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Phase 2a - ICS > HIV infection > Flashcards

HIV infection Flashcards

1
Q

HIV is…

A

An RNA retrovirus which uses reverse transcriptase (RT) to make DNA which is then integrated into the DNA of the host cell.

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2
Q

HIV was first identified by…

A

Robert Gallo (USA), Françoise Barré-Sinoussi and Luc Montagnier (France): initially called HTLV-III/LAV

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3
Q

Where did HIV come from?

A

Monkey - SIV but no disease.

HIV-1 similar to SIV in chimps from Central Africa.

HIV-2 SIV from West African sooty mangabey monkeys.

HIV-1 is classified into several clades.

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4
Q

Where was the first documented human infection?

A

DRC in 1959.

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5
Q

HIV-1

A

SIVcpz SIVgor
(M, N, O, P)

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6
Q

HIV-2

A

SIVsm
(A, B, C, D, E, F, G, H)

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7
Q

What is a possible route of transmission in West and Central Africa?

A

Bushmeat

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8
Q

HIV-2 infection…

A

Natural model or functional cure.

35-40% elite controllers - maintain undetectable load for a decade or more and have a normal lifespan.

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9
Q

HIV genome structure…

A

Small - 10 genes
Lentivirus - long incubation period
Structural - Regulatory - Accessory genes

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10
Q

Mechanism of viral replication

A
  • Glycoproteins on the HIV molecule (gP160 made of gP120 and gP 41) allow it to dock and fuse onto the CD4 and CCR5 receptors.
  • The viral capsid the enters the cell and enzymes and nucleic acid are released.
  • Using reverse transcriptase single stranded RNA is converted into double stranded DNA.
  • Viral DNA then is integrated into the cells own DNA by integrase enzyme.
  • When the infected cell divides the viral DNA is read and long chains of viral proteins are made.
  • Assembly the viral protein chains are cleaved and reassembled.
  • Budding here immature virus pushes out of the cell taking with it some cell membrane.
  • Immature virus breaks free to undergo more maturation.
  • Maturation protein chains in the new viral particle are cut by the protease enzyme into individual proteins that combine to form a working virus.
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11
Q

Pol gene

A

encodes the enzymes: reverse transcriptase, integrase and protease

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12
Q

Env gene

A

encodes the envelope proteins

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13
Q

Nef gene

A

increases the infectivity

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14
Q

Tat gene

A

contributes to viral replication. Enhances production of host transcription factors (NF-kB).

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15
Q

Gag gene

A

encodes structural proteins.
Made as a polyprotein and cleaved by HIV protease

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16
Q

Rev gene

A

binds to viral RNA and allows export from nucleus and also regulates RNA splicing

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17
Q

Explain the HIV Replication Cycle

A

gp120 bind to CD4.

Primary receptor for HIV is CD4. Co-receptors are CCR5 and CXCR4 chemokine receptors. CCR5 is used by HIV-1 in early infection, may switch to use CXCR4 later in infection. Once viral integration has occurred, infection persists for life in a reservoir of latently infected cells.

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18
Q

What are the targets for antiretroviral therapy?

A

Fusion/Entry inhibitors
Reverse Transcriptase inhibitors
Protease inhibitors
Integrase inhibitors

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19
Q

Describe the genetic resistance to HIV infection

A

1% of Caucasians are homozygous for a 32bp deletion in the CCR5 gene (CCR5D32) necessary for primary HIV-1 infection

People with only one copy of the mutant gene can be infected with HIV but show delayed disease progression

It has been hypothesised that the origin in Caucasians could be related to protection from the Plague

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20
Q

What are the reasons for the rapid mutation of HIV-1?

A

Error-prone replication (RT makes at least 1 error in every replication cycle).

Rapid viral replication (generation time 2.5 days).

Large population sizes (10^10 new virus particles every day).

21
Q

HIV-1 clades differ by what?

A

AA sequence (~>20%). Recombination between clades in the same person significantly increases HIV-1 diversity.

