sykes monkeys (SIVsyk)
  • Chimpanzee (SMcpz) ——– HIV-1
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9
Q

What are the properties of Lentiviruses?

A

Family: retrovirus

Major human virus: HIV-1, HIV-2

Size: 80-130mm

Capsid symmetry: icosahedral

Envelope: yes

Genome: diploid linear 10kb, + sense ssRNA

Genome replicated: nucleus

Virus assembly: cytoplasm - plasma membrane

Common features: slow disease

Diseases: AIDS; neurologic; arthritis; pneumonia

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10
Q

What does the HIV genome contain?

A

gag (structural proteins), pol (viral enzymes) and env proteins (envelope glycoproteins) for all HIVs, however they differ by their regulatory proteins which control viral life cycle

*a high degree of variability exists for gag and env proteins

Regulatory proteins: tat, rev, vpr, vpu, vif, nef

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11
Q

What is the structure of the retrovirus?

A

env:

  • gp120 - SU (surface); cell attachment
  • gp41 - TM (transmembrane); fusion domain

gag:

  • p17 - MA (matrix)
  • p24 - CA (capsid)
  • p7 - NC (nucleocapsid)

pol:

  • p66/51 - RT (reverse transcriptase)
  • p32 - IN (integrase)
  • p11 - PR (protease)
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12
Q

Why is knowledge about HIV clades important?

A

Important for:

  • epidemiology
  • understanding origins
  • developing vaccines which need to be clade-specific
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13
Q

What is the HIV life cycle?

A
  1. CD4 binding
  2. Co-receptor binding: chemokine co-receptors CCR5, CXCR4
  3. Fusion where ssRNA is injected into the cell, reverse transcription of the viral RNA genome occurs to give proviral DNA. In the nucleus, proviral DNA is integrated into host cell genome and transcribed to produce viral RNAs which are translated, and assembled at the membrane.
  4. Budding
  5. Maturation
  6. New HIV virion *once it’s in host genome, it will survive for as long as the cell lives
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14
Q

What are the key features of HIV replication?

A
  • Rapid: 24 hr replication cycle, but occurs at very high frequencies
  • Error prone reverse transcriptase 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
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15
Q

What is an R5 virus and what does it target?

A

CCR5-tropic virus

Enters CD4+ T cells via CCR5

95% of people are infected with R5 virus

  • nearly all infections are caused by R5 viruses
  • more easily transmitted
  • R5 viruses cause less T-cell destruction
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16
Q

What is an X4 virus and what does it target?

A

CXCR4-tropic virus

Enters CD4+ T cells via CXCR4

  • rarely transmitted (don’t efficiently cross mucosal membranes)
  • emerge late in course of infection
  • 50% of patients with AIDS carry X4 virus
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17
Q

What is a dual tropic HIV virus and what are mixed tropic viral populations?

A

Dual tropic = HIV that can use either CCR5 or CXCR4

*about 50% of AIDs patients carry both by the time they develop AIDS

Mixed tropic (D/M) = virus populations containing a mixture of R5-tropic, X4-tropic and/or dual-tropic HIV

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18
Q

Describe the natural resistance to HIV in terms of CCR5 mutations

A

Approx. 1% of population carry a mutation in CCR5, and 5% are heterozygotes.

  • wt/wt = normal CCR5 expression, progression of HIV and normal immune function
  • wt/delta 32 = decreased CCR5 expression, delayed progression to AIDS/death, normal immune function
  • delta 32/delta 32 = no CCR5 expression, rare infection with X4, normal immune function

The delta 32 mutation leads to a deletion of 32bp and no expression of CCR5.

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19
Q

What is the global prevalence of the CCR5delta32 mutation?

A

5-14% Caucasians of European descent carry it

10% Australians

10-15% North America

The origin has been traced to European geography approx 1000 years ago.

Possible selection by pandemic pathogen, ie. smallbox, bubonic plague

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20
Q

Which cells do HIV infect?

A

Cells that express CD4+ lymphocytes:

  • activated T cells
  • massive & early depletion in the GIT

Monocytes & macrophages:

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

Dendritic cells:

  • allow HIV entry, but productive infection is rare

Other cells:

  • thymocytes
  • CD34+ progenitor cells
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21
Q

What is APOBEC3G how does HIV counter it?

A

APOBEC3G is an innate anti-viral cellular factor that edits RNA when it sees foreign RNA so it doesn’t persist in cell.

Counteracted by the HIV protein vif, which inhibits APOBEC3G.

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22
Q

What is TRIM 5α how does HIV counter it?

A

TRIM 5α is an innate anti-viral cellular factor that blocks uncoating of retroviruses.

