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40 Cards in this Set
- Front
- Back
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HIV-1 and HIV-2
Overview |
Belong to Lentivirus group of retroviruses
Contain the same group of genes as the “simple” retroviruses: Gag, Pol, and Env Additionally encode Auxiliary proteins not found with other retroviruses HIV-1 and HIV-2 differ in severity and timeline of disease -HIV-1 is world wide, HIV-2 is largely restricted to Africa Contain essentially the same viral proteins |
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HIV Modes of Transmission
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Unprotected sex with infected partner: 1 in 1000 risk
Sharing needles: 1 in 150 Mother to fetus: 1 in 4 Transfusion 95 in 100 |
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Characteristics of Lentivirus Infections
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Long incubation periods
High mutation rates -ss RNA virus with no “proof-reading” mechanism -Copy-choice recombination between two strands of RNA during genome replication -Virus packages two “identical” strands of genomic RNA Three phases of disease A. Acute transient disease phase – “flu-like” symptoms B. Latent phase – immune system controls virus, asymptomatic (provirus integrated into chromosome) C. Active replication resumes –typically many years after initial infection, immune suppressed |
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HIV Envelope protein
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Often referred to as gp160
Synthesized in ER and is glycosylated Nicked by protease in Golgi which results in two subunits: -SU (surface) and TM (transmembrane) portions gp120: receptor binding domain gp41: fusion part -fusion of incoming virion with plasma membrane of cell its infecting -cell to cell fusion, syncitia |
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gp120 receptor
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CD4 is the Major Cellular Receptor for HIV gp120
Few individuals that are resistant to HIV infection. Fusion and entry also requires a co-receptor – Chemokine receptor. -CCR5 for Macrophage-, and T cell-tropic strains (dual tropic): Slow replication, non-syncytia inducing. -CXCR4 for T-cell-tropic strains: Rapid replication, induces syncytia and rapid T cell death |
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Co-receptor specificity changes during the course
of HIV Infection |
Virus begins as R5 and evolves into X4
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Initial Interactions of HIV with Mucosal Surface and Lymph Nodes
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Initial infection at mucosal surface
DC or macrophages thought to be first cells that HIV interacts with. Transport to lymph node via infected DC, macrophages or T cells. Begin spread into T cells. Ab responses are generated Follicular DC or macrophages may be reservoir of latently infected cells. |
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HIV acute infection to chronic infection to clinical symptoms
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HIV infects 1 of 3 cells: T-cells, DC, mac
DC go to lymph nodes and serve as reservoir for provirus Macs latent or low level infection reactivated by cytokines which produces virions that disseminate T-cells provirus latently infected or low level infection. Antigenic or cytokine stimulation leads to reactivations. CD4 cell lysis and depletion. Opportunistic infections, malignancy, dementia take place. |
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Steps in HIV Growth Cycle are Similar to “Simple” Retroviruses
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Attach, penetrate, uncoat
Reverse transcribe RNA to double-stranded DNA Integrate (recombination) into host DNA Gene expression - transcription, splicing, mRNA transport, translation Assembly, budding, maturation |
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The Timing of Expression of HIV Auxilliary Proteins is Important
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Early auxilliary proteins:
-Tat (transcriptional activator) -Rev (regulator of viral proteins) -Nef (negative regulatory factor) Goal is to modify host machinery, facilitate viral gene expression Late auxilliary proteins: -Vif (virion infectivity factor) -Vpr (virion protein regulator of transcription) -Vpu (Virion protein for efficient budding) Goal is to facilitate expression of structural proteins; Improve Infectivity. |
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Two Phases of Transcription directed by Provirus form of HIV Genome
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Early:
Transcription from the LTR produces full length viral genome This is spliced (default pathway) multiple times to produce mRNAs for Tat, Rev, Nef Late: Splicing is inhibited (similar to simple retrovirus) Transport of full length unspliced copy of genome or singly spliced mRNA produces gag, pol, env, etc. Two key regulators: The HIV Tat and Rev proteins. Both Tat and Rev are RNA binding proteins. -Rev binds to the rev-response element RRE to control splicing of HIV transcription products. -Tat binds to the Tat-associated RNA element TAR to enhance transcription by cellular Polym |
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The HIV Rev Protein Controls Early/Late Gene Expression
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-Three proteins are made in the absence of rev – rev, tat, nef. (Early)
-When rev is present, rev binds to RRE and inhibits splicing. (late) -Proteins needed for late functions (e.g., assembly) are produced by unspliced or singly-spliced mRNAs. |
