HIV / AIDS

How many deaths have been attributed to HIV / AIDS since the beginning of the epidemic?

39 million

Why was HIV / AIDS initially a silent epidemic (2)?

• young, healthy, gay men dying of infections that should be non-fatal

• stigma surrounding gay men

What are the features of the HIV virus (3)?

• complex retrovirus

• RNA genome

• enveloped

What were the origins of HIV (2)?

• zoonoses - 4 distinct transmission events to humans

• likely from other primate species (chimps, gorillas)

Which HIV group became pandemic?

HIV-1 group M (subtypes A to K)

When did HIV-1 group M appear in the West and take off?

1978

What is the HIV-1 replication cycle (4)?

1. RNA virus with 2 ssRNA copies in glycoprotein envelope

2. RNA → DNA

3. arrives in nucleus and DNA deposited into host chromatin

4. incorporated and proteins produced by host cell

What cells are targeted by HIV (2)?

• T cells

• macrophages

What happens if a retrovirus deposits into gametes (2)?

• can become fixed into genome and be passed on

• 8% human genome = historic retroviruses

Why did we have a headstart when HIV emerged in the West (3)?

• had studied retroviruses in mice before HIV emergence

• allowed HIV to be understood faster

• importance of animal disease research

What is reverse transcription?

process of RNA → DNA

How does reverse transcription work (in HIV) (5)?

1. requires reverse transcriptase (RT), tRNA primer, RNA strand

2. RT begins replicating RNA strand as DNA

3. end up with ds RNA / DNA hybrid (one strand of each)

4. second DNA strand made as original RNA degraded

5. end up with dsDNA

What enzyme is used by HIV to convert genomic ssRNA into dsDNA?

HIV-1 revers transcriptase

What enzyme is used by HIV to integrate the newly formed reverse transcribed dsDNA into the host chromatin?

HIV-1 integrase

How is reverse transcribed dsDNA integrated into host chromatin (3)?

• free dsDNA signals damage so must be integrated

• integrase inserts into host chromatin

• normally inserted into open, transcribed DNA (but not fussy)

Why must reverse transcribed dsDNA be rapidly integrated into host chromatin?

free dsDNA signals damage = cell apoptosis

What are the 3 key targets of HIV therapeutics and why (4)?

• HIV-1 reverse transcriptase

• HIV-1 integrase

• HIV-1 protease

• all unique to HIV (not shared with human host)

What does HIV use the HIV-1 protease enzyme for?

cleaves viral polypeptides into functional units - maturation

How does HIV replicate itself (3)?

• replicates as one big polypeptide (multiple proteins together)

• carries protease to separate proteins

• only requires one promoter (advantage for small size)

What is required for HIV to infect target cells (3)?

• CD4 and a chemokine receptor

• CD4 + CXCR4 on lymphocytes

• CD4 + CCR5 on macrophages

What evidence suggests the importance of CCR5 for HIV cell entry (3)?

• mutations in CCR5 gene ∆32 = largely HIV resistant

• heterogenous mutation on only one allele = suffer less disease

• drugs inhibiting CCR5 entry = reduced viral load

How is HIV-1 transmitted (2)?

• fluid contact - sexual transmission / blood-to-blood contact

• perinatally mother to foetus (during birth and lactation)

What is the time course of a typical HIV infection (5)?

1. primary infection

2. acute HIV with wide distribution, appearance of anti-HIV CTL’s

3. clinical latency period - CD4 T cells still dying but no symptoms

4. CD4 T cell major drop

5. symptom onset and susceptible to opportunistic infections

What are the 3 different clinical features of HIV infection?

• acute primary infection syndrome

• asymptomatic infection

• symptomatic HIV and AIDS

What are the features of HIV acute primary infection syndrome (2)?

• flu like illness

• high levels of viral replication until infection brought under immune control

What are the features of HIV asymptomatic infection (4)?

• no outward sign of disease

• slow decline in CD4 T cells

• very active viral replication

• can persist for 10+ years

What are the features of symptomatic HIV infection and AIDS (2)?

• immune system ceases to function

• disease progresses → death

What are the viral dynamics of HIV infection in the primary infection (3)?

• 10hr doubling time - each infected cell seeds ~20 more

• peak viremia at 21 days

• viral load rapidly drops as immune system kicks in

What are the viral dynamics of HIV infection in the asymptomatic phase (3)?

• 10¹⁰ viral particles made and eliminated daily

• 10⁹ CD4 T cells made and eliminated daily

• ‘steady state’

What are the viral dynamics of HIV infection in the virus reservoir?

10⁶-10⁷ T cells sustain HIV-1 infection (productively infected)

What is predictive of functional immune loss in a HIV infection?

CD4 T cell loss

Where is HIV found during infection (6)?

• cellular reserves:

  • principally CD4 T cells and macrophages in lymph nodes

• anatomical reserves:

  • CNS

  • GI tract

  • genital tract

What is a viral reservoir?

cell type / site within body where HIV accumulates and persists with greater stability than main pool of actively replicating virus

When is a viral reservoir termed ‘latent’?

if cells harbouring the virus are not actively producing virus but retain capacity to do so

How can viral reservoirs be resilient to clearance (2)?

• poor penetration of ARVs

• could be in an immuno privileged site

What happens if HIV uses the gut as a reservoir (3)?

• HIV depleted gut CD4 T cells in acute phase - never bounce back

• loss of GALT = local immune dysfunction

• virus has preference to replicate in gut no matter how transmitted

What are the terms given to the 2 groups of people who do better than others in HIV infection?

• elite controllers - low viral load, healthy CD4 levels

• long-term non progressors - significant viral load but no CD4 depletion

What are the possible explanations for the existence of elite controllers and long-term non progressors in HIV infection (5)?

host factors:

• CCR5∆32 mutation

• able to mount strong immune response (HLA alleles)

viral factors:

• infection with attenuated viral strains

What % of Caucasians have CCR5∆32 mutations?

0.5-2%

What does HAART stand for?

Highly Active Antiretroviral Therapy

What does HAART do (3)?

• controls HIV

• restores immune function

• individual is 100% non-transmissable

Why does HAART therapy not cure HIV (3)?

• circulating virus reseeded from latent reservoir

• infected memory CD4 T cells can be periodically activated

• therapy only targets actively replicating virus

Who were the only 2 people to be cured of HIV?

• first = Timothy Ray Brown (aka Berlin patient)

• second = the London patient

How was the Berlin patient cured of HIV (Timothy Ray Brown) (4)?

• had acute myeloid leukaemia

• heterologous transplant of HSC from CCR5 ∆32/∆32 patient

• 33% chance of death - only justified due to leukaemia

• viral clearance

How was the London patient cured of HIV ()?

• treatment resistant Hodgkin’s lymphoma

• heterologous transplant of HSC from CCR5 ∆32/∆32 patient

• less aggressive treatment than Berlin patient

What are the issues with humoral immunity in HIV vaccines (seen in chimps) (4)?

• passive immunisation of chimps with neutralising antibodies = protection (chronic established infection?)

• low levels of SIV viral load = high levels of neutralising antibodies in chronic infection

• rapid escape from neutralising antibodies

• HIV highly diverse and rapidly mutates

What may be a future avenue for HIV vaccination (2)?

• broadly neutralising antibodies (bNAbs) do exist

• no idea how arise and how to stimulate B cells to produce

What is vectored immunoprophylaxis (VIP) (3)?

• deposit correct gene for bNAbs into infected individuals

• bypasses immune system → can directly code for bNAbs

• works in mice