/mi/prednasky/HIV_2005.ppt

  • 545 views
Uploaded on

 

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
545
On Slideshare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
15
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. HIV 1981 objeven 1983 izol. retrovir - Pasteur institute 1984 izol. retrovir - NIH 1986 název HIV do 2002 20 mil. mrtvých 2002 5 mil. nově infikovaných 2002 42 mil. infikovaných – 1 ze 100 mezi 15 a 49 r. Subsaharská Afrika 2,4 mil. mrtvých 25-30% osob infikováno 1/3 dětí mladších 15 let ztratilo rodiče
  • 2. Od HIV+ k AIDS • 10% infikovaných lidí do 2-3 let AIDS • 80% do 10 let progrese viru – z nich polovina AIDS • 10-17% AIDS free po více než 20 let • HIV II mnohem pomalejší – navíc Vpx, • Větší nebezpečí když aktivovaný imun systém – více aktiv. T-lymf. + aktivní Nf-kappaB • Delece v Nef, MHC I alely, chemokinové receptory
  • 3. Články pro příští týden • Trafficking HIV • Sherer NM, Lehmann MJ, Jimenez-Soto LF, Ingmundson A, Horner SM, Cicchetti G, Allen PG, Pypaert M, Cunningham JM, Mothes W.Related Articles, Links Visualization of retroviral replication in living cells reveals budding into multivesicular bodies. Traffic. 2003 Nov;4(11):785-801. • DC-SIGN – DC jako Trojský kůň Exp Med. 2004 Nov 15;200(10):DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells. Arrighi JF, Pion M, Garcia E, Escola JM, van Kooyk Y, Geijtenbeek TB, Piguet V. • Přirozená antiviremika TRIM5 Stremlau, M. et al. Nature 427:848-852, 2004, APOBEC3G Gu Y & Sundquist WI. Naure 424:21-22, 2003. • Evoluční atenuace viru HIV • Arien KK, Troyer RM, Gali Y, Colebunders RL, Arts EJ, Vanham G.Related Articles, Links Replicative fitness of historical and recent HIV-1 isolates suggests HIV-1 attenuation over time. AIDS. 2005 Oct 14;19(15):1555-1564. •
  • 4. 1981 HIV I - minimálně 3 nezávislé přenosy z šimpanze 1986 HIV II - téměř identický s mangabejím SIV – podobnou chorobu dostane i makak
  • 5. Regionální rozložení subtypů
  • 6. Prevalence
  • 7. Osoby nově infikované v roce 2003 Eastern Europe Western Europe & Central Asia 30 000 – 40 000 180 000 – 280 000 North America 36 000 – 54 000 East Asia & Pacific North Africa & Middle East 150 000 – 270 000 Caribbean 43 000 – 67 000 South 45 000 – 80 000 & South-East Asia Sub-Saharan Africa 610 000 – 1.1 million Latin America 3.0 – 3.4 million Australia 120 000 – 180 000 & New Zealand 700 – 1 000 celkem: 4.2 – 5.8 milionů
  • 8. Projected life expectancy at birth Selected sub-Saharan countries 65 years 60 55 Kenya 50 Botswana Zimbabwe 45 Zambia Uganda 40 Malawi 35 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 Source: World Population Prospects: The 1996 revision, United Nations Population Division, 1996 10 -GE-98001/10 – 1 December 1997 UNAIDS/WHO
  • 9. U.S. HIV/AIDS epidemic: New infections 2001 Men 70% Women 30%
  • 10. AIDS Incidence* for Women and Percentage of AIDS Cases, January 1986 - June 2000, United States Number of Cases Percent of Cases 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Half-Year of Diagnosis *Adjusted for reporting delay delays
  • 11. HAART
  • 12. HIV structure:
  • 13. Struktura virionu
  • 14. HIV Lifecycle Rambaut A. et al. Nat. Rev. Genet. 5:52-61, 2004
  • 15. Glykoproteiny virového obalu Synthesis. Initial product is gp160; processed by a cellular protease into gp41 (transmembrane) and gp120 (surface). Gp41 and gp120 are linked by a non-covalent interaction. Gp120. Oligomeric and heavily glycosylated. Includes highly variable surface domains (such as V3) which influence virus host cell range and antigenicity. Gp120 interacts with CD4 and also with the chemokine receptors (CCR5, CXCR4). Gp41. Oligomeric. Contains a hydrophobic N- terminus fusion domain, that mediates fusion of the viral envelope with the host cell plasma membrane.
