IMMUNO: Secondary immune deficiencies and HIV infection Pt.2 Flashcards
How long does it take for HIV to infect cells?
HIV provirus integrates into memory CD4 T cells within 72 hours of infection producing a long-lived reservoid of latent infection which is not responsive to ART
Does ART affect the latent HIV infection present in memory CD4 T cells?
No
- Latent cells infected with HIV do not respond to ART
- ART can prevent new cell from becoming infected but cannot eliminate infection once HIV-1 has integrated into host DNA
Describe the changes in these immune factors in the three phases of HIV infection:
- CD4+ T cells in blood
- Mucosal CD4+ T cells (including GIT)
- Viraemia
- Immune activation
What are the effects of HIV on the immune system?
- CD4 T cell depletion
- Impaired CD4 and CD8 T cell function
- Loss of antigen-specific humoral response
- Chronic immune activation
- Disruption of lymph nodes and impaired ability to generate protective T/B cell immune responses
What types of test are used in the diagnosis of HIV infection? Compare their uses.
Screening Test: Detects anti-HIV Ab via ELISA
Confirmation Test: Detects Ab via Western Blot
- A positive test requires patient to have SEROCONVERTED (i.e. started to produce Ab)
- This happens after ~10 weeks incubation period
HIV-1 RNA tests:
- When negative serology + high clinical suspicion
- In children <18m (serology not useful bc. passive transfer Abs from Mum)
Rapid point of care tests: Finger prick, 20 minutes but not sensitive
Assays to detect p24 antigen, gp41 from HIV-1 group O, gp160 envelope protein in HIV-1 and gp36 HIV-2
Which proteins are used in diagnostic assays for HIV-1 and HIV-2?
- HIV-1 O group = gp41
- HIV-1 M group = gp160
- HIV-2 = gp36
What are some HIV-1 specific-tests used after diagnosis ?
- Viral load - PCR used to detect viral RNA (very sensitive)
- Genotyping for drug resistance
- Tropism to confirm co-receptor (whether CCR5 positive - can use CCR5 antagonist)
- HLA-B*5701 blood test - abacavir
- T cell counts - CD4 T cell count via FACS (flow cytometry), used to assess course of disease, onset of AIDS, and CD4:CD8 T cell ratio
Deficiency of which cell receptor renders a person resistant to HIV?
CCR5
Why do HIV patients need to be tested for HLA-B*5701?
Risk of severe hypersensitivity to abacavir with this allele. Present in 8% of population in NW London.
What is the viral load set point significance? What factors affect the VL set point?
VL set point = the point to which, after 3-6 months of infection, the viral concentration plateaus
VL set point significance:
- Correlates with long term outcome
- Stratifies progression to symptomatic HIV-1 infection
VL set point is affected by:
- Viral genotype
- CD8 T cell immunity
- Host genetics (HLA/CCR5)
- Immune activation
As CD4 T cell count drops below 800 cells/mm^2, what infections are patients at risk of?
- <800 - lymphadenopathy, thrombocytopenia
- <500 - bacterial or fungal skin, oral, herpes simplex/zoster
- <400 - Kaposi’s sarcoma
- <300 - hairy leukoplakia, tuberculosis
- <200 - PCP, cryptococcosis, toxoplasmosis
- <100 - CMV, lymphoma
MAC (myobacterium avium complex)
(Other slide says CD4 thresholds for PCP, toxoplasma gondii and MAC are 200, 100 and 75 x10^9 cells/L respectively)
What are the 5 classes of ART available in the UK? Give an example of each.
- Reverse transcriptase inhibitors - NRTI, NNRTI
- Boosted protease inhibitors - ritonavir + lopinavir
- Integrase inhibitors - dolutegravir, raltegravir
- CCR5 antagonists - maraviroc (rarely) used
- Fusion inhibitors - T20 (not used)
What are the 3 main uses of ART?
TEST AND TREAT
- Those with active HIV-1, irrespective of CD4 T cell count
TREAT TO PREVENT INFECTION
- Prevent transmission to seronegative partner
- In pregnancy to prevent fetus infection
PROPHYLAXIS
- PReP to reduce risk of acquisition
- PEP after inadvertent exposure to HIV-1 infection following occupational exposure or after high risk sex
What is the first line HIV therapy regimen?
2 NRTI and 1 NNRTI
OR
2 NRTI and 1 integrase inhibitor
Example regimen: Emtricitabine + Tenofovir + Efavirenz (Available as 1 pill: Atripla)
What is the management of HIV in pregnany?