22
Q

Acute HIV-1 infection

A

Acute HIV-1 infection:
Detection of very high levels of virus in the blood
Symptoms of Acute Retroviral Syndrome
“Glandular fever”-like illness
Fever, lymphadenopathy
Sore throat, oral ulcers
Skin rash (upper trunk)
May include neurological features

23
Q

Immune responses during AHI determine what?

A

Long-term viral control
Disease progression

Early initiation of ART is beneficial
Reduced risk of transmission
Smaller reservoir, lower set-point, delayed progression

24
Q

What is the importance of early immune control?

A

Effector cells near target cells led to better viral control.

25
Q

Stages of HIV infection

A

Infectious period
Latency
AIDS and death

26
Q

Clinical features of untreated HIV-1 infection between 500 and 200 C4+ count

A

Vaginal/oral candidiasis
Skin disease
Fatigue
Bacterial pneumonia
Herpes Zoster
Oral hairy leukoplakia
Thrush
Fever
Diarrhoea
Weight loss

27
Q

Clinical features of untreated HIV-1 infection below 200 CD4 +ve count

A

Kaposi’s sarcome
Non-Hodgkin’s Lymphoma
Pneumocystis carinii pneumonia
Toxoplasmosis
Oesophageal candidiasis
Cryptococcsis
CNS lymphoma
CMV
Mycobacterium Avium Complex

28
Q

Key features of HIV pathogenesis

A

HIV is integrated into the DNA of the infected CD4-expressing cells

HIV infects a range of CD4 + immune cells in addition to helper T-cells, (including regulatory T-cells, T follicular helper cells, dendritic cells, macrophages and thymocytes)

However, the number of HIV-infected CD4+ T-cells in the blood does not explain the extent of immune suppression

HIV can pass directly from cell to cell, and so it is relatively inaccessible to antibodies in the blood

The small HIV genome encodes a range of genes that enable the virus to evade human immune system responses

29
Q

What provides a better correlate of disease progression than viral load?

A

T-cell activation (CD38 and HLA-DR expression).

30
Q

What is lost during early infection?

A

Dramatic loss of CD4+ T-cells in the lymphoid tissue in the gut (GALT): this increases gut mucosal permeability, allowing passage of bacterial products, such as LPS (microbial translocation).

31
Q

What is the consequence of these circulating bacterial products?

A

They stimulate circulating immune cells (particularly monocytes), setting up a cycle of chronic immune activation that ultimately exhausts the immune system.

32
Q

Immune activation is also driven by what?

A

HIV e.g. through a form of inflammatory cell death, pyroptosis, and co-infections, particularly CMV

33
Q

This persistent immune activation leads to…

A

Cell death and intense proliferation cycles that result in impaired function and exhaustion.

34
Q

Why does the immune system fail clearing up the infection?

A

The immune system generates a massive immune response to HIV infection, involving up to 20% of all circulating T and B lymphocytes
Antibodies develop against most viral proteins, but neutralising antibodies take months to develop and rarely neutralise the primary HIV strains that are transmitted from person to person

One of the key immune responses to HIV-1, from CD4+ T-helper cells, is lost from very early in infection, because these are the cells HIV infects first.

There is a very vigorous response from cytotoxic CD8+ T-cells, which provides the major force controlling viral replication but ultimately fail when “immune exhaustion” sets in.

35
Q

Why making effective ABs fails in most people?

A

The surface of the virion is derived from the host cell membrane containing only a few (6 – 10) envelope spikes.

The HIV-1 envelope spike is heavily glycosylated (with sugars resembling human types), which makes it difficult for antibodies to bind to the surface

The really critical parts of the viral envelope that are needed to enter.
CD4+ T-cells are either in deep pockets overhung by sugar molecules or only revealed when the virus docks onto the CD4 molecule.

The envelope (gp120/41) proteins can change substantially without affecting virus function.