Human trim 5α is inactive against HIV due to the HIV capsid protein.

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23
Q

What is Tetherin how does HIV counter it?

A

Tetherin is an innate anti-viral cellular factor that blocks release of virus and is inhibited by vpu (HIV protein).

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24
Q

What is LEDGF how does HIV counter it?

A

LEDGF is an innate anti-viral cellular factor that tethers HIV to host chromatin and HIV takes advantage of this with integrase, which facilitates its integration once it is tethered to host chromatin.

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25
Q

Why is HIV more easily transmitted in sexual interaction?

A

Virus enters through breaks in mucosal epithelia

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26
Q

What happens in the first few hours post-infection?

A

Virus crosses barrier through microbreaks in epithelia where it meets DCs.

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27
Q

What happens in the first 3-4 days post-infection?

A

Local expansion occurs, DCs present virus to T cells, resulting in productive infection of activated T cells and also production of latent infections in resting CD4+ T cells.

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28
Q

What happens days-weeks after infection?

A

Dessemination to lymphatic tissue. LN is perfect environment for HIV viral replication as it has plenty of DCs and activated T cells.

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29
Q

What happens 1-2 weeks after infection?

A

Local proliferation Peak plasma virus levels CD4+ memory cell loss

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30
Q

What happens weeks-months-years after infection?

A

Partial immune control with neutralising Abs

Or can develop into AIDS

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31
Q

Cell mediated immunity to HIV

A

Foreign antigens are presented via APCs to CD4+ T cells.

The beta chain of APC’s MHC Class II binds to the alpha chain of the CD4+ T cell and vice versa.

A similar process occurs for CD8+ T cells and MHC Class I.

32
Q

Immune response to HIV

A

We actually make really good immune response to HIV, however cannot completely clear it.

At the beginning you make HIV-specific CD8+ T cells, but then they decrease in number (and plateau slightly lower than peak number), and instead HIV-neutralising Abs are made which are less effective as HIV escapes very readily. The CD8+ response brings HIV numbers to a low level (set point).

*Implication on results: Abs are made around 1-3 mths post-infection, hence must wait to get reliable results.

33
Q

How does HIV evade host immune responses? (briefly)

A
  1. Sequence variation
  2. Altered Ag presentation
  3. Loss of effector cells
  4. Latency
  5. Privileged sites of viral replication: brain, testis, GIT
34
Q

How does sequence variation aid in HIV’s evasion of the host imm. response?

A
  1. Sequence variation:
  • lack of recognition (both CTL & Ab): mistakes from reverse transcriptase
  • antagonism: HIV-specific Ab can no longer access virus
35
Q

How does altered Ag presentation aid in HIV’s evasion of the host imm. response?

A
  1. Altered Ag presentation
    * down reg. of MHC class I molecules by Tat, Vpu & Nef, impairing the ability of APC to induce imm resp.
36
Q

How does loss of effector cells aid in HIV’s evasion of the host imm. response?

A
  1. Loss of effector cells
  • clonal exhaustion
  • loss of CD4 T cell help
37
Q

How does latency aid in HIV’s evasion of the host imm. response?

A
  1. Latency: particularly in resting T cells, MPs & astrocytes

*if there are no proteins made on the cell surface, there’s minimal imm response

38
Q

How does privileged sites of viral replication aid in HIV’s evasion of the host imm. response?

A
  1. Privileged sites of viral replication: brain, testis, GIT *various barriers, ie. presence of blood brain barrier, can block the transport of HIV specific T cells to those sites
39
Q

Describe the acute phase of CD4 T cell depletion?

A

Primary infection with acute phase of CD4 depletion.

Massive depletion of CD4 T cells from GIT in acute infection.

Viral numbers increase, acute HIV syndrome occurs with wide dissemination of virus and seeding of lymphoid organs.

40
Q

Describe the chronic phase of CD4 T cell depletion?

A

Clinical latency: chronic phase of CD4 depletion will lead to constitutional symptoms, opportunistic diseases and death

41
Q

What is the most important coinfection and why?

A

Tuberculosis because it occurs with greater frequency and severity in people with HIV, even with intermediate suppression.

42
Q

What are the causes of CD4+ T cell decline?

A

INCREASED DESTRUCTION

  • direct infection: *GIT >>>> blood
    • incomplete reverse transcription in naive T cells (don’t need productive infection to eliminate T cells, presence of foreign viral DNA can induce death)
  • indirect effects:
    • syncitium formation
    • apoptosis
    • immune activation
    • LN fibrosis

IMPAIRED PRODUCTION (through direct infection)

  • thymus
  • CD34+ progenitor cells
43
Q

Why is CD4 T cell depletion variable?