Zidovudine: Antepartum PO; For delivery IV
PO to newborn for 6/52 (reduces transmission from 26% to 8%)
What is the main reason for changes to HIV-1 therapy?
Drug toxicity rather than virological failure
BUT it is safer to continue ART than to interrupt the anti-HIV treatment in almost all cases (SMART study)
Does ART reverse chronic inflammation?
ART does not usually reverse chronic immune inflammation which is still a risk factor for cardiovascular, liver and bone and CNS disease
BUT if they start ART before significant immune damage, they will have a similar life expectancy to seronegative controls
How soon after stopping ART does HIV-1 become detectable in blood?
2-3 weeks later
What should be monitored on ART for HIV-1?
- Compliance and side-effects
- Regular viral load
- Liver, renal, bone and lipid toxicity
- CD4 T cells (only if <350 cells/ul)
- CVD and osteoporosis risk
- Monitor sexual health and vaccine uptake
Should be undetectable within 3 months of starting ART
What are vaccine trials for HIV-1 focusing on?
Development of neutralising and non-neutralising antibodies
Use of CMV vectors, TLR adjuvants, checkpoint inhibitors to stimulate CD8 T cell immune responses
What are the main strategies proposed/used for HIV-1 cure?
- Allogeneic stem cell transpants from CCR-delta32 HLA matched donors (used in Berlin and London patients)
- Shock and Kill strategy
A 65 year-old male with a history of steroid dependent asthma, hypertension, Type 2 Diabetes Mellitus and osteoporosis presents with recurrent chest, sinus, and skin infections. Past medical history of chemotherapy for follicular lymphoma and he has recently completed a 2 year maintenance therapy of 3 monthly rituximab. Current oral medication includes Prednisolone 5mg OD, Losartan 50mg OD, metformin500mg BD, alendronic acid 70mg weekly.
Serum immunoglobulins are as follows
- IgG – 3.9g/L (ref interval 6.4-16.0g/L)
- IgA – 0.9g/L (ref interval 0.8-3.4g/L)
- IgM – 0.1g/L (ref interval 0.5-2.0g/L)
- IgE 200IU/ml (reference interval 3-120IU/ml)
Which of the following medication are most likely to have cause antibody deficiency
- A) Metformin
- B) Losartan
- C) Prednisolone
- D) Alendronic Acid
- E) Rituximab
Rituximab
A 57-year-old male is referred to the Chest clinic with recurrent chest infections, requiring antibiotic therapy. Past medical history reveal lichen planus and a history of surgery for an anterior mediastinal mass 4 year previously. Physical examination show nail candidiasis, sternotomy scar and bi-basal crepitations. A HRCT chest scan shows extensive bronchiectasis.
Immune investigation are as follows
- IgG – 3.1g/L (ref interval 6.4-16.0g/L)
- IgA – 0.4g/L (ref interval 0.8-3.4g/L)
- IgM – 0.2g/L (ref interval 0.5-2.0g/L)
- IgE 500IU/ml (reference interval 3-120IU/ml)
- B cell count 10cell/ul ( ref interval 100-500)
What is the most likely diagnosis?
- A) Partial antibody deficiency syndrome
- B) Common variable immune deficiency
- C) High grade B cell Mediastinal Lymphoma
- D) Thymoma with antibody deficiency/Good’s syndrome
- E) Hyper IgE syndrome
Thymoma with antibody deficiency/Goods’ syndrome
Which of the following condition are more likely to present in patients with a CD4 T cell counts of more than 350cells/ul
- A) CMV retinitis, Toxoplasma encephalitis, visceral Kaposi sarcoma
- B) Herpes zoster, Pulmonary Tuberculosis, Pneumococcal pneumonia
- C) Pneumocystis jirovecci pneumonia, disseminated MAC, ITP
- D) EBV CNS lymphoma, oral candida, cryptococcal meningitis
- E) Cutaneous Kaposi sarcoma, disseminated MAC, HSV infection
Herpes zoster, Pulmonary Tuberculosis, Pneumococcal pneumonia
Which of the following statements are true about HIV-1 infection
- A) Reverse transcription is associated with few errors in copying HIV-1 RNA template
- B) Preferred option to commence ART in the UK is dual combination therapy containing an integrase inhibitor and NRTI
- C) HLA-B*5701 blood test is used to prevent hypersensitivity reaction with protease inhibitors
- D) Residual immune activation is commonly seen in patients on suppressive ART regimens
- E) HIV-1 serology point care tests have similar diagnostic performance to 4th generation combined p24antigen/antibody tests
Residual immune activation is commonly seen in patients on suppressive ART regimens
