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BSMS204 Theme I Immunology > HIV symposium > Flashcards

HIV symposium Flashcards

1
Q

Where did HIV come from?

A

Origins traced back to chimpanzees (HIV-1) & sooty mangabeys (HIV-2)
‘Bushmeat practices’ - cross species transmission during killing or butchering
Transfer to humans beginning of 20th century in central & W. Africa
Social changes / migratory routes / urbanisation

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2
Q

How did HIV cross from Africa to the west?

A

Stored specimens test positive early as 1959
Introduced to Haiti by individuals working in the DR Congo ~ 1966 – outbreak followed
Transferred to US ~ 1969-72
Increase in international travel / transfusion / blood products / IVDU
Rapid spread within gay community
1st clinical cases 1981

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3
Q

Early 1980s

A

HIV discovered

  • Institut Pasteur 1983
  • Robert Gallo 1984

Increasing reports of Pneumocystis & KS

  • developed world, gay men
  • IVDUs, haemophiliacs
  • developing world

Antibody test in 1985

Management

  • treatment of infections
  • palliative care
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4
Q

Late 1980s

A

AZT - zidovudine (monotherapy)
- first manufactured in 1964

Patient activism

Management:

  • prevention opportunistic infections
  • nebulised pentamidine 1989
  • palliative care

Widespread prevention campaigns

  • reduction in STIs
  • needle exchange
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5
Q

1991-1992

A

More HIV tests than any other time

  • Mark Fowler diagnosed with HIV on East Enders
  • Freddy Mercury died
  • Arthur Ashe, Kenny Everett, Holly Johnson all HIV +

Resistance to AZT documented in people who had never taken AZT

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6
Q

1993-1994

A

Concorde - AZT monotherapy ineffective
Dual therapy (addition of ddC) ineffective
Therapeutic nihilism
Treatment limited to treatment and prophylaxis of OIs
Reduction in HIV testing

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7
Q

1994

A

ACTG 076

  • antenatal & intrapartum AZT
  • post partum AZT to neonate
  • decreased transmission 25% -> 8%

Current practice

  • combination therapy (3 drugs)
  • normal vaginal delivery if VL <40
  • transmission rates <1%
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8
Q

1994-1996

A

More ARVs approved +++

1994/5: dual therapy works (Delta)

1996: everything changes ……

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9
Q

1996/7

A 
Protease inhibitors
Triple therapy
Nevirapine, ritonavir, indinavir 
Vancouver AIDS conference (July)
"Lazarus Syndrome” - ward closures
Viral load testing
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10
Q

HAART (highly active anti-retroviral therapy)

A

HAART = ART = combination therapy = ‘triple’ therapy = usually at least 3 anti-retroviral drugs (ARVs)
Aim to reduce viral load to ‘undetectable’ levels - allowing immune system to partially recover
Need to take all the drugs, on time
Need to think about food restrictions, drug interactions

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11
Q

1997-2000: ART side effects

A 
lipodystrophy
hyperlipidaemia and CVD
Glucose intolerance / diabetes
Loss bone mineral density 
Gastrointestinal – N&amp;V, diarrhoea
Peripheral neuropathy, CNS side effects
Hepatotoxicity
Renal – nephrolithiasis, proteinuria
Skin rash / hypersensitivity
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12
Q

2000-2016

A

Improvement in tolerability of ART

Improvement of toxicity of ART

Improvement of formulation of ART
Reduced daily dosing
Co-formulation

Shift towards earlier treatment

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13
Q

HIV lifecycle

A

1) binding, 2) fusion, 3) reverse transcription, 4) integration, 5) replication, 6) assembly, and 7) budding.