  • 16. Structure of HIV-1 gp120/CD4 Complex gp120 CD4 Blue: glycosylation sites
  • 17. Vazba HIV a vstup do buňky CD4 binding. Gp120 binds CD4, via conserved conformational domains in gp120. Gp120 conformational change. CD4 binding exposes the coreceptor binding domain in gp120. Coreceptor binding. Gp120 binds to the chemokine receptors which act as viral coreceptors (principally, CCR5 and CXCR4). Gp41 conformational change. The combined effect of CD4 binding and coreceptor binding is that a coiled- coil structure is induced in gp41, thereby exposing the hydrophobic fusion domain in gp41. This allows fusion to occur.
  • 18. Vstup viru HIV vstup mukózními povrchy epiteliální buňky infikovatelné M buňky a Langerhansovy buňky DC-SIGN – dendritic cell specific Icam-grabbing nonitregrin -vysokoafinní interakce s HIV -v krvi jako první monocyty a aktivované T-lymfocyty
  • 19. R5 and X4 Viruses R5 strains of HIV: Use CC-chemokine receptor 5 (CCR5). CCR5 is found on dendritic cells, macrophages and T cells. R5 viruses predominate in early infection and are believed to be the major species involved in mucosal (sexual) transmission. X4 strains of HIV: Use CXCR4 as a coreceptor. X4 viruses can infect T cells only, and come to predominate over time. These strains are associated with the elimination of TH cells.
  • 20. Other Receptors Additional chemokine receptors: CCR2b, CCR3, CCR8, APJ, Bonzo (STRL33), BOB (GPR15). None of these is as important as CCR5 or CXCR4, though CCR3 may be important in microglia. Dendritic cells: Can capture virus via DC-SIGN (DC-specific ICAM3-grabbing non-integrin, which is a lectin-like receptor). DC-SIGN can bind and store HIV in a stable infectious form, and transmit it subsequently to T cells during the process of T cell activation.
  • 21. Tropismus viru HIV Mutace v ligandu pro CXCr4 – Mutace v CCr5 – rezistence k HIV rezistence – blokuje vazu HIV na koreceptor
  • 22. HIV-1 Fusion and Entry Flint. Fig. 5.5
  • 23. CCR5 Binding Site on gp120 Yellow: CD4 Green: gp120 Gp120 domains: Blue: Glycosylations Purple: CD4-binding Orange: Coreceptor-binding PDB (http://www.rcsb.org/pdb/): 1GC1
  • 24. Genetics of HIV Susceptibility CCR5: CCR5D32. 32 bp deletion in gene leads to translational frameshift and protein truncation; no CCR5 is made. Heterozygotes (10% of caucasians) have delayed progression; homozygotes (1% of caucasians) resist infection with R5 strains. CCL3L1 gene dosage. The number of copies of a segmental duplication encompassing the gene for CC chemokine ligand 3- like protein (CCL3L1), a ligand for CCR5. A low CCL3L1 copy number is associated with an increased susceptibility to AIDS progression. Gonzalez S et al. Science 307:1434, 2005. Major histocompatibility complex: human HLA genes. Influence immune responsiveness. Full heterozygosity for class I HLA results in delayed progression, presumably because it allows the host to respond to a greater diversity of viral antigenic epitopes.
  • 25. Figure 1: Generalised molecular interactions taking place between cells in the immunological synapse (top) and the virological synapse (bottom). Some of the interactions are probably shared between the two types of synapse, such as LFA-1-ICAM-1 and LFA-1-talin-actin, whereas others are specific for each type of synapse.
