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Year 5 Immunology > 2: HIV Infection > Flashcards

2: HIV Infection Flashcards

1
Q

HIV1 vs HIV2

A

HIV2 less virulent and harder to transmit

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2
Q

HIV1 structure

A
  • retrovirus
  • RNA = replicated inside a cell using RT to convert RNA to DNA to be integrated into host genome

Structure:

  • icosahedral (20-faced)
  • diploid genome
  • 9 genes that encode 15 structural, regulatory and auxiliary proteins i.e. gp120, gp41, RT
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3
Q

What does HIV1 target

protection from HIV requires

A

CD4+ Th, CD4+ monocytes, CD4+ dendritic cells

selective loss of CD4 Th cells

Protection from HIV requires:

  • antibodies (B cells)
  • sufficient CD8+ T cells
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4
Q

HIV1-R and co-receptor

A

Receptor = CD4 molecule/antigen

Co-receptor (most strains require) = CCR5 / CXCR4

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5
Q

How is HIV transmitted?

A

Sexually = via mucosa (esp. damaged sites/MSM), infects CD4 cells which carry virus to LN

Infected blood = transfusion, needle sharing, blood products

Vertical (mother to child) = ante/intrapartum, breastmilk

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6
Q

Natural immunity to HIV: mobilised within hours of infection and involves

A
  • inflammation
  • nonspecific activation of macrophages, NK cells and complement
  • release of cytokines and chemokine (only those made by NK cells can reduce infection of CD4 T cells by HIV)
  • stimulation of plasmacytoid dendritic cells (pDC) by TLRs
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7
Q

Acquired immunity to HIV (antibody and B cells): specific humeral responses where neutralising antibodies are produced

A
  • Anti-gp120 and anti-gp41 (Nt) antibodies are important in protective immunity
  • Non-neutralising anti-p24 gag IgG are also produced
  • HIV remains infectious even when coated with antibodies
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8
Q

Role of CD8+ T cells in HIV

A
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9
Q

Summary of effects immune system

A
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10
Q

Variation and mutation of HIV, advantages of this

A
  • Reverse Transcriptase (RNA to DNA) – lacks proof-reading mechanisms from cellular DNA polymerases
  • Transcription of DNA into RNA copies

→ accumulate lots of mutations with numerous variants

The propensity to mutate can lead to the development of advantageous features such as:

  • Escape from neutralising antibodies
  • Escape from HIV-1 specific T cells
  • Resistance and escape from antiretroviral drugs
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11
Q

Life cycle of HIV

A
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12
Q

Therapy targets within the life cycle of HIV

A
  • Attachment (Attachment Inhibitors / AI)
  • Fusion (FI)
  • Reverse transcription (RTI)
  • Integration of viral DNA into host (INI)
  • Transcription of DNA to viral RNA
  • Translation of viral RNA to produce viral proteins
  • Viral protein cleavage by proteases (PI)
  • Assembly and budding of new HIV

-gravir = integrase inhibitor

-avir = protease inhibitor

-ines = NRTI

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13
Q

Clinical course of disease

A

HIV to AIDS = 8-10 years

viral burden predicts disease progression:

  • rapid progressors (10%) take 2-3 years (mainly seen in Africa)
  • LTNP (<5%) will have stable CD4+ counts and no sx’s after 10 years
  • Exposed-seronegatives (ESN) = people exposed to HIV but do not seroconvert
  • Elite Controllers = can suppress viral replication

HAART significantly improves prognosis

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14
Q

How do we detect HIV?

A

Anti-HIV antibodies (ELISA) – screening test

Anti-HIV antibodies (Western Blot) – confirmation test

Viral load (viral RNA detection using PCR) – very sensitive; steps:

  • Reagent preparation
  • Specimen preparation
  • Amplification
  • Detection

Initial baseline plasma viral load is a good predictor of the time taken for the disease to appear

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15
Q

How do monitor CD4+ T cell counts?

