PBL 30

Question 1

Pathophysiology and microbiology of HIV and AIDS

1. Mechanism
2. Microbiology
3. Risk factors
4. Presentation
5. Diagnosis
6. Treatment

Answer 1

1. Mechanism
   - BINDING: HIV envelope glycoprotein gp120 binds to CD4 molecule on T-lymphocytes. Gp120 can also bind CXCR4 (T-cells) and CCR-5 (phagocytic cells)

• INTERNALISATION: Gp120 binding allows gp41 to insert into the target cell’s plasma membrane, leading to its fusion with the viral envelope and virus entry
• DNA SYNTHESIS: Virus uncoats in the cytoplasm, its RNA is copied into ds DNA by reverse transcriptase
• INTEGRATION: Virus cDNA integrates into the host genome using viral integrase, generating a latent proviral form of HIV-1
• REPLICATION: Viral RNA is reproduced by transcriptional activation of the integrated HIV provirus
• DISSEMINATION: Nascent virus is assembled in the cytoplasm just beneath the cell membrane and disseminated to other target cells. This is done by either fusion of an infected cell with an uninfected cell or by the budding of virions from the plasma membrane of the infected cell

2. Microbiology
   - HIV-1 virion has gp120 external glycoprotein and gp41 is the TM domain
   - Capsid within which are two RNA molecules encoding the genetic information of the virus, and also reverse transcriptase, integrase and protease are present
3. Risk factors
   - Unprotected anal or vaginal sex
   - Having another STI
   - Sharing contaminated needles
   - Receiving unsafe injections, blood transfusions
   - Needle stick injuries
4. Presentation
   - Primary (acute) HIV infection
   Lasts a few weeks
   Fever
   Headache
   Swollen lymph nodes, mainly of the neck
   Muscle aches and joint pain
   Rash
   Diarrhoea
   Weight loss
   Night sweats

• Chronic latent infection (chronic HIV)
  Patients don’t usually experience symptoms during this stage

- Symptomatic HIV infection
As virus continues to multiply and destroy immune cells, you may develop mild infections
Fever
Fatigue
Swollen lymph nodes
Diarrhoea
Oral yeast infection (thrush)
Shingles
Pneumonia

5. Diagnosis
   - CD4 count
   - >500 is good
   - 200-500 = little risk
   - <200 = increased risk of serious opportunistic infection (pneumonia, toxoplasmosis, oesophageal candida etc)
   - <100 = Additional risk of myobacterium avuium intracellulare and cytomegalovirus. AGGRESSIVE DISEASE
6. Treatment
7. Anti-retroviral treatment
   NRTIs: abacavir, tenofovir, emtricitabine. Stop ssRNA to dsDNA, inhibit reverse transcriptase activity
   NNRTIs: reverse transcriptase inhibitors
   Protease inhibitors: stop HIV from being broken down and reassembled into new infectious particles
   Integrase inhibitors: stop HIV being integrated into cell DNA
   Capsid inhibitors
   Entry inhibitors: CCR5 antagonists. Bind CCR5 so blocking HIV protein gp120 from associating with the receptor of T-lymphocytes, and therefore blocking entry. But HIV can use CXCR4 as an alternate route
   Attachment and post-attachment inhibitors: bind to gp120

Question 2

Epidemiology and control of HIV (&PrEP)

Answer 2

• Sub-Saharan African inhabitants suffer more from AIDS than any other regions, USA is affected also

- Control:
Less risky sex
Less sexual partners
Use condoms
Get tested regularly for STIs
Don't share needles/inject drugs
Know partner's HIV status
PrEP

-PrEP
Way for people who are at high risk of HIV to prevent infections
Taking a pill every day
Give a drug such as truvada (tenofovir and emtricitabine) as a prophylactic medication

Question 3

HIV –> AIDS?