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TAT binds to TAR to Promote HIV Transcription
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Makes cellular polymerase more processive (ability to stay on template)
1 – Cellular RNA polymerase starts to transcribe genome beginning in the LTR. Newly synthesized RNA containing the HIV TAR (tat-response) sequence emerges from the RNA polymerase. 2 – The HIV Tat protein binding specifically to the TAR sequence. 3 – This Tat-TAR complex acts on the cellular polymerase (with other cellular proteins) to increase efficiency of transcription In the absence of Tat, transcription of the provirus genome is aborted. |
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VPU
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Inhibits Cellular Tetherin Which Would Otherwise “Tether” Progeny Particles to the Plasma Membrane
Tetherin is an interferon-inducible protein which prevents HIV from releasing from the infected cell. Vpu is an HIV protein which inhibits tetherin to promote dissemination. Expressed late |
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General Classes of HIV Inhibitors
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Reverse Transcriptase Inhibitors – nucleoside derivatives
-e.g., AZT; competitive inhibitor of RT and a chain terminator; rapid resistance seen due to point mutations in RT, etc. Reverse Transcriptase Inhibitors – Non-nucleoside derivatives -e.g., Nevirapine; noncompetitive binding to pocket near active site of RT Protease Inhibitors e.g., Saquinavir; peptide mimics that resemble substrate for the protease Glycoprotein Inhibitors – blocks gp41-mediated fusion -e.g., T20, enfuviritide Other Targets: Integrase, NC, MA, and Nef |
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HIV mechanism of immune evasion
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-Makes 10 billion copies/day -> rapid mutation of HIV antigens
-Integrates into host DNA -Depletes CD4 lymphocytes – syncytia, apoptosis. -Down-regulation of MHC-I process -Impairs Th1 response of CD4 helper T lymphocyte -Infects cells in regions of the body where antibodies penetrate poorly, e.g., the central nervous system |
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What contributes to challenges for HIV therapies
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-Lack of knowledge on what specific immune responses are essential for protection.
-No clear animal models that accurately reflect human infection -Glycoprotein is poorly immunogenic -Virus attacks cells of immune system and promotes opportunistic infections. -Enormous replication capacity with vast populations of mutants -Most complex of the retroviruses with many auxiliary proteins |
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When should HIV treatment begin?
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Symptomatic HIV or history of AIDS defining illness
Asymptomatic disease -Everyone with CD4 count < 350/µL -Recommended if CD4 count 350-500 Individualize if CD4 count >500 (optional) |
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HIV Treatment Special considerations
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Pregnancy (need to start antiretroviral)
HIV-associated nephropathy (HIVAN) (need to start antiretroviral) Chronic HBV (need to start antiretroviral) or HCV infection Discordant couples High viral load (HIV RNA > 100,000c/mL) Rapid rate of CD4 decline (>100/year) Risk factors for non-AIDS diseases Acute HIV |
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Co-receptor antagonists
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HIV is tropic for CCR5 (R5) or CXCR4 (X4)
-R5 tropism found in most patients -Conversion to X4 in latter stages of disease -Dual/mixed virus Maraviroc (Selzentry) – R5 antagonist -Tropism assay required before therapy -Alternative for naïve patients or as salvage No X4 antagonists available |
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Fusion Inhibitor
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Enfuvirtide
ENF, Fuzeon® 36-amino acid peptide Binds to a portion of gp41 to prevent gp41-mediated fusion of viral surface with CD4 cell membrane SC injection BID Must be combined with effective background regimen (pills) No cross-resistance (yet) |
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Reverse Transcriptase Inhibitors Mechanisms
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NRTIs (nucleoside reverse transcriptase inhibitors)
-False nucleoside analogs -Cause termination of DNA chain elongation -Parent compound must be phosphorylated by cytoplasmic or mitochondrial kinases and phosphotransferases to 5’-triphosphate Non-NRTIs (NNRTIs) -Noncompetitively bind to and inhibit reverse transcriptase Standard treatment is two "nukes" plus a drug from another class -don't want to use two nukes that target same nucleoside |
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NRTIs "Nukes"
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Abacavir - G
Didanosine - A Tenofovir - A Emtricitabine - C Lamivudine - C Stavudine - T Zidovudine - T |
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Combination formulas
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Combivir (zidovudine + lamivudine)
Trizivir (zidovudine + lamivudine + abacavir) Epizicom (lamivudine + abacavir) Truvada (emtricitabine + tenovir) Atripla (emtricitabine + tenofovir + efavirenz) -1 pill 1 time a day Complera (emtricitabine + tenofovir + rilpivirine) - 1 pill 1 time a day |