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14
Q

Viral dynamics and resistance

A 
10 billion viruses produced/person/day
10,000 bases in viral genome
Mutations every 10,000 bases
Every mutation likely to occur each day 
Just one mutation can cause resistance
Pools of resistant virus exists before exposure to drug therapy
Combination antivirals essential
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15
Q

Viral load

A
  • Lower the better
    • Higher viral load associated with more rapid disease progression
    • Very high levels in early infection (>10,000,000 copies/ml)
    • Viral load marker of treatment success: aim for “undetectable” (<40)
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16
Q

CD4 Count

A

Measure of immune function
Higher the better
Decreasing count associated with increasing risk of disease progression
Normal values >500
Significant risk of morbidity/ mortality if CD4 count < 200

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17
Q

Aims of treatment of HIV

A

To start as soon as possible
To reduce HIV transmission
To prevent further damage to the immune system ( ‘CD4 count’)
Reduce risk of opportunistic infections, tumours, direct effects e.g. HIV neurocognitive impairment
Prolong healthy life

18
Q

Untreated HIV infection

A

Seroconversion

Then later on TB, Kaposi’s Sarcoma, shingles, oral thrush, seborrhoeic dermatitis

Then later on Pneumocystis pneumonia, toxoplasmosis, lymphoma

Then MAC, CMV, PML, CNS lymphoma

19
Q

HIV treatment effect

A

Reduced morbidity and mortality
HIV patients now living very long
As long as have no comorbidities

20
Q

Global statistics

A

In 2017:

36.9 million globally were living with HIV
New HIV infections have fallen by 35% since 2000
1.8 million became newly infected with HIV
AIDS-related deaths have fallen by 48% since the peak in 2005
940,000 died from AIDS-related illnesses

21
Q

Global ARV rollout

A

Made possible by generic drug production
£60 per year vs £10,000
‘3 by 5’ target - 3 million on ARVs by 2005
‘15 by 15’ target - 15 million people taking ARVs by 2015 was reached in June 15
21.7 million accessing ARVs (2017)
Clinical response similar in all settings
Next target 90:90:90 by 2020

22
Q

What is the 2020 90-90-90 target?

A

By 2020, 90% of all people living with HIV will know their HIV status. By 2020, 90% of all people with diagnosed HIV infection will receive sustainedantiretroviral therapy. By 2020, 90% of all people receiving antiretroviral therapy will have viral suppression.

23
Q

by 2020 and by 2030…

A

Fewer than 500 000 people newly infected with HIV (currently 1.8m)

Fewer than 500 000 people dying from AIDS-related causes (currently ~1m)

Elimination of HIV-related discrimination

75:79:81 globally

48% of all PLWH have supressed virus

Reduce the number of new HIV infections by 89% by 2030 and the number of AIDS-related deaths by 81%

24
Q

Combination prevention

A

Treatment as prevention - TasP
Pre-exposure prophylaxis- PrEP
Expansion of HIV testing
Condoms wherever possible

25
Q

What is U=U

A

Undetectable=Untransmittable

ART is now so effective that those who are treated and have an undetectable viral load (<200 copies) have levels of virus that are untransmissible, even if having sex without condoms. This is sometimes referred to as U=U.

The Swiss Statement 2008

Partner study - zero transmissions after >58,000 episodes sex without condoms when viral load was undetectable <200

26
Q

Test and treat programmes

A

Aim for 90% of new diagnoses to be taking ARVs by 90 daysAim for 98-100% PLWH to be taking effective treatmentAim for 100% PLWH have undetectable viral loads

27
Q

What is PrEP?

A

Pre-exposure prophylaxis (or PrEP) is when people at very high risk of HIV take daily HIV medicines to reduce the chances of getting infected

It works – trials showed 86% effective, but actually 100% for those who took it

Historical lack of availability on NHS…

Truvada (tenofovir/emtricitabine)

28
Q

PrEP impact trial

A 
10,000 patients (then 13,000, now 26,000)
3 years
Generic Truvada – daily or event based
GUM clinics across UK
Open for recruitment
29
Q

Other Prevention strategies

A

HIV testing
Sexually transmitted infection treatment - 40% reduction (1)
Circumcision - South Africa, Kenya, Uganda - 58% reduction

30
Q

What kind of surfaces are the best for HIV entry

A

Most of the pathogens that cause the deaths of large numbers of people are those of mucosal surfaces or enter the body through these routes. The genitourinary, rectal and oral mucosa are the mucosal HIV transmission routes. An effective vaccine that can induce both systemic and local mucosal immunity is generally accepted as a major means of protection against mucosal HIV transmission and AIDS.