  • 26. Schematic diagram of the virological synapse formed between a retrovirally infected (effector) and an uninfected (target) T cell. The cell cell contact zone contains tight junctions and, in the case of the HIV-1 VS, a synaptic cleft into which virions are released from the effector cell. The HTLV-1 VS may differ from the HIV-1 VS: there is no evidence for HTLV-1 virion budding or release or of a synaptic cleft (C. Bangham, unpublished results). The MTOC is polarised towards the site of cell cell contact and viral Gag may be associated with, and be transported along, microtubules. Figure based on results presented in (20 22).
  • 27. DC-SIGN • DC-SIGN is present in the infectious synapse between DCs and CD4+ T cells. Mature DC- SIGN+ DCs were loaded with HIV- GFP for 2 h at 37°C and incubated with highly purified resting CD4+ T cells for 30 min at 37°C, allowing infectious synapse formation. Two representative examples are shown (a–c and d–f). DC-SIGN was readily detected at the infectious synapse by confocal microscopy, appearing sometimes enriched (f), but not consistently (c). (green) HIV-GFP; (red) DC-SIGN. •
  • 28. HUT 78 infikovaná HIV + epiteliální buňka
  • 29. Struktura genomu
  • 30. Cis-Acting Regulator: LTR Structural Genes: Gag, Pol, Env Essential Trans-Acting Genes: Tat, Rev “Accessory” Genes: Vif, Vpr, Vpu, Nef
  • 31. Genetická diverzita viru HIV v jednom infikovaném člověku je větší než diverzita chřipkových virů celosvětové populace při epidemii!!! Umožňuje efektivní únik nových variant, protilátky nestíhají… Nejvyyšší titr aktuální protilátky často proti historické variantě… Protilátky interferují, ale i pomáhají viru do buňky – Fc receptory…
  • 32. Strategie úniku imunitní odpovědi Stealth: • Infection of cells in immune-privileged sites (CNS, resting T cells) & establishment of latency • Downregulation of MHC class I by Nef. HLA-A, B are downregulated (needed for target recognition by CD8+ cells) but HLA-C, -E are not (transduce inhibitory signals to NK cells) • Glycosylation and conformation of Env hides epitopes
  • 33. Strategie úniku imunitní odpovědi Counter-attack: • HIV selectively infects HIV-specific CD4+ memory T cells • HIV targets DC-SIGN and infects dendritic cells (DC); it then uses DC to infect T cells • HIV interferes with both T cell and DC function/maturation • Vif counteracts the endogenous antiviral activity of APOBEC3G (CEM15) • Nef induces FasL, which leads to death of Fas+ T cells
  • 34. Dynamika viru HIV • 90% partikulí v krvi produkováno CD4-T lymfocyty s délkou života okolo 1 dne • Zbytek déležijícími T-lymfocyty s odlišným fenotypem • Lymfocyty v krvi – pouze 1/50 všech T-buněk – zbytek periferie – hlavně uzliny – zde mnohem větší procento infikovaných buněk než v krvi
  • 35. 1/3 pacientů s AIDS – neurologické problémy!!! virus do NS vstupuje brzy po infekci makrofágotropní varianty – infikovány astrocyty a mikroglie
  • 36. Virus HIV a nádory obecně incidence a nebezpečnost některých typů stoupá hlavně ty spojené s infekcí onkogenními viry • Kaposhiho sarkom – endotheliálního původu, 20% homosexuálních mužů, kauzalita s human herpes virus 8 – HHV-8 • B-buněčné lymfomy –důsledek infekce EBV a HHV-8 • Anogenitální karcinomy 3x vyšší incid. - papilomaviry
  • 37. Patologie imunitního systému při AIDS • CD 4 T-buňky každý rok úbytek o cca 60/ml, target CTL, sám virus mění jejich fyziologii – snižuje CD4, MHC I (A,B), CD28, produkci IL-2, IL-2 receptor • CTLn aopak více, hlavně na začátku, aktivace targety, řešení disbalance v počtu T-lymfocytů • Monocyty a makrofágy – defekty v chemotaxi, funkci Fc receptorů • B-buňky zpočátku overprodukce IgG, IgA, IgD, hlavně u HIV 1 klesá množství – málo helperů, množí se in vitro bez aktivace – čřasto infikovány EBV a cytomegalovirem • NK buňky – aktivita se snižuje – IL-2 dependentní • Autoimunita – obvyklá – dramatická disbalance imun. syst.