Answer 3

• AIDS diagnosis is CD4 below 200 and when you develop one or more opportunistic infections

Question 4

Explain the CD4+ count and link to symptoms in HIV

Answer 4

• Patients remain asymptomatic until CD4+ T-lymphocyte count falls below 500uL, then you will get constitutional symptoms and opportunistic infections.
• CD4+ <350 = patients become susceptible to primary or reactivation of TB.
• CD4+ <150 and CD4:CD8 = disease progresses rapidly. Kaposi sarcoma and lymphoproliferative disorders may appear

Question 5

HIV treatment doses

Answer 5

Drugs from two (or sometimes three) classes are combined to ensure a powerful attack on HIV

• Start with two drugs from NRTI/NNRTI and combine with one integrase inhibitor, or protease inhibitor
• Hence TRIPLE THERAPY

Question 6

What are the major groups of fungi? Explain each

Answer 6

1. Mould
   - Growth by formation of filaments - hyphae. Entangled mass of hyphae forms a mycelium which is visible to naked eye. Aspergillus is a mould which causes human infection
   - Asexual reproduction through production of conidia (asexual spores)
2. Yeast
   - Single cell, round/ovoid organisms
   - Reproduce by budding
   - Include candida species and cryptococcus neoformans
   - Some form elongated buds (pseudohyphae) which are seen when they cause invasive disease
   - Candida albicans can form true hyphae and pseudohyphae, true hyphae presence is a diagnostic test for this type of yeast
3. Dimorphic fungi
   - Grow as yeasts or moulds. Yeast form causes infection, mould form is saprophytic
   - Usually acquired through inhalation of spores (found in soil)
   - Disease may disseminate to other organs

Question 7

Define superficial, cutaneous, subcutaneous and deep (systemic) mycoses

Answer 7

• Mycosis is a fungal infection of animals and humans

1. Superficial mycoses
   - Limited to outermost layers of the skin and hair
   - No living tissue invaded
   - No cellular response from host & no pathological elicited
   - E.g Tinea versicolor: affects skin of young people, especially chest, back, upper arms and legs. Causes lightening of the skin due to fungus’ production of azelaic acid which has a slight bleaching effect
2. Cutaneous mycoses
   - Extends deeper into the epidermis and also includes hair and nails
   - Restricted to keratinised layers of the skin, hair and nails
   - No living tissue invaded
   - Host immune response may be evoked resulting in pathological changes in the deeper layers of the skin
   - E.g. dermatophytosis (ringworm or tinea). Dermatophytes can use keratin as a nutrient, presence of fungus elicits host response. Candidiasis (thrush) - candida are part of normal flora of mouth and female genital infections are usually due to impaired epithelial barrier functions
3. Subcutaneous mycoses
   - Involve dermis, subcutaneous tissues, muscles and fascia
   - Chronic infection which can be locally invasive and involve bone
   - Can be initiated by piercing trauma to the skin which allows fungi to enter
   - Difficult to treat and may require surgical interventions such as debridement
4. Deep mycoses
   - Deep mycoses due to primary pathogens originate primarily in the lungs and may spread to many organs (pathogen usually dimorphic)

Question 8

Vaccination schedule

• 2 months
• 3 months
• 4 months
• Between 12-13 months
• 2-7 years
• 3 years and 4 months
• 12-13 years (girls)
• 14 years
• Adults

Answer 8

• 2 months
  1. 5 in 1
  2. PCV
  3. Rotavirus (oral)
  4. Meningitis B
• 3 months
  1. 5 in 1
  2. Rotavirus
• 4 months
  1. 5 in 1 (3rd dose)
  2. PCV
  3. Meningitis B
• Between 12-13 months
  1. Hib/MenC
  2. MMR
  3. PCV
  4. Meningitis B
• 2-7 years
  1. Nasal flu spray
• 3 years and 4 months
  1. Preschool boost of DtAp/Polio (4 in 1)
  2. MMR (2nd dose)
• 12-13 years (girls)
  1. HPV - 2 injections (2nd after 6-12 months)
• 14 years
  1. Td/polio booster (3 in 1)
  2. Men ACWY
• Adults
  1. Influenza and PPV over 65y/o and high-risk groups
  2. DTaP - pregnant women from 20wks to protect baby against pertussis
  3. Shingles - over 70y/o