31
Q

Which cells are the main host cells for HIV?

A

CD4 T cells are the main host cells for HIV.
Entry: CD4/gp120
& CXCR4/CCR5

32
Q

What are activated CD4 T cells in the terminal ileum?

A

Activated CD4 T-cells are primary targets for infection. Activated CD4 T cells in the terminal ileum are CCR5+

HIV can use CCR5 (‘R5 viruses’)
CXCR4 (‘X4 viruses’)
Or both (‘R5X4 viruses’)

33
Q

Differential targetting of CD4 T cells by HIV

A

During primary HIV infection (mostly R5), effector CD4 T cells are eliminated rapidly owing to their high expression of CCR5 and their highly activated state, which supports lytic viral replication. Although CD4 T-cells are essentially depleted from the effector lymphoid tissues, most of the CD4 T cells residing in the inductive lymphoid tissues are spared owing to their lack of CCR5 expression.

34
Q

R5 viruses

A

R5 viruses are the strains most commonly transmitted sexually. This is in agreement with the high resistance to infection of individuals lacking CCR5.

After about five years, viruses that are able to use CXCR4, with or without concurrent use of CCR5, evolve in about 50% of patients. These viruses would now be called R5X4 and X4 viruses, respectively.

35
Q

What are the main ways through which CD4 T cells are depleted?

A

Cytopathic effects
Apoptosis
CTL mediated killing

36
Q

Importance of intestinal mucosal infection

A

60% or so of all CD4 T cells are in the gut, a minority is in the blood (think of other compartments: lung, spleen etc.)
The main mucosal sites for HIV entry are oral, rectal, and vaginal mucosa.
Depletion of CD4 T-cells in the gut is rapid (weeks in the monkey model)

37
Q

What can measure intestinal leakage?

A

Bacterial translocation is a good measure of intestinal leakage and hence a measure for the destruction of the gut mucosal immune system after HIV infection.

38
Q

Development of AIDS

A

Early conditions: Rash, fever, myalgia, arthralgia Guillian-Barre syndrome, chronic demyelinating neuropathy, Bell’s palsy, Sjogren’s syndrome

Intermediate: gingivitis, warts, TB, herpes Zoster, oral candidiasis, Kaposi’s sarcoma

Late: Pneumocystitis, toxoplasmosis, cryptococci

39
Q

Early changes

A

Poor CD4 T cell proliferation after stimulation by specific antigen
Normal CD8 T cell activity
Reduced ability of TH1 cells to proliferate
Some histological abnormalities in lymph nodes
Elevated IgG and A (but non-specific), reduced IgM
Small changes in cytokine levels

40
Q

Late changes

A

Dramatic loss of CD4 T cells and function
Reduction of cytotoxic capacity of CD8 T cells
Complete loss of tuberculin-type response
Major histological disruption of lymph nodes & loss of DCs
Eventual loss of anti-HIV antibody
Significant change from TH1 to
TH2 type cytokine production

41
Q

Who needs a HIV test?

A

Anyone who has ever been exposed to even a small risk of HIV infection needs an HIV test. It is better to test more people than not enough, because a positive test always requires action. Widespread testing is the best way to stop the virus from being passed on.

42
Q

Detecting HIV infection

A

HIV antibody and HIV p24 ELISA

So-called ‘fourth-generation’ HIV tests have been successfully used for the past decade.

Compared with third-generation assays, fourth-generation assays have greater sensitivity because of their ability to detect p24 antigen as well as conventional HIV antibodies.

BSMS204 Theme I Immunology (22 decks)

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