  • 38. HIV-1 Env glycoproteins Surfac e glycoprotein (SU) Transmembrane glycoprotein (TM) gp120 gp41 Variable domain s (gp120) 1 100 200 300 400 500 600 70 | | | | | | | | signal transmembrane peptide anchor V3 loop GR CD4 binding Fus ion P A domain domain G F proteolytic cleavage C C (c ellular enzyme) important for ch emok ine re ceptor binding
  • 39. Genetics of HIV Susceptibility Major histocompatibility complex: human HLA genes. Influence immune responsiveness. Full heterozygosity for class I HLA results in delayed progression, presumably because it allows the host to respond to a greater diversity of viral antigenic epitopes.
  • 40. Nuclear Import & Integration Nuclear import. The viral preintegration complex (the partially uncoated core particle, including RT and RNA) enters the nucleus via an active uptake process that depends on (multiple) viral nuclear localization signals. The ability to traverse the nuclear pore allows HIV to infect non-dividing cells, unlike oncoretroviruses. Integration. This is non-random and occurs preferentially in transcriptionally active genes.
  • 41. Viral Transcription The viral long terminal repeat (LTR) contains the major promoter which drives viral RNA transcription. Elements include: Core promoter. Recruits cellular RNA pol II. Enhancer elements. Bind NFAT, NFkB; allow virus to respond to cellular activation. Modulatory elements. Additional regulatory domains. TAR (trans-activation response element). Located in R region of LTR; allows HIV LTR to undergo Tat- mediated activation
  • 42. Trans cription elements within the HIV-1 LTR Adapted from Luciw, Chap ter 60 , Fields Virolog y, 3rd Edn. U3 R U5 modulatory elements enhancer TAR core mRNA TAT AA gag gene Various fac tors NF- kB Sp1 LBP1 Cellular stimuli HIV LTR - Transcriptional Regulation
  • 43. Viral Transactivators Multiply spliced mRNAs. “Simple” retroviruses encode only unspliced or singly spliced mRNAs. Tat: trans-activator of transcription • Regulates viral transcription (enhances elongation) • Binds RNA (TAR: Tat-responsive element) • Acts in concert with cellular proteins (P-TEFb) which bind Tat & TAR (P-TEFb = CYCT1 + CDK9) Rev: regulator of viral expression • Regulates splicing (overcomes restriction on nuclear export of unspliced transcripts) • Binds RNA (RRE: Rev-response element) • Acts in concert with cellular proteins which bind
  • 44. HIV-1 Transactivators: Schematic HIV-1 transactivators Ref.: Cullen. J. Virol. 6 5:105 3, 1 991 DNA provirus + RNA trans cription (regulated by Tat) RNA nuclear export RNA s plicing Early (regulated by Rev) Late regulatory mRNAs struc tural mRNAs (doubly splic ed) (unspliced, s ingly spliced) - + Gag-pol (uns pliced mRNA) Env (singly spliced mRNA) Tat also: Vpr, Vpu, Vif encoded by Rev singly spliced mRNAs also: Nef encoded by doubly spliced mRNA
  • 45. Action of Tat Tat interacts cooperatively with the TAR RNA sequence and with the cellular protein complex, positive transcription elongation factor b (P-TEFb). P-TEFb includes cyclin T1 (CYCT1) and cyclin- dependent kinase 9 (CDK9). CDK9, once recruited to nascent HIV RNA, phosphorylates the C-terminus of RNA polymerase II (RNAPII) and negative transcription elongation factor (N-TEF), thereby enhancing elongation.
