Immunology - HIV Flashcards
What is the epidemiology of HIV?
- > 37m people living with HIV-1/AIDs worldwide (2018)
- 21m ppl receiving ART
- 101,200 affected UK individuals
- ~70% those on ART have undetectable viral load (UK)
- Transmission: sexual, infected blood, mother to child (vertical - breastfeeding, in utero, intrapartum)
What is the HIV replication cycle?
- RNA retrovirus
- Binds CD4 via gp120 (initial binding) + gp41 (conformational change) on T helper cells, also CD4+ monocytes, DCs
- Binds CCR5 or CXCR4 chemokine co-receptor
- Replicates inside cells using reverse transcriptase enzyme to convert RNA into DNA which can be integrated into host genome
- Hijacks host cell machinery to transcribe DNA + translate mRNA to viral proteins
- Viral proteins packaged + released as mature virions
- Gag protein: intra-structural support for HIV
What is the innate immune response to HIV?
- Non-specific activation of macrophages, NK cells + complement
- Stimulation of dendritic cells via TLR
- Release of cytokines + chemokines
What is the adaptive immune response to HIV?
- Neutralising Abs: Anti-gp41 IgM (first wks), anti-gp120 (later)
- Non-neutralising Abs: anti-p24 gag IgG
- CD8+ T cells can prevent HIV entry by producing chemokines MIP-1a, MIP-1b + RANTES which block co-receptors
What are some key features of HIV-1 infection?
- CD4+ T cell depletino
- Chronic immune activation
- CD4 + CD8 T cell exhaustion
- Disruption of lymph node architecture
- Loss of Ag-specific humoral response
How does HIV damage the immune system?
- Remains infectious even when Ab coated
- Activated infected CD4+ helper T cells killed by CD8+ T cells
- Activated infected CD4+ helper T cells anergised (disabled)
- CD4 T cell memory lost + failure to activate memory CTL
- Monocytes + dendritic cells are therefore not activated by CD4+ T cells + can’t prime naiive CD8+ CTL (due to impaired antigen presenting functions)
- Infected monocytes + dendritic cells killed by virus or CTL
- Quasispecies are produced due to error-prone reverse transcriptase = these escape from immune response
- Effective immunity requires auto-antibodies to prevent infection + neutralise virus + sufficient CTL to eliminate latently infected cells
What are the 3 stages of HIV disease progression?
- Acute
- Asymptomatic (but progressive)
- AIDS
What is the overall process of HIV disease progression?
- Transmission high during first 6 mths
- Flu-like Sx in 70%
- Median time from infection to development of AIDS = 8-10yrs (typical progressors)
- Median time from infection to development of AIDS = 2-3yrs (rapid progressors = 10%)
- Long term non-progressors = <5% (show stable CD4 counts + no Sx after 10yrs
- Initial viral burden (set point) predicts disease progression
What are some important CD4 counts in a patient with HIV?
- 75: Mycobacterium Avium Complex (MAC) disease
- 75: Pneumocystis jiroveci
- 300-350: Pulmonary TB
- 400: Kaposi’s sarcoma
What is the screening test for HIV + what does it test for?
- ELISA
- Detects anti-HIV Ab
What is the confirmation test for HIV + what does it look for?
- Western Blot
- Detects Abs
What are some requirements for a positive screening/confirmation test for HIV?
- Requires pt to have Seroconverted
- Happens >~10wks incubation period
When are HIV-1 RNA tests used?
- Negative serology
- High clinical suspicion
What testing is used for children <18mths
HIV-1 RNA +/or DNA
- Serology not useful due to passive transfer of Abs from Mum
What tests are required post-HIV diagnosis and why?
- Viral load (PCR): Detects viral RNA (v. Sens)
- CD4 count (FACS/flow cytometry): Assesses course of disease, onset of AIDS correlated with diminution in number of CD4+ T cells
- Resistance testing: Resistance to ARVs
