Human Immunodeficiency Virus

Question 1

HIV - Risk Groups

Answer 1

• Orginating from sub-Saharan Africa
• Men who have sex with men (MSM)
• Intravenous drug users

Question 2

HIV - Epidemiology

Answer 2

• 33.3 million people worldwide living with HIV in 2009 (approximately 0.5%)
• 2.7 million new HIV infections a year in 2010
  
  • 7000 a day​
  • Decrease of 17% since 2001
  • Maternal transmisiion accounted for 430,000 cases in 2008
• 1.8 million deaths due to AIDS in 2009
• 7 million people need but cannot get antiretroviral therapy

Question 3

HIV - Transmission

Answer 3

• Virus may be transmitted by:
  
  • Semen
  • Vaginal secretions
  • Breast milk
  • Blood
• Infects CD4 positive cells - tends to be macrophages in sexual route as many present in anogenital mucosa)
• Sexual contact (most important)​​​
  
  • Risk reduced with circumcision
  • Risk greatest with:
    
    • Concurrent STI (more macrophages in mucosa)
    • During seroconversion
    • During 1st few months of illness
• IVDU, blood transfusions, needlestick (uncommon)
• Vertical transmission before/during birth and through breast milk

Question 4

HIV - Viral Structure

Answer 4

• Envelop derived from host cell membrane produced by budding = lipid bilayer
• Embedded viral glycoproteins - coded for by env gene
  
  • Gp120 and Gp41 - interact non-covalently
    
    • Mediate specific binding to CD4 comples on hose cells
• p16 matrix protein helps maintain viral structure
• p24 capsid protein core - inside 2 identical copies of:
  
  • ssDNA
  • Enzymes:
    
    • Reverse transcriptase
    • Protease
    • Integrase

Question 5

HIV - Host Cell Entry

Answer 5

• HIV infects CD4 positive cells: Langerhan’s cells, macrophages, T-helper cells, B-cells, monocytes
  
  • GP120 mediated target recognition - binds CD4
    
    • Requires host cell co-receptor in addition
      
      • CXCR4 - T-cells
        
        • Lymphotrophic virus preferentially binds
      • CCR5 - Macrophages
        
        • Macrophage-trophic virus preferentially binds
      • Both types present in individual during infection - lymphotrophic becomes predominant later in course of infection
        
        • Immune response may actually promote spread
  • GP41 mediates fusion
    
    • After CP120 binds CD4 it breaks away exposing hypdrophobic tip of GP41 which buries deeply into the lipid membrane of the target cell
      
      • ==> Virus particle is drawn close to cell surface facilitating fusion

Question 6

HIV - Replication

Answer 6

• Reverse transcriptase synthesises a complementary DNA copy of the viral RNA whilst simultaneously degrading the RNA
  
  • It then synthesises the complementary DNA strand to the new DNA strand
• The cDNA is transported to the nucleus where viral integrase inserts it into the host cell genome = proviral DNA
• Remains dormant in resting cell until host cell activation ==> transcription
  
  • Viral genome RNA
  • Viral messenger RNA
    
    • Translated into long polypeptide chains
      
      • Cleaved by protease into functional protetins (viral enzymes and structural proteins)
    • ==> Assembled into new virus
      
      • Virus buds from cell surface

Question 7

HIV - Mutation

Answer 7

• Viral reverse transcriptase:
  
  • Is error prone
  • Has no proof-reading mechanism
• ==> About 1 new mutation per new virus
  
  • Every possible mutation in 1 day
• Virus rapidly forms a ‘swarm’ of quasi-species
  
  • Rapid selection of viruses with survival advantage

Question 8

HIV - Treatment Options

Answer 8

• Nucloside reverse transcription inhibitors (reverse transcriptase)
• Non-nucleoside reverse transcription inhibitors (reverse transcriptase)
• Protease inhibitors (viral protease)
• Fusion inhibitors (bind gp41)
• Co-receptor inhibitors (Anti-CCR5)
• Integrase inhibitor (viral integrase)

Question 9

Innate Immunity

Answer 9

• Mucosal barriers
• Bone marrow derived phagocytes
• Alternative complement pathway
• Acute phase response
• Cytokines/chemokines
• Interferons
• NO MEMORY

Question 10

Adaptive Immunity

Answer 10

• Lymphocyte mediated - T + B cell
• Specific receptors for antigens –TCR / sIg
• Specific recognition for activation
• Delay in primary response
• Memory gives more effective subsequent response
• SPECIFICITY + MEMORY

Question 11

B-Lymphocytes

Answer 11

• Created in the bone marrow
• Responds to unprocessed antigens as whole proteins binding and cross-linking the B-cell receptor
• 2 types of activation
  
  • T-cell dependent:
    
    • B-cell receptor activated by antigen
    • Digests and displays antigen fragments on MHC - binds matching T-Helper cell previously primed to antigen by exposure to froman antigen-presenting cell
      
      • ==> immunological synapse - T-cell produces cytokines ==> B-cell activation
        
        • Proliferation and differentiation into antibody producing plasma cells and also memory cells
  • T-cell independant activation (rapid but more restricted)