  • 46. Action of HIV-1 Tat Ref .: Cullen Cell 93:685, 1998 CDK9 Tat inte racts cooperative ly with TAR & with the cyclin T1 compone nt of pos itive Cyclin transcription elon gation loop T1 factor-b (P-TEFb). This allows the CDK9 compon ent No Tat TAR + Tat of P-TEFb to phos phorylate bulge TAT polII . Pre mature te rmination (short transcripts) Greatly e nhanced elongation RNA pol II transcript ion CDK9 ph osphoryl ate s complex polII P HIV DNA TAT AA HIV DNA TAT AA Action of HIV-1 Tat
  • 47. Additional Actions of Tat Translocated across the plasma membrane. A basic domain within Tat (RKKRRQRRR) allows it to enter intact cells; this is being exploited for gene therapy and immunization. Tat is thus the prototype of so- called “protein transduction domains” or PTDs. Causes T cell activation. May “prime” virus-negative T cells for HIV-1 infection and replication. Induces apoptosis. Occurs in T cells and in neurons; may contribute to HIV neuropathogenesis and immune evasion
  • 48. Effect of Rev Nuclear export of late HIV-1 mRNAs. Incompletely spliced (singly spliced or unspliced) mRNAs contain the RRE and fail to exit the nucleus in the absence of Rev. These late mRNAs encode the viral structural proteins (Gag, Pol & Env). Inhibits splicing of late HIV-1 mRNAs. Rev binding to the RRE may prevent the formation of a spliceosome on the late HIV-1 mRNAs.
  • 49. Effect of HIV-1 Rev on Viral RNAs Flint. Fig. 10.15
  • 50. Action of Rev 1. Nuclear import of Rev: The Rev NLS binds importin b (IMPb), and the complex enters the nucleus 2. Rev binds to the RRE, and multimerizes 3. Nuclear export of Rev and its cargo: The Rev NES is bound by CRM1, and the ATP-dependent RNA helicase DDX3 (a nucleo-cytoplasmic shuttling protein) then binds CRM1 and localizes to the nuclear pore (and subsequently to the cytosol).
  • 51. Tat & Rev: Common Themes  Bind specific RNA sequences  Require cellular cofactors  Nuclear acting  Made up of modular domains  Act in concert to regulate HIV transcription
  • 52. Virion Proteins: Core & Enzymes Core proteins. Gag gene products (MA, CA, NC). Initial product is Pr55Gag; proteolytically cleaved by viral protease. A molecular chaperone (Cyclophilin A) interacts with CA and is required for virus replication. Viral enzymes. Pol products (IN, PR, RT); made by read-through of Gag stop codon (translational frameshift). Initial product is Pr160Gag-Pol; processed by viral protease. PR (protease) is a major antiviral target, as is RT (reverse transcriptase), which also has a high error
  • 53. Virion Proteins: Enzymes Viral enzymes. Pol products; made by read-through of Gag stop codon (translational frameshift). Initial product is Pr160Gag-Pol; processed by viral protease. PR (protease). Cleaves Gag, Gag-Pol precursors. Involved in virion maturation. Antiviral target. RT (reverse transcriptase). An RNA-dependent DNA-polymerase; lacks proof-reading capacity (high error rate). Antiviral target. IN (integrase). Catalyzes insertion of viral DNA into the host chromosome.
  • 54. Viral Accessory Proteins Vif (virion infectivity factor). Important for virion maturation and infectivity; counteracts an innate antiviral protein (APOBEC3G/CEM15). Vpu (viral protein, unknown). Downregulates CD4; enhances virus release. Absent in HIV-2. Vpr (viral protein, regulatory). Causes G2 cell cycle arrest; facilitates infection of macrophages; induces apoptosis.
