4.1 WHITT HIV Flashcards
Characteristics of HIV
Retroviridae family (lentivirus subfam)
-non-oncogenic, cytopahtic retrovirus
-life-long persistence; high mutation rate
Stages: Acute, Latent, Symptomatic
Cell Tropism
- CXCR4 (t-tropic) and CCR5 (m-tropic)
- Usually starts as CCR5 and transforms to CXCR4
- NSI= Non-syncytium inducing
- SI= Syncytium inducing (envelope), CXCR4 are SI
Genome Organization
- Long-terminal Repeats (LTR) at ends
- -serve as promoters for host RNA polymerase II following integration
- Accessory proteins: tat, rev, nef, vpr, vpu, vif
HIV Entry
Bind CD4 first: induces conformational changes in gp120
- gp120 next binds one of several chemokind coreceptors
- coreceptor that is used dictates cell tropism
- coreecptor binding induces additional conformational changes, activates gp41, induces membrane fusion
Reverse Transcription and Replication
- After entry RNA genome is converted to a linear ds DNA molecule by reverse transcriptase
- This conversion is obligatory step in retrovirus replication (drug target)
Integration
DNA intermediate is inserted into the chromo DNA of the cell
- Integrase does (target) and now called provirus.
- Unique feat: HIV integration does not require cell division, HIV can integrate and replicate in non-dividing, terminally diff cells
- 3 steps: (1) integrase trims ends of provirus (2) cleaves host DNA at random sites (3) joins ends of the virus and host DNAs
HIV gene expression
2 phases:
-Early: viral regulatory proteins, low level expression, provirus is not transcribed in resting T cell
Late: structural protein syn, high level syn due to activity of tat and rev (transport of unspliced mRNAs from nucleus***)
HIV Assembly and Release
- Assembly occurs in the plasma membrane of host
- -packing of RNA genome into core
- -release of particles by budding
- -budding requires cellular ubiquitin ligases
- Maturation cleavage of core proteins by viral proteases
- Dimerization of gag-pol generates the active proteases
- -provides another target
- -protease inhibitors result in release of non-infectious particles
Route of Transmission
-sex
-Blood and blood products
perinatal transmission (~20% w/o prophylactic treatment)
Sources of Virus: body fluids (semen, ceverical secretions, breast milk)
Body fluids w/ low amounts: urine, saliva, tears, CFS
Acute Phase
Symptoms: infection, influenza-like illness w/ fever, maliase, headache, diarrhea, lymphadenopathy
–3 to 6 months after infection, high-level viremia, detectable immune response
Asymptomatic
Clinical latency
- mild or no clinical synmptoms
- slight rebound in CD4 T cells, then steady decline
- *virus cont to replicate at high levels
Symptomatic Infections
AIDS
- once CD4 drop to <200/ml
- patient becomes susceptible to opportunistic infection and AIDS related cancers
Predict Disease Progression
- Correlation b/t CD4 counts and risk for progression
- Strong correlation b/t viral load and disease onset
HIV resistance
- Long-term survivors
- Elite controllers (never develop symptoms)
- Mutation in CCR5 gene can make resistant to infection, hetero ~2yr delay in disease progression
- Infection with Nef mutants: some long-term survivors were infect Nef-deleted
Reverse Trans Inhibitors
- Nucleoside analogs: AZT, d4T, 3TC
- -all bind to RT with high affinity; disrupt DNA chain elongation-synthesis
- Non-nucleoside inhibitors: binds to regions adjacent to NTP binding pocket, inhibits synthesis of provirus DNA