Thus the virus can evolve very quickly to avoid antibody recognition (including by the addition of more sugar molecules).

In infected people the circulating neutralising antibodies rarely recognise their own prevailing viral envelope variants.

36
Q

Broadly neutralising Abs

A

Around 20% of PWH generate broadly neutralising antibodies (BNAbs) that can neutralise multiple HIV strains.

Found 3-4 years after infection, not associated with viral control or good outcome.

Involves considerable somatic mutation of the antibodies (50+ mutations from the original antibody), so hard to generate with a vaccine.

Often depend on effector functions (e.g. antibody-dependent cellular cytotoxicity, ADCC), may also be auto-reactive.

37
Q

What are the targets of BNAbs?

A

CD4 binding site
Membrane-proximal region
V2V3 conformational epitope
Envelope glycans
Potential use in therapy and to prevent infection

38
Q

Cytotoxic T-cells

A

CD8 - MHC-I

Different HLA class I molecules are able to present peptides with different characteristics: a set of three distinct HLA class I molecules (A, B & C) are inherited from each parent.

These peptides can come from any part of a pathogen, so include more conserved structural and functional internal proteins (whereas antibody recognition is largely limited to surface proteins).

Recognition triggers the release of soluble anti-viral factors and the death of the infected cell.

39
Q

CD8 release

A

Cytokines - solule anti-viral factors.

CC - chemokines (compete with HIV for CCR5).

Cytotoxic factors - kill the cell.

40
Q

CTL

A

Appear early - coincident with rapid drop in viral load.

41
Q

How does HIV-1 evade CTL response?

A

Mutation within weeks of primary infection.

Initially responses develop to the new variants but these are progressively undermined by the failure of CD4+ cell help and dendritic cell function.

The HIV-1 nef protein reduces cell-surface expression of HLA class I molecules needed for CTL recognition, whilst at the same time upregulating the “death” molecule Fas that can kill virus-specific CTL before they can kill the virus-infected cell.

HLA- A and B molecules are down-regulated to undermine CTL killing of infected cells but HLA-C expression is maintained to prevent NK cell killing.

Ultimately CTLs develop functional “exhaustion”, associated with expression of inhibitory molecules such as PD-1: levels of expression correlate with viral load.

42
Q

Long-term non-progressors

A

defined as survivors with HIV-1 infection for >7-10 years, no therapy, no symptoms and stable CD4+ T-cell count > 500mm3; RARE - around < 1-5 % of cohorts

43
Q

Elite controllers

A

defined as HIV-1 infected individuals with plasma VL <50 copies/ml for over one year without ART: VERY RARE - 0.35-0.8% of cohorts

44
Q

Summary of immune responses to HIV

A

Vigorous immune response but no demonstrable protective immunity with rare exceptions.

Excessive immune activation which favours viral replication.

Immunological dysfunction with involvement of all elements of host defence.

Ongoing viral replication with progressive immunological impairment leading to clinical manifestations of immunodeficiency.

45
Q

Why is life expectancy still reduced in infected individuals?

A

Issues of adherence, side-effects, drug resistance

Increase in non-AIDS-defining illnesses (NADIs): lung, cardiovascular and renal disease

Incidence of NADIs is related to:
Size of latent HIV reservoir
Persistent immune activation
CMV co-infection

46
Q

ART controls what?

A

HIV replication but the viral reservoir still persists.

47
Q

HIV may continue to replicate in where despite ART?

A

In lymphoid tissue or immune-privileged sites.

48
Q

Cure strategies

A

Current attempts to achieve a cure are focusing on stimulating HIV from the reservoir using Latency Reversing Agents, e.g. histone deacetylator drugs such as Vorinostat (anti-cancer drug), followed by intensive ART to try to wipe out the viral reservoir, together with immune-based therapies such as infusion of genetically modified (CCR5 negative) T-cells or therapeutic vaccination to boost long-term immune control of HIV replication (without ART).

Phase 2a - ICS (43 decks)

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