HIV Flashcards
What are examples of human retroviruses?
Retriviral DNA exists in human genome as product of evolution. Does not produce infectious virus
Family - retrovirus Sub-family - orthoretrovirinae Genus - lentivirus Species - HIV1 HIV2 - West Africa, less virulent
Family - retrovirus
Sub-family - orthoretrovirinae
Genus - deltavirus
Species - HTLV1/ HTLV2 - West Indies/ Japan.
Also known has tropical spastic paraparesis. T- cell leukaemia
What is structure of HIV virus
GP41/ GP120 envelope glycoproteins
Lipid mebrane - host derived
Matrix protein p17
Single stranded RNA
RT
Integrase
Virion core proteins - p7, p9, p 24
HIV nuclear material is two copies of positive sense SS RNA.
It codes for virion proteins/ regulatory proteins.
What virion proteins does it code for?
LTR
gag
pol
env
HIV nuclear material is two copies of positive sense SS RNA.
It codes for virion proteins/ regulatory proteins.
What regulatory proteins does it code for?
nef
rev
tat
vif
vpr
vpu
What do these HIV virion proteins code for?
LTR
gag
pol
env
LTR - long terminal repeat promotes transcription/ replication
gag - virion core proteins -
- p7
- p9
- p17 - matrix
- p24 - nucleocapsid
pol - RT, integrase, protease
env - gp160 glyocprotein which is cleaved into gp120 and gp41
gp 41 and gp 120 formed from env gene.
What are their roles?
gp 120 - attachment protein
gp 41 - fusion protein
What do these HIV regulatory proteins code for?
nef
rev
tat
nef - negative regulatory factor - important for virulence
rev - promote export viral RNA from nucleus
tat - transactivator protein regulates viral transcription
What do these HIV regulatory proteins code for?
vif
vpr
vpu
What do these HIV regulatory proteins code for?
vif - virion infectivity factor
vpr - weak transcriptional activator
vpu - for efficient budding
What is replication cycle of HIV?
Absorption of HIV gp120 onto CD4 cell Fusion via GP41 Penetration Uncoating Reverse transcription of positive sense ssRNA into DNA Integration into host DNA - now provirus
Transcription of viral mRNA and progeny RNA
Translation of viral proteins
Assembly of virions
Budding via envelope proteins
HIV also binds to dendritic cells/ macrophages, which transport to lymph nodes, which helps spread infection to other CD4 cells
Most CD4 cells die. Only few survive to continue HIV virion production
HIV-2 confined to West Africa, originally zoonosis from sooty mangabeys
HIV-1 has different groups, what are they?
During transmission from chimpanzees, groups evolved.
M - major. 90% of cases, worldwide distribution. Emerged between 1910-1930 in West Africa
N - new. West Africa. Very rare
O - outlier. West Africa
P - only one case ever
HIV1 group M (major), has further subtypes, based on geographical spread. What are they?
Subtype A: Central and East Africa, Eastern Europe
Subtype B: West and Central Europe, the Americas, Australia, South America, and several southeast Asian countries (Thailand, and Japan), as well as northern Africa and the Middle East. Most common in UK
Subtype C: Sub-Saharan Africa, India, and Brazil.
Subtype D: North Africa and the Middle East.
Subtype F: South and southeast Asia.
Subtype G: West and Central Africa.
Subtypes H, J, and K: Africa and the Middle East
CRF - circulating recombinant types, due to recombination between different subtypes
HIV virus uses gp120 to bind to CD4 receptor on which cell types?
T-helper cell Monocyte Dendritic cell Langerhans cell Microglia
HIV virus binds gp120 to CD4. What other receptors are required for entry?
chemokine co-receptor CCR5 absolutely required
CXCR4 co-receptor is also desired by virus
If CCR5 gene deletion, host can be resistant to HIV progression- elite controllers 0.3%.
Once infected Th rests in lymphoid tissue, it can continue to produce new virions. If Th cell becomes activated, cell will die.
What is immune response to HIV infection?
CD8 T cells which kill infected cells
B cells produce antibodies directed towards infected cells
CD4 Th cells directly killed by virus, undergo apoptosis, damaged by CD8/ B cells
As Th count decreases, immune response wanes, and HIV load rises
Why does having another STI increase risk of HIV transmission?
Other STIs cause genital ulcers/ discharge, which can provide route for HIV transmission
Uncircumcised males more likely to be affected
What are transmission routes of HIV?
Blood transfusion - haemophiliacs
IVDU/ tattoo/ accupuncture/ needlestick
Sex
Vertical - up to 50% of HIV mothers will pass on to children (if untreated). Avoid breast-feeding, perform C-section
What are initial symptoms of HIV infection?
fever
malaise
maculopapular rash
lymphadenopathy
Can invade CNS and cause self-limiting aseptic meningitis
After initial HIV exposure, what tests can be used to diagnose HIV, and when are they used in timeline?