A

Viral factors

  • CXCR4 virus accelerated T cell loss (it is expressed on resting T cells too)
  • Nef deleted virus limits T cell loss (Nef downreg. MHC class II, limiting amount of Ag presentation)
  • Co-infection with other viruses, eg. CMV, GBV-C

Host factors

  • Immune response: HLA type
  • Genetic factors: CCR5 delta 32
  • Age: impaired thymic function in very young/old
44
Q

Why is HLA type important for immune response?

A

Certain HLA molecules present HIV epitopes more effectively which enhances the adaptive immune response

*can determine viral set point

Good Px: B13, B27, B51, B57

Rapid disease progression: A23, B37, B49

45
Q

What is the immunopathological effect of HIV on CTL?

A

abnormally high #s during acute phase decline at later stages

46
Q

What is the immunopathological effect of HIV on NK cells?

A

impaired numbers & function

47
Q

What is the immunopathological effect of HIV on monocytes & macrophages?

A

defects in chemotaxis and Fc receptor function inability to promote T cell proliferation

48
Q

What is the immunopathological effect of HIV on B cells?

A

increase in production of IgG and IgA decrease in Ab responses

49
Q

What markers of immune activation are elevated in HIV infection?

A
50
Q

What causes immune activation?

A
  • *Mucosal depletion of CD4 T cells**:
  • increased microbial translocation due to loss of GIT mucosal integrity
  • (chronic) activation of TLR4 by bacterial products
  • *Activation of innate imm response (pDCs)**
  • HIV RNA is a TLR7/8 ligand
  • increased plasma IFN-α
  • *Cytomegalovirus-specific repsonse**
  • expansion of CMV-specific activated CD4+ & CD8+ T cells
  • *Loss of T regulatory cells**
  • T reg. usually dampens immune response
51
Q

What are IL-6 & IL-10?

A
  • Proinflammatory cytokines released by monocyte/macrophages when triggered by HIV infection.
  • They are characterised low level inflammation cytokines.
52
Q

HIV & pathogenic & non pathogenic SIV

A
53
Q

What different antiretroviral drugs are available to treat HIV?

A

​HAART combines different classes of antiretroviral drugs

  1. Cellular chemokine receptor antagonists (against CCR5/CXCR4)
  2. Fusion inhibitors
  3. Reverse transcriptase inhibitors (NRTIs & NNRTIs)
  4. Integrase inhibitors
  5. Protease inhibitors (targets maturation)
54
Q

Use of cART

A
  • cART leads to rapid decline in HIV RNA, recovery of CD4 (variable recovery)
  • there is now improved access to cART in low and middle income countries
  • persistant immune abnormalities in patients on cART similar to aging
  • CD4+ T cell recovery after 7 years of cART is assoc. with baseline CD4+ T cell count

There is a dramatic improvement of life expectancy on HAART and if you start treatment before CD4 levels drop below 200 & you contract no other significant disease, then you will can now expect a normal life expectancy.

55
Q

Why is there persistence of non AIDS deaths?

A

People with HIV now live longer, hence are seeing a greater prevalence in other non-AIDS conditions such as:

  • non AIDS malignancy
  • acute myocardial infarction

These conditions are seen in non-HIV individuals too, but at a greater than normal rate in HIV patients.

56
Q

What significant morbidities may persist on HAART?

A
  • cardiovascular disease
  • metabolic disorders
  • neurocognitive abnormality
  • liver disease
  • renal disease
  • bone disorders
  • malignancy
  • frailty

Together they give the phenotype of accelerated aging.

57
Q

What are the biological determinants of CD4 T cell recovery?

A

Viral factors

  • CXCR4 using viruses result in poorer reconsitution
  • co-infection with other viruses, eg. Hep C virus

Host factors

  • Genetic factors: CCR5 mutations, IL-7R mutations
  • Residual immune activation (high levels = less recovery)
  • Thymus function: age
58
Q

Behavioural strategies for HIV prevention

A
  • education
  • testing
  • condoms
59
Q

Biomedical strategies for HIV prevention

A
  • vaccines
  • circumcision
  • microbicides
  • antiretroviral therapy: PREP, treatment as prevention
  • treat sexually transmitted infection

*treatment reduces infectiousness of HIV patients by 96%

60
Q

What vaccine approaches do we have?