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Notable NRTI adverse effects
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Abacavir - hypersensitivity
Didanosine - pancreatitis, peripheral neuropathy Emtricitabine - none Lamivudine - none Stavudine - lipoatrophy, lactic acidosis, peripheral neuropathy Tenofovir - renal dysfunction Zidovudine - headache, anemia, lipoatrophy |
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Lactic acidosis
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Related to NRTI-induced mitochondrial dysfunction
-Greatest risk with stavudine Must have high clinical suspicion -frequently misinterpreted as viral enteritis Up to 50% fatal Early symptoms -Nausea, vomiting, fatigue, abdominal pain, weight loss, dyspnea - +/- liver failure Lab values -Decreased bicarbonate, increased lactate, increased anion gap, +/- increased LFTs |
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Abacavir Hypersensitivity
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5-6% incidence; higher in whites
Usually occurs within first 6 weeks Generalized symptoms (flu like AND rash) -Fever -GI: nausea, vomiting -Fatigue -Respiratory: cough, SOB, sore throat -Rash Resolves upon discontinuation Fatal cases reported Practically no risk if not HLA B5701 |
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NNRTIs "Non-nukes"
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Nevirapine (Viramune)
Hepatotoxicity risk -Risk depends on baseline CD4 count -Women >250 -Men >400 Etravirine (Intelence) -Active against HIV resistant to efavirenz -Primarily prescribed as salvage -Studies ongoing for naïve patients Rilpivirine (Edurant) -Probably not as potent Delavirdine (Rescriptor) Efavirenz (Sustiva) -preferred treatment |
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Notable NNRTI adverse effects
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Class adverse effects
-Rash -Hepatotoxicity Efavirenz: CNS effects -Dizziness -Drowsiness -Vivid dreams |
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Integrase Inhibitors
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Raltegravir (Isentress)
-Rate of virologic suppression faster than any antiretroviral yet -Resistance development mimics NNRTIs (low threshold) Elvitegravir in development -“Quad” pill Very well tolerated |
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Protease Inhibitors Mechanisms
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A precursor polyprotein must be cleaved by viral protease to form structural proteins as well as viral encoded enzymes (RT, integrase, protease)
Cleavage of the polyprotein by protease is necessary for the formation of infectious virions |
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Protease Inhibitors (“PIs”)
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Atazanavir
Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir |
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Notable PI adverse effects
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Class effects
-Gastrointestinal adverse effects -Hyperlipidemia (less with atazanavir, darunavir) -Lipodystrophy Atazanavir – hyperbilirubinemia, jaundice, scleral icterus Saquinavir – QT prolongation Indinavir – nephrolithiasis Lopinavir/r, nelfinavir – diarrhea |
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Metabolic Complications: “Lipodystrophy”
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Lipid abnormalities
-Increased LDL -Increased triglycerides Glucose intolerance -Type 2 diabetes -Insulin resistance Body fat composition abnormalities |
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Ritonavir Boosting
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Ritonavir is a potent inhibitor of cytochrome P450 enzymes (CYP450)
Inhibits CYP450 mediated metabolism of other protease inhibitors Increases concentrations of other PIs Reduces pill count Minimizes resistance due to incomplete adherence (?) |
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Boosted PIs
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Co-formulated with lopinavir (Kaletra)
Atazanavir & darunavir – primary therapies or as salvage Fosamprenavir -Twice daily to once daily dosing Saquinavir – improves PK Tipranavir – salvage therapy |
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Standard initial treatment
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One PI and two NRTIs
OR One NNRTI and two NRTIs OR Raltegravir and two NRTIs |
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DHHS “preferred” regimens for naïve patients
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NNRTI - Based
-Efavirenz plus tenofovir and emtricitabine -1 pill PI - Based -(Atazanavir/r or Darunavir/r) plus tenovir and emtricitabine -3 to 5 pills Integrase inhibitor based -raltegravir plus tenofovir and emtricitabine -3 pills |
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Resistance Testing
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Genotype
-Detects codon mutations in RT and protease genes that confer resistance to specific drugs Phenotype -Detects increases or decreases in the IC50, relative to wild-type virus (similar to an MIC) Virtual phenotype -Genotype with results expressed like phenotype |
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Impact of reducing inflammation
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Slower development of chronic diseases
-Heart disease -Kidney disease -Liver disease Limit additive effects on underlying chronic diseases, e.g. diabetes, hypertension Optimize life expectancy and improve mortality |