A

Flow cytometry

Onset of AIDS correlated with decrease in number of CD4 T cells

antigens on T cells:

  • CD3,CD4
  • CD19
  • CD8
  • CD56
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16
Q

HIV1 ART resistance testing: 2 established assays to measure ART resistance

A

(1) Phenotypic → viral replication is measured in cell cultures under selective pressure of increasing concentrations of antiretroviral drugs (compared to wildtype)
(2) Genotypic → mutations detected by sequencing amplified HIV genome (limited to sequencing RT and P)

Both assays are available commercially (but are EXPENSIVE)

17
Q

Outcomes of HAART (3)

A

Substantial control of viral replications

Increase in CD4+ T cell counts

  • initial rise = redistribution of memory T cells
  • later rise = thymic naive T cell creation

Improvement in host defences (decline in opportunistic infections (AIDS) and mortality)

NOTE: HAART does NOT eliminate HIV from the body as there is a reservoir in CD4+ T cells

18
Q

What is HAART?

A

Combination of 3 or more ART drugs

  • 2 backbone drugs (x2 NRTIs)
  • >1 binding agent (x1 NNRTI or INI), 2nd line = boosted PI
19
Q

Types of ART

A

Backbone drugs:

  • Nucleoside Reverse Transcriptase Inhibitors (NRTI) – e.g. Zidovudine / AZT
  • Nucleotide RTI – e.g. Tenofovir
  • Non-NRTI (NNRTI) – e.g. Efavirenz
  • Protease inhibitor (PI) – e.g. Indinavir

Binding agents:

  • Integrase inhibitors (INI) – e.g. Raltegravir
  • Attachment inhibitors (AI) – e.g. Maraviroc
  • Fusion inhibitors (FI) – e.g. Enfuvirtide
20
Q

When to start HAART

A
  • All symptomatic patients
  • All CD4+ count < 200 cells/uL
  • CD4 count 200-350 cells/uL

All offered IMMEDIATE treatment – more for _public health_ than an individual’s health

21
Q

HAART interactions

A
  • Boosted PI – block cytochrome P450
  • Efavirenz – P450 inducer
  • INI – interacts with indigestion remedies (Gaviscon, aluminium salts, calcium salts) and is sequestered which can be very bad as some INI is absorbed but very little and so resistance is bred very quickly

I.E. if treating >55yo HTN with amlodipine, the amlodipine will seem to not work if the patient is also on Efavirenz (they might not tell you this) as the amlodipine will be broken down too quickly

22
Q

Limitations and complications of HAART

A
  • Does NOT eradicate latent HIV-1
  • Fails to restore HIV-specific T cell responses
  • Threat of drug resistance
  • Significant toxicities
  • High pill burden
  • Adherence
  • Quality of life
  • Cost (>40% with no access)
23
Q

Prevention of HIV-1 spread

A
  • Male circumcision (APCs in foreskin at a high density)
  • Condoms
  • PrEP (Truvada)
  • TasP (Treatment as Prevention – if on treatment, cannot transmit infection; i.e. U=U)
24
Q

Summary

A
  • HIV-1 infection interferes with basic aspects of CD4+ and CD8+ T cell activation
  • HIV-1 infection may interfere with APC function
  • Effective immunity requires antibodies to prevent infection and neutralise virus, and sufficient CTL to eliminate latently infected cells
  • An effective vaccine must elicit potent antibodies and CTL
  • Permanent control of latently infected cells by CTL may prevent progression to AIDS
  • Effective ART requires combinations of at least 3 agents, typically from different classes
  • Arrest of viral replication does not lead to diminution of latently infected cells; thus a residual reservoir persists which his capable of establishing ongoing viral activity upon therapy discontinuation
  • Host immune responses may reduce this risk of even deplete residual reservoirs
25
Q

HIV epidemiology

A
26
Q

HIV pathogenesis

A
27
Q

Immune response to HIV

A
27
Q

Immune response to HIV

A
28
Q

Natural history of HIV

A
29
Q

Natural history of HIV

A
30
Q

Diagnosis of HIV

A
31
Q

HIV treatment

A
32
Q

HIV treatment

A
33
Q

Life cycle and treatment of HIV

A

Year 5 Immunology (5 decks)

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