Can also perform genome sequencing to assess antiretroviral drug resistance and tropism (CCR5/ CXCR4)
p24 antigen - 1-8 weeks after exposure, then levels will drop as Ab produced
HIV antibody - 4 weeks 95% will test positive. If negative, can check up to 12 weeks after exposure
Diagnosis is infants is difficult as passively acquired IgG will be detected up to 12 months after birth. Test infant at various intervals from 12-24 months
Tests available:
p24 antigen
HIV RNA
HIV proviral DNA - check mother will always remain positive
HIV antibody
Point-of-care tests - less sensitive/ specific
How is HIV viral load measured?
RT-PCR of HIV RNA
AIDS is when:
- patient with HIV antibodies
- develops opportunistic infections (usually CD4 <200)
What are viral opportunistic infectious?
CMV - retina, brain, GI
HSV - lungs, GI, CNS, skin
JC - brain PML
EBV - hairy leukoplakia, primary cerebral lymphoma
HHV8 - Kaposi sarcoma
AIDS is when:
- patient with HIV antibodies
- develops opportunistic infections (usually CD4 <200)
What are bacterial opportunistic infectious?
Mycobacterium tuberculosis - disseminated/ extrapulmonary
Mycobacterium avium
Salmonella dissemninated
Also higher risk of common bacterial pathogens - streptococcus/ haemophilus
AIDS is when:
- patient with HIV antibodies
- develops opportunistic infections (usually CD4 <200)
What are protozoal/ fungal opportunistic infectious?
Cryptococcus neofromans - CNS
Coccidioides
Histoplamosis
PCP
Toxoplasma
Cryptosporidium
Isospora
What are ways to reduce HIV spread?
Combatting HIV/ AIDS was 6th Millenium Development Goal
Change sexual behaviours - condoms
Pregnant women start ART after first trimester
Treat other STIs
Clean needles
Blood product screening
HIV transmission can be explained via R0 equation. What are factors in this?
R0 >1 epidemic spread can occur
R0 <1 infection will eliminate
R0 is proportional to C x beta x D
C - is the average rate of contact between susceptible and infected
individuals
beta - transmissibility - probability of HIV transmission per given exposure e.g anal intercourse has 1.65 % risk transmission
D - duration of infectious period
What are risk factors for more rapid progression of HIV?
Female Older Depression Poor pre-morbid nutritional state Certain HLA types Co-infection HBV/HCV/ TB can alter immune system
WHO HIV staging is grouped into:
Primary HIV infection
Clinical stage 1 - asymptomatic
Clinical stage 2 - mild symptoms (CD4 <500)
Clinical stage 3 - moderate symptoms (CD4 200-500)
Clinical stage 4 - severe symptoms (CD4 <200)
On average, untreated it will take 8-10 years from HIV acquisition to AIDS. WHO staging does not use CD4 count
What symptoms might primary/ clinical stage 1 have?
Asymptomatic - time from acquisition of virus, to development of HIV antibody, HIV p24 antigen or HIV RNA
Viral illness - fever, malaise, sore throat, lymphadenopathy, maculopapular rash - approx 50% of patients
WHO HIV staging is grouped into:
Primary HIV infection
Clinical stage 1 - asymptomatic
Clinical stage 2 - mild symptoms
Clinical stage 3 - moderate symptoms
Clinical stage 4 - severe symptoms
What symptoms might primary/ clinical stage 2 have?
Moderate weight loss - <10% body Recurrent URTI VZV Angular chellitis Recurrent oral ulceration Sebhorrhoeic dermatitis Fungal nail infections
WHO HIV staging is grouped into:
Primary HIV infection
Clinical stage 1 - asymptomatic
Clinical stage 2 - mild symptoms
Clinical stage 3 - moderate symptoms
Clinical stage 4 - severe symptoms
What symptoms might primary/ clinical stage 3 have?
Unexplained weight loss >10% body
Chronic diarrhoea - two or more loose stools per day
Persistent oral candidiasis
Oral hairy leukoplakia
Pulmonary TB
Severe bacterial infections - pneumonia, meningitis
WHO HIV staging is grouped into:
Primary HIV infection
Clinical stage 1 - asymptomatic
Clinical stage 2 - mild symptoms
Clinical stage 3 - moderate symptoms
Clinical stage 4 - severe symptoms
What symptoms might primary/ clinical stage 4 have?
HIV wasting syndrome - >10% weight loss and diarrhoea PCP Recurrent severe bacterial pneumonia Oesophageal candidiasis Extrapulmonary TB KS CMV Toxoplasmosis HIV encephalopathy Cryptococcus Cryptosporidiosis Isosporiasis Coccidiomycosis Histoplasmosis Non-typhoidal salmoneall Lymphoma - cerebral or B-cell non Hodgkin Cervical carcinoma HIV neuropathy
What are the UNAIDS 90-90-90 targets?
90% living with HIV, know their status
90% diagnosed with receive ART
90% on treatment will have suppressed viral loads
What is U=U in regards to HIV?
