HIV Flashcards
HIV structure
Two identical (+)RNA Enveloped
Three essential enzymes: - reverse transcriptase - integrase - protease Complex - also has regulatory enzymes (immune modulators, regulation of virion production)
Classification of HIV
aka Human T-cell lymphotrophic virus (HTLV)
Retrovirus -> lentivirus subtype
Not an oncovirus
HIV 1 = most prevalent
HIV 2 = West Africa, both cause AIDS
HIV replication
Attachment -> co-receptor required -> fusion
Reverse transcriptase -> DNA -> integrase ->
Transcription -> translation -> processing (protease) ->
Assembly -> budding -> maturation (protease)
HIV tropism
Viral gp120 -> CD4
- Th (CD4+), also monocytes/macrophages, dendritic, glial
Coreceptor necessary for binding
- CCR5 = chemokine receptor (mutation -> resistant to HIV)
- also can use CXCR4
Fusion = gp41 (viral)
Integration of HIV
Fusion -> entry
Reverse transcriptase: three different functions
ssRNA -> RNA-dep DNA -> ssDNA -> RNAse activity -> DNA-dep DNA -> dsDNA
-> nucleus
Integrase necessary for integration
HIV production
Requires activation of T cell (via immune response)
Active transcription -> mRNA -> translation
Protease cleaves -> assembly
HIV RNA disrupted by APOBEC3G but virus inhibits this with Vif
Maturation - after budding, via protease action
HIV latency
Integrates into T cells
- many T cells are latent (ie memory)
- little transcription
Forms reservoir in host
Can also have low levels of virion production (cell stays alive) vs high levels of production -> cell death
HIV mutations
Reverse transcriptase and host RNA-polymerase
- neither has proofreading function
1: 5-10 virions are mutated (1 billion/day)
HIV transmission
Sex: - Anal > vaginal, receptive > penetrative, oral Blood: - IVDU probably highest risk - also needle sticks, occupational Maternal - child: - 25% in transplacental and perinatal (more common) - 25% breastfeeding
Additional risks:
VIRAL LOAD correlates with risk
Mucosal injury or infection (ex STDs)
HIV prevention (the basics)
Condoms
+ prophylactic ARVs effective if high risk
Circumcision - works in some populations
Microbicidals (ie vaginal cream) - in testing
Don’t share needles
Blood supply quality controls
Testing and treatment
HIV pathogenesis
Acute infection = super high viral load, drop in CD4 (infected and inflammatory cell death)
- CD4 cells respond to infection -> activation -> makes more virions (vicious cycle…)
- cytokines, CD8 -> antibodies -> partial immune control (“set point”) ->
Chronic - still actively making virions in lymphoid tissue
Acute HIV presentation
Similar to mono:
- fatigue, fever, headache, sometimes rash
- lymphadenopathy
Diagnose through viral load (super high)
- not yet making antibodies (seroconversion takes 2 months)
HIV “set point”
Transition from acute to chronic infection
- represents partial immune control
- lowest viral production level (will amplify from there as more CD4 activated)
Only true predictor for progression of disease
Chronic HIV infection
Often asymptomatic
Diagnosis - antigen and antibody by ELISA -> Western Blot
Active production of virus in lymphoid tissue (10 billion/day)
- constant mutation to evade immune response (Ab, CD8)
Immune activation
-> kills CD4 (1 billion/day, most through activation-induced)
- HIV proliferates
Slow decline in CD4
Definition of AIDS
Presence of opportunistic infection
HIV+ and CD4 <15% lymphocytes
Progression to AIDS
Usually takes 5-10 years (8 average without tx)
Predicted by viral load at set point
- women start with lower viral loads but progress faster
Monitor BOTH
- viral loads - progression of HIV
- CD4 count - susceptibility to infection
AIDS pathophysiology
Severe depletion of CD4
-> depletion of CD8 number and function
Death (within two years)
- opportunistic infection (viral, parasitic, fungal, bacterial)
- malignancy - cervical, anal, brain, B cell lymphoma
- other causes (psych, cardiovascular)
AIDS opportunistic infections
Severe/reactivated: Hep B and C HSV Zoster CMV EBV -> oral hairy leukoplakia Molluscum contagiosum JC -> progressive multifocal encephalopathy
Tumor viruses:
HHV8 -> Kaposi’s sarcoma and B cell lymphoma
EBV -> Burkitt’s lymphoma
HPV -> anal, cervical cancer
Indications for ARV therapy
AIDS-related infection CD4: 500 possible Pregnancy (mother to child transmission) Nephropathy Hep B coinfection
Will reduce viral load, restore immune system (CD4)
Must be compliant/adherent to prevent resistance
HAART
Highly active anti-retroviral therapy
3 drugs from at least 2 different classes (mechanisms)
- usually nRTI, nnRTI, PI (others saved for resistance, second line)
- improves CD4
- reduces viral load (to undetectable, but still HIV+)
- less risk of resistance
Complications during HAART
Immune reconstitution syndrome
- more CD4 -> inflammation if co-infection (ex hepatitis)
NeuroAIDS - 25% develop memory or cognitive loss
HIV still replicating in lymph, retina, brain, testes
Nucleoside Reverse Transcriptase Inhibitors
NRTI
Similar structure to nucleosides but no 3’ OH group
Converted to nucleotide triphos -> incorporate -> terminate chain
Either reverse transcriptase step (ssDNA or dsDNA)
No dsDNA is produced to be integrated into cell
Ex AZT
Non-Nucleotide Reverse Transcriptase Inhibitors
NNRTI
Bind near active site
Prevent enzymatic action
Prevent production of dsDNA -> no integration
Protease inhibitors
Bind near active site and prevent enzymatic action
Protease necessary for maturation of budding virions
- new virions don’t become infectious
Fusion inhibitors
Block gp41 fusion complex -> no entry into cell
Similar:
CCR5 antagonist - blocks host cell co-receptor (needed for fusion complex to form)
Integrase inhibitors
Block enzymatic action of integrase
Provirus can’t be integrated, transcribed
Classes of ARV meds
Nucleoside RT Inhibitors Non-nucleotide RT Inhibitors Protease Inhibitors Integrase Inhibitors CCR5 antagonists Fusion inhibitors