  • 55. Nef Initially described as a dispensible “negative factor”; later realized to be critical for pathogenicity. Functions: CD4 and MHC class I downregulation. Binds the cytoplasmic domains of these molecules & targets them to the intracellular sorting/degradation pathways. Enhances virion infectivity. Increases viral replication in primary cells by increasing virion infectivity. Apoptosis. May upregulate FasL expression, leading to killing of virus-reactive cytotoxic T cells. Modulation of host cell; kinase binding. A central SH3-binding domain recruits cellular protein tyrosine
  • 56. Attenuated SIV (Nef-delete) Attenuated SIV Ref.: Kestter et al., Cell 65:651, 1991 gag vif re v nef LTR pol vpx tat LTR vpr env Virus Clone Deaths (5 mo) ----------------------------- Mac239 3/7 M a c 2 3DN e f 9 0/6 ----------------------------- Deletion (Mac239DNef)
  • 57. SIVDnef Viral attenuation: Deletion of Nef from SIVmac239 rendered the virus much less pathogenic for macaques, and dramatically reduced in vivo virus replication. Protection by attenuated virus: Animals infected with SIVDNef were found to be protected against infection with other strains of SIV. Attenuation is not complete: SIVDNef can cause disease in neonatal animals, and some adult animals infected with SIVDNef also go on to develop disease at later times
  • 58. Attenuated HIV-1 (Nef-delete) Attenuated HIV-1 Ref.: Deacon et al., S cience 270:988, 1995 gag vif re v nef LTR pol tat LTR vpr vpu env Deletions
  • 59. Sydney Blood Bank Cohort HIV+ blood donor: use of contaminated blood from this person resulted in the infection of 7 recipients. Non-progression: 1 patient died of unrelated causes soon after, but the other 7 (donor + 6 recipients) remained healthy for 10+ years. All turned out to have the same strain of HIV, with has a deletion in Nef. Incomplete attenuation: In 1999, at 14-18 years after infection with the virus, several of the members of this cohort showed evidence of a decline in their CD4 count.
  • 60. Endogenous Antivirals: APOBEC3G Reuben S. Harris & Mark T. Liddament. Nature Reviews Immunology 4, 868-877 (2004)
  • 61. Endogenous Antivirals: APOBEC3G (II) Gu Y & Sundquist WI. Naure 424:21-22, 2003.
  • 62. Endogenous Antivirals: APOBEC Family Reuben S. Harris & Mark T. Liddament. Nature Reviews Immunology 4, 868-877 (2004)
  • 63. Endogenous Antivirals: TRIM5 Greene, W.C. Nature Med. 10:778-80, 2004; Stremlau, M. et al. Nature 427:848-852, 2004.
  • 64. Funkce proteinů HIV CD4 downregulation. Nef, Vpu, gp120 can downregulate CD4. Important for virus release? Nuclear import. There are nuclear localization signals in Vpr, MA and IN, which contribute to infection of non-dividing cells. T cell activation. Gp120, Tat and Nef activate T cells. Immune evasion. Vpu and Nef downregulate class I major histocompatibility complex (MHC) proteins. Nef can also upregulate FasL and trigger apoptosis of virus-reactive T cells. Rev can regulate epitope density on target cells.
