4.1 WHITT HIV Flashcards Preview

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Flashcards in 4.1 WHITT HIV Deck (19):
1

Characteristics of HIV

Retroviridae family (lentivirus subfam)
-non-oncogenic, cytopahtic retrovirus
-life-long persistence; high mutation rate
Stages: Acute, Latent, Symptomatic

2

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

3

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

4

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

5

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)

6

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

7

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***)

8

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

9

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

10

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

11

Asymptomatic

Clinical latency
-mild or no clinical synmptoms
-slight rebound in CD4 T cells, then steady decline
**virus cont to replicate at high levels

12

Symptomatic Infections

AIDS
-once CD4 drop to <200/ml
-patient becomes susceptible to opportunistic infection and AIDS related cancers

13

Predict Disease Progression

-Correlation b/t CD4 counts and risk for progression
-Strong correlation b/t viral load and disease onset

14

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

15

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

16

Protease Inhibitors

Bind to active site on the protease and prevent gag-pol cleavage, prevents formation of mature viron

17

Entry inhibitor

-Fuzeon: peptide that binds gp41 and prevents membrane fusion, given s.c. injection 2x day, used in treatment-experience pts that are failing HAART
Selzentry:
-Newest
-CCR5 antagonist, tablet 2xday, treatment-experience pts

18

Integrase Inhibitor

Newest class of drugs
-sp inhibits the final step in integration, strand transfer of viral DNA to host cell DNA

19

Treatments

Usually give about 3 medications
-when you change one drug you change all the drugs