Imm - HIV Flashcards
Describe the structure of HIV-1
RNA retrovirus
Has a 20-faced structure
Diploid genome
Contains 9 genes → 15 proteins
Describe the HIV-1 replication cycle
- Binds CD4+ via gp120 (initial binding) and gp41 (conformational change) on T helper cells (As well as CD4+ monocytes, dendritic cells)
- Binds CCR5 or CXCR4 chemokine co-receptors
- Replicates inside the cells using reverse transcriptase (RNA → DNA) - lacks proof-reading mechanisms from cellular DNA polymerases
- Integration of DNA into host genome
- Host cell machinery transcribes DNA → mRNA → viral proteins
- Viral proteins packaged and released as a mature virion
Gag protein - intrastructural support for HIV
How is HIV transmitted
Sexually – through mucosa (esp. damaged sites / MSM), infects CD4+ cells (inc. CD4+ DC) which carry virus to LN
Infected blood – transfusion, needle sharing, blood products
Vertical (mother to child) – ante-/intra-partum, breastmilk
High transmission in the first 6m (flu-like symptoms 70%)
What is the mechanism natural immunity to HIV
Innate
Inflammation and non-specific macrophage, NK cells and complement
Cytokine + chemokine release
Adaptive
Anti-gp41(first weeks) → Anti-gp120 (later)
Non-neutralising anti-p24 gag IgG
CD8+ T Cells can prevent HIV entry by producing chemokines MIP-1a, MIP-1b, and RANTES which block co-receptors.
What is the effect of HIV in the immune system
Even when antibody-coated it remains infectious
Infected CD4+ T-helper cells killed by CD8+ T cells
CD4+ T cells disabled/anergised
- Monocyte and dendritic cells not activated
- CD8+T and B cell responses diminished
- Memory cells lost
Dendritic cells killed → no antigen presentation → cannot activate memory cells
Quasispecies are produced due to error-prone reverse transcriptase = these escape from
immune response
What is the clinical course of HIV and what are the different pathways to progression
Acute → asymptomatic/progressive → AIDS
Typical progressors (85%): 8-10 years from infection to AIDS
Rapid progressor (10%): 2-3 years
Long-term progressor (<5%): stable CD4+ counts and no symptoms after 10 years
Exposed seronegatives: repeatedly exposed but do not seroconvert
Elite controller: can suppress viral replication
What infections may be seen for the following CD4 cell counts: 500, 400, 300-350, 200, 100, 75
500: skin, oral, fungal infections, HSV, VZV
400: Kaposi’s sarcoma
300-350: pulmonary TB, hairy leukoplakia
200: PCP, cryptococcus, toxoplasmosis
100: CMV, lymphoma
75: Mycobacterium avium complex (MAC), PCP
How is HIV diagnosed
Screening Test: Detects anti-HIV Ab via ELISA
Confirmation Test: Detects Ab via Western Blot
-ve serology + high suspicion → HIV-1 RNA tests
Children <18yo → HIV-2 RNA/DNA
+ve test: patient must have seroconverted (producing ABs) - occurs after 10 weeks incubation
(note: 4th gen test: 1 month post infection, Rapid point: available within 20 minutes, less sensitive)
What investigations should be done for HIV after diagnosis
VIral load (PCR)
CD4 count via FACS (flow cytometry) (CD 3,4,8,19,56)
Resistance testing (for antivirals)
- Phenotypic: Viral replication is measured in cell cultures under selective pressure of
increasing concentrations of antiretroviral drugs – compared to wild-type
- Genotypic: Mutations determined by direct sequencing of the amplified HIV genome
HIV-1 tropism test (confirm co-receptor/CCR5)
HLA-B*5701 test (for abacavir)
What defines AIDS
<200 cells/microlitre of blood
What is HAART and its aims
Highly Active Anti-Retroviral Therapy
2 NRTIs + NNRTI / INI / PI
BHIVA guidelines: started immediately after diagnosis
Aim: control viral replication, increase CD4 counts, improve host defences
What are the types of anti-retrovirals
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
What are the drug interactions of anti-retrovirals
Protease inhibitors: blocks cytochrome P450
Efavirenz: P450 inducer
Integrase inhibitors: interacts with indigestion remedies and sequestered
What are the limitations of HAART
Does not eradicate latent HIV-1
Fails to restore HIV-specific T cell responses
Does not reverse chronic immune inflammation (RF for CV, liver, bone, CNS disease)
Drug resistance
Significant roxicity
High pill burden → impact on adherence
Reduced QOL
High cost
If stopped → HIV detectable in blood 2-3 weeks later
How can HIV-1 transmission be prevented
Male circumcision (APCs in foreskin at a high density)
Condoms
PrEP (Truvada) - pre-exposure prophylaxis
PEP: ART after exposure
TasP (Treatment as Prevention – if on treatment, cannot transmit infection; i.e. U=U)