  • 65. Funkce Rev
  • 66. Životní cyklus viru HIV
  • 67. HIV targets for therapy CD4 cell X Integrase NRTI NNRTI inhibitor PI X Fusion inhibitor
  • 68. CD4 cell count and opportunistic infection
  • 69. HIV Testing • Drug resistance testing- genotypic and phenotypic assays • Antibody detection – ELISA- color change (optical density) P24 antigen test - present early in disease and later – ELISA sandwich technique – Western blot- confirmatory • need at least two bands (p24, gp41, gp160/120) Drug resistance testing- genotypic and phenotypic assays
  • 70. HIV seroconversion + - 0 15 21 34 47d
  • 71. Akutní retrovirální syndrom • Occurs in up to 75% of patients • Flu-like/mono-like illness- fevers, myalgias, exudative pharyngitis, rash (maculopapullar), thrush, • May be the best time to start treatment • Produkce velkého množství virionů v aktivovaných lymfocytech v uzlinách • 5x103 inf. virionů na ml plasmy
  • 72. Časná choroba • CD4 counts above 500 cells • Infections – Sinusitis – Pneumonias • Pneumococcal vaccine – Herpes infections – Papilloma viruses • Other- Lymphoma
  • 73. Pozdní stádium • CD4<200 • Infections – CMV – Toxoplasmosis • Bactrim prophylaxis – Fungal – Mycobacteria • Clarithromycin prophylaxis
  • 74. NRTI NNRTI PI FI AZT Nevirapine Ritonavir Enfurvitide - T-20 3TC/FTC Sustiva Saquinavir d4T Delavirdine Indinavir DDI Nelfinavir DDC Amprenavi r Abacavir Lopinavir Tenofovir Atazanavir Tipranavir
  • 75. Treatment Options: HAART: Highly Active Antiretroviral Therapy 1) Three nucleosides (Trizivir – AZT/3TC/abacavir)  Now not recommended as first line therapy 2) Two nucleosides + One non-nucleoside reverse transcriptase inhibitor 3) Two nucleosides + One ritonavir boosted protease inhibitor
  • 76. Summary: Indications for initiation of antiretroviral therapy • CD4 count < 350 • “Symptomatic”: HIV associated opportunistic infection or neoplasm • Acute retroviral syndrome DHHS Guidelines, Nov 10, 2003 aidsinfo.nih.gov
  • 77. Expected response to therapy • At one month – 1 log10 reduction in viral load • At three months – “undetectable” viral load (<50 copies/cc) • Hope for a CD4 count boost over time – Increase variable from patient to patient
  • 78. Antiretrovirals: 1) Nucleoside reverse transcriptase inhibitors (NRTI’s) – AZT (zidovudine, Retrovir) – d4T (Zerit, stavudine) – 3TC (Epivir, lamivudine) – FTC (Emtriva) – ddI (Videx, didanosine) – ddC (Hivid, zalcitabine) – abacavir (Ziagen) – tenofovir (Viread)
  • 79. Antiretrovirals: 2) Non-nucleoside reverse transcriptase inhibitors (NNRTI’s) – Sustiva (efavirenz) – nevirapine (Viramune) – delavirdine (Rescriptor)
  • 80. Antiretrovirals: 3) Protease inhibitors (PI’s) – indinavir (Crixivan) – saquinavir (Fortovase, Invirase) – nelfinavir (Viracept) – ritonavir (Norvir) – Fos/amprenavir (Agenerase) – Kaletra (lopinavir/ritonavir) – Atazanavir (Reyataz)
  • 81. Antiretrovirals: 4) Fusion Inhibitors – T-20 (Fuzeon, enfuvirtide ) • Synthetic 36 amino acid sequence • Binds to heptad repeat regions (HR1, HR2) of gp41 • Inhibits fusion of viral particle to CD4 cell by interfering with required conformational changes
  • 82. T-20: Mechanism of action HIV capsid T-cell
  • 83. Interleukin 2 (IL-2) • Regulates lymphoid proliferation and maturation • Production decreased in HIV • Toxic at high doses • Expensive- SQ injections bid for 1 week every month- 2 months
  • 84. IL-2- Clinical Trials • 3 controlled trials • Increase in CD4 cells (poly clonal-naïve and memory) • Stable viral loads • Does not work as well when CD4<200 • ?Clinical benefit • Two international trials underway
  • 85. Vaccination • Theraputic and Preventative • No satisfying results to date • Treatment interruptions to restimulate the immune system have been disappointing and even detrimental
  • 86. Rezistence k virovým inhibitorům Resistance of HIV to protease inhibitors. After the administration of a single protease inhibitor to a patient with HIV there is a precipitous fall in viral RNA levels in plasma with a half-life of approximately 2 days (top panel). This is accompanied by an initial rise in the number of CD4 T cells in peripheral blood (center panel). Within days of starting the drug, mutant drug- resistant variants can be detected in plasma (bottom panel) and in peripheral blood lymphocytes. After only 4 weeks of treatment, viral RNA levels and CD4 lymphocyte levels have returned to baseline levels, and 100% of plasma HIV is present as the drug-resistant mutant. Reprinted with permission from Nature 373:117-122, ©1995 Macmillan Magazines Limited