Undetectable viral load = transmissible
Data on 58 000 episodes of unprotected sex in HIV individuals, showed no transmission
Patient presents 8 weeks after unprotected sex, with fever, sore throat.
HIV p24 positive
HIV antibody negative
What steps should you take next
Diagnosis is primary HIV infection
Need to refer to HIV specialist and start ART within 2 weeks
Early ART is associated with better preservation of immune function, CD4 count, morbidity associated with high viraemia, and reduced risk of transmission. It may also prevent HIV developing a reservoir in deep lymph nodes.
If initial HIV test positive, what are next steps labs take to confirm this?
Initial diagnosis on Architect
Use same sample to confirm on VIDAS
New sample to confirm on Archiect
Geenius to check HIV1/HIV2 as different treatment
Viral load by PCR
Whole genome sequencing for resistance pattern
After initial HIV diagnosis, baseline laboratory tests are required.
HIV related/ other infectious/ metabolic
What are HIV related tests?
Confirm HIV1/HIV2
Viral load
Genotypic resistance testing
CD4 T cell count
Viral tropism test is sometimes performed, if considering CCR5 inhibitor as first line therapy
If PCP - consider G6PD if needing dapsone/co-trimxoazole/primaquine as contraindicated otherwise. African/ mediterranean/ Chinese
After initial HIV diagnosis, baseline laboratory tests are required.
HIV related/ other infectious/ metabolic
What are other infectious agents to test for?
viral/ bacterial/ protozoal
Viral
HAV IgG
HBV surface antigen/ core antibody
HCV IgG
EBV/ CMV - serology initially, but can be negative in HIV. Check viral load buy PCR
Measles IgG - if no history of vaccine/ infection
Varicella IgG - if no history of vaccine/ infection
Rubella IgG - in women of child-bearing age
Note - vaccine preventable diseases -
HAV/ HBV/ Measles/ varicella/ rubella
Bacteria
Chlamydia NAAT
Gonorrhoea NAAT
Syphilis serology
IGRA
Sputum for AAFB - BAL
Protozoa/ fungal CrAg Toxoplasmosis Strongyloides Giardia Beta-d-glucan/ galactomannan
Must screen partner/ children
After initial HIV diagnosis, baseline laboratory tests are required.
HIV related/ other infectious/ metabolic
What metabolic tests are required?
FBC U+Es LFTs Bone Lipids Glucose
Urinalysis
Urine PCR - if proteinuria
Pregnancy test
HLA-B*57:01 - if abacavir being considered
When do perform HIV resistance testing?
At baseline
At commencement of ART if there is a delay
Suboptimal viral load response to therapy - <1 log10 drop in 4 weeks
Virological failure - viral load >200 copies/ml on two samples while on ART. Always perform whilst on ART - as otherwise resistant strain will become smaller part of opulation
On CSF samples if CSF viral load detectable on therapy
Pregnancy - if detectable viral load at week 36 of pregnancy
If on CCR5 antagnoist, and has virological failure, check tropism to ensure no tropism switch
Pregnant women with HIV, starting ART.
When should repeat viral load be measured?
Baseline 2-4 weeks after starting ART (first trimester) Second trimester 36 weeks (third trimester) Time of delivery
Children born to HIV infected mothers.
When should HIV testing be performed?
HIV proviral DNA or RNA PCR -
- Within 48 hours of birth
- 6 weeks of age - after completing 4 weeks anti-retroviral prophylaxis
- 12 weeks of age - two months after completing prophylaxis
- Monthly if breastfeeding is taking place, to detect late transmission
HIV antibody testing -
- 18 months - following loss of maternal antibodies at this time
- 6 weeks after stopping breastfeeding
What are elite controllers?
What are negatives to this?
Have HIV antibodies, but no HIV RNA in blood, and normal CD4 count.
Usually lacking CCR5 gene, so HIV cannot bind
Studies show they are in low grade inflammatory state, and may have more issues with illness compared to those on ART
When must HIV post-exposure prophylaxis be taken?
Within 72 hours of exposure
Patient commenced on ART, 4 weeks later viral load has not dropped by 1log10. Resistance testing initially negative
What is the next step?
Check medication compliance/ drug side effects
Re-check HIV resistance testing. Testing can detect resistant species if make up 25% of virus population. So if <25% of population, will not be detected. Once ART given, these resistant strains can emerge, and become dominant population, which can be detected.
When checking CD4 count and viral load, how often do you need to check CD4 count?
If patient has CD4 count >350, on two occasions, with low viral load, then no longer need to check. As we can presume CD4 will be higher than this.
Re-check if new symptoms, or signs of treatment failure.
When should ART be initiated?
Within two weeks from diagnosis, regardless of CD4 count
Hold if TB meningitis
What classes of ART exist?
NRTI - nucleoside/ nucleotide reverse transcriptase inhibitor
NNRTI - non-nucleoside reverse transcriptase inhibitor
Protease inhibitor
Fusion inhibitor
INSTI - integrase strand transfer inhibitors