Question 12

T-Lymphocytes

Answer 12

• Develop in the thymus - positive and negative selection
• Recognise processed antigen via T-cell receptor
  
  • Presented as part of MHC complex by cells
• Subdivided into:
  
  • CD4 cells - Helper T-Cells ==> recognise class II MHCs
    
    • Produce cytokines:
    • TH1 cells = IFNgamma, IL-2, IL-12
      
      • Involved in cell-mediated immunity
        
        • Macrophage activation
    • TH2 cells = IL-4, IL-13
      
      • Involved in humoral immunity (antibody production)
  • CD8 cells - Cytotoxic ‘killer’ T Cells ==> recognise class I MHCs
    
    • Kill virally infected cells
    • Direct contact with target cell ==> release perforin and granzyme
    • Produce interferons

Question 13

HIV - Natural History

Answer 13

• HIV virus infects macrophages in genital tract
  
  • Regional lymph nodes by day 3 (PEP)
  • Disseminated by day 10
  • Uncontrolled viral replication
• Acute seroconversion (stage I) - most by 3 months
  
  • Flu-like illness +/- maculopapular rash
• Asymptomatic and Progressive Glandular Lymphadenopathy (Stage II and III)
• Symptomatic (Stage IV C2)
• AIDS (Stage IV)

Question 14

HIV - Prognosis

Answer 14

• Aymptomatic ==> AIDs in 9-10 years
• AIDs - 3 years untreated
• Currently longer due to reduced death rates on combination therapy - end point not reached

Question 15

HIV - Antibody Response

Answer 15

• B-cells produce a ‘neutralising antibody’
  
  • Found in all patients
  • Directed against GP120
  • Fails to clear virus
• HIV evades antibody response but it is principally an intracellular infection

Question 16

HIV - Clinical Latency

Answer 16

• During clinical latency
  
  • Huge numbers of virions produced and destroyed daily
  • Viral load maintained at a relatively constant level
  • In most patients there is a gradual fall in CD4 cell count over time ==> T-cell immunodeficiency

Question 17

HIV - Cytotoxic Lymphocytes (CD8 Cells)

Answer 17

• Long-term non-progressors have strong cytotoxic lymphocyte response to virus
• Inverse relationship between viral load and CTL levels
• Viral load at seroconversion correlates inversely with CTL response
• Presence of HIV-specific CTL in cord blood is associated with viral clearance in infants
• Primate models – removal of CD8 cells leads to uncontrolled replication, reversed by reconstitution

Question 18

HIV - Immune Evasion

Answer 18

• Current understanding is that once a productiv infection is established HIV is never eliminated
• In most patients HIV evades the immune control by:
  
  • Progressive damage to the immune system reducing its ability to clear viruses
  • Archiving of virus in DNA therefore hidden
  • Viral mutation

Question 19

HIV - AIDs Defining Illnesses (Key Criteria)

Infective: Fungal

Answer 19

• Oesophageal candidiasis
• Candidiasis of bronchi, lungs or trachea
• Coccidiomycosis - disseminated or extrapulmonary
• Cryptococcosis - extrapulmonary
• Histoplasmosis
• Isospsoriasis

Question 20

HIV - AIDs Defining Illnesses (Key Criteria)

Infective: Bacterial

Answer 20

• Mycobacterium tuberculosis - any site
• Atypical mycobacteria
• Salmonella
• Recurrent bacterial pneumonia

Question 21

HIV - AIDs Defining Illnesses (Key Criteria)

Infective: Protozoal/Parasitic

Answer 21

• Toxoplasmosis
• Cryptosporidiosis - chronic
• Pneumocystis cariini pneumonia

Question 22

HIV - AIDs Defining Illnesses (Key Criteria)

Infective: Viral

Answer 22

• CMV retinitis
• CMV disease in other sites
• EBV ==> hairy leukoplakia
  
  • ​White plaques on lateral aspect of tongue
• Multidimensional herpes zoster
• HHV-8 - cause of Kaposi’s sarcoma
• Progressive multifocal leucoencephalopathy

Question 23

HIV - AIDs Defining Illnesses (Key Criteria)

Neoplastic

Answer 23

• Kaposi’s sarcoma
• Lymphoma (NHL) - likely EBV driven
• Primary brain lymphoma - likely EBV driven

Question 24

HIV - AIDs Defining Illnesses (Key Criteria)

Neurological

Answer 24

• HIV dementia

Question 25

HIV - AIDs Defining Illnesses** (Key Criteria)** Constitutional

Answer 25

* **HIV wasting syndrome**

Question 26

HIV - T-cell Monitoring

Answer 26

* CD4 count can be used to montior the progression of HIV: * \>500 - normal * 200 to 500 - asymptomatic HIV but may start highly active antiretroviral therapy * \<200 - AIDs * \<50 - high risk of death within next 12 months * **! **- Be aware of: * Possible leukaemia * Other cause of immunodeficiency

Question 27

HIV - Testing Considerations

Answer 27

* Anyone can test provided: * Give adequate counselling * Pros and Cons of testing: * Survival * Efficacy of treatment * Maternal transmission * Criminality of infecting * Psychological * Life insurance * Document such * Give results or arrange to be given * Appropriate follow up