A
  • Recombinant proteins
    • good Ab but poor T cell responses
    • no protection
  • DNA vaccines
    • ​good T cell responses but poor Ab responses
  • Live vector vaccines
    • ​non-replicating poxviruses expressing HIV-1 genes –> good T cell responses
    • Ad5 virus
      • STEP trial 2008, non effective, possible increased risk of infection
  • Live attenuated virus
    • potentially unsafe
  • Prime boost
    • DNA + protein/vector
  • Broadly neutralising Abs
  • CMV vectors
    • ​persistent Ag presentation
61
Q

Thai trial

A

Prime/boost partially effective

ALVAC (canarypox) x2 + gp120 x3

reduced risk by 30%, however vaccines usually aim for at least 80% efficacy

62
Q

DNA prime recombinant Ad5 boost

A

showed no protection

Weeks 0, 4, 8: DNA vaccine (gag, env, nef & pol)
+ week 24: rAD5 boost (gag-pol protein & env)

63
Q

Broadly neutralising Abs

A
  • can neutralise a large number of viruses
  • are directed against highly conserved regions of envelope that are “hidden”
  • detected after 1-2 years of infection and of limited help to patient
64
Q

What are the unusual features of CMV vectors?

A
  • unconventional MHC II restricted CD8+ T cells
  • breadth of epitope recognition: recognises far more epitopes!
  • promiscuity

► Induce a response that is quite different to conventional vaccines

MHC-II-restricted CD8 T cells can recognise more infected cells than the conventional/regular CD8 T cell

*CMV vector vaccines promising in macaques.

65
Q

How does circumcision reduce changes of acquisition of HIV?

A

Reduces acquisition by 70%

Langerhan cells in foreskin

In the inner foreskin - lots of DCs
*Dendritic cells best cells to be infected with HIV & deliver to LNs. Removing these cells removes this risk factor.

66
Q

Tenofovir

A

Tenofovir containing microbicide reduces female acquisition by 40%.

BAT 24 coitally-related gel use

  • insert 1 gel up to 12 hrs before sex
  • insert 1 gel as soon as possible within 12 hrs after sex
  • no more than two doses in 24 hours
  • HIVNET 012 nevirapine regimen for mothers giving birth
67
Q

PREP

A

=pre exposure prophylaxis

  • give daily antivirals (tenofovir or truvada) either orally or vaginally
  • highly effective in preventing transmission in monkey models
  • oral truvada as PREP reduced risk of transmission amonst gay men by 40% (up to 70% if compliance is high)
68
Q

Treatment as prevention

A

HPTN 052

Trial with discordant couples, randomised with either immediate or delayed HAART showed that ART reduces HIV trnamission by 96% in HIV serodiscordant heterosexual couples.

69
Q

HIV eradication: cure vs remission model

A

CURE

REMISSION

infectious diseases model

cancer model

elimination of all HIV-infected cells

long term health in absence of cART

HIV RNA <1 copy/ml

HIV RNA <50 copies/ml

Sterilising cure

Functional cure

70
Q

Barriers to a HIV cure

A
  • latently infected T cells
    • latent reservoir: naive T cells, transitional and central memory cells
  • residual viral replication
    • evidence for residual replication in about 1/3 of patients on cART
  • anatomical reservoirs
    • brain
    • GIT
    • penis
    • LNs
71
Q

Strategies for cure

A
  • eliminate latently infected cells
  • make cells “resistant” to HIV
  • eliminate residual virus replication
  • enhance HIV-specific immunity
72
Q

What are some agents that activate latent viruses?

A
  • HDACi: histone deacetylase inhibitors turn HIV genes “on”
  • Cytokines, eg. IL7
  • disulfiram
  • quinolines
  • methylation inh
  • histone methyl transf inh
  • BET inh
73
Q

What is vorinostat?

A

Activates latent HIV in vivo (promotes transcription)

74
Q

How do you make cells resistant to HIV via gene therapy?

A
  • Block the action of a HIV protein
    • RNA interference
  • expresss an anti-viral factor
    • mutant APOBEC3G
  • eliminate integrated HIV
    • LTR
  • remove an essential host protein
    • CCR5 - zinc finger nucleases can recognise gene of interest & cause db strand break, resulting in gene disruption
75
Q

What is the hallmark of HIV infection?

A

Loss of CD4+ T cells, however HIV also causes multiple other immunological abnormalities including immune activation.

76
Q

Patient interview: PAUL

A

1985 - 21 yo. infection with HIV

1991 - diagnosis, ‘death sentence’, expected prognosis at the time was 4-5 years, maybe 10 years with better treatment

1991-1993 - peak impact of HIV on gay community in Sydney

  • Has taken a variety of drugs, started with AZT monotherapy for 3-4 years, side effects: constant nausea, weight loss, muscle loss, anemia
  • No side effects with current drugs - 3 tablets/day + antihypertensive
  • Has had Hepatitis C (now cured), was involved in clinical trials for Hep C
  • Had many other sexual infections including syphilis, gonorrhea etc.

M2M: Mod 1, 3 (13 decks)

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