Modern antiretroviral therapy: All problems solved? Happiness all - - PowerPoint PPT Presentation
Modern antiretroviral therapy: All problems solved? Happiness all around PD Dr. Jens Verheyen Institut fr Virologie Universittsklinikum Essen Background: HIV-1 HIV-1: Retroviridae, Lentivirus, (+)RNA: 9.4 kb group M (subtypes), N, O, P
Institut für Virologie Universitätsklinikum Essen
HAART (Highly active antiretroviral therapy) HIV-1: Retroviridae, Lentivirus, (+)RNA: 9.4 kb group M (subtypes), N, O, P Target cells: T-cells (naive, activated), macrophages Receptors: CD4, CCR5, CXCR4
entry reverse transcription integration transcription translation assembly and budding maturation
1980 1990 2010 2000
AZT d4T ddI 3TC NVP EFV ABC TDF MV C TPV SQV DRV FPV APV
LPV/r
NFV IDV RPV ETV FTC T-20 RAL DLV ddC RTV ATV AZT+3TC TDF+FTC +EFV AZT+3TC+ABC 3TC+ABC TDF+FTC AZT+3TC +DGV/c TDF+FTC +RPV EVG DGV
1980 1990 2010 2000
3TC EFV ABC TDF DRV
LPV/r
RPV FTC /r EVG DGV ATV TDF+FTC +EFV 3TC+ABC TDF+FTC AZT+3TC +DGV/c TDF+FTC +RPV
2020 2030
Coreceptor blocker (maraviroc) Fusion inhibitor (T-20) Book: HIV2011 Attachment inhibitor
BMS-448043: proof of concept BMS-626529:
BMS-663068: pro-drug Thompson et al. CROI 2015, Seattle
Langley et al. Proteins 2015: 83: 331-350
Microbiologybook.org R Hunt University of South Carolina School of Medicine
Resistance-associated mutations (gp160): L116Q C1 A204D, A281V C2 S375H C3 M426L, M434I C4 M475I C5
Zhou et al. JAC 2014 69: 573-581
C1 C2 C3 C4 C5
Zhou et al. JAC 2014: 69: 573-581
Baseline resistence (IC50 >100 nM): subtype B: <1% subtype C: <6% Subtype A: <10% Baseline resistence (IC50 >100 nM): monotherapy in Germany (subtype B): n=47 15% baseline resistance
HIV-1 Assembly, Budding, and Maturation. Sundquist and Kräusslich. Cold Spring Harb Perspect Med 2012
p17 (MA) p24 (CA) p2 p7 p1 p6-gag p17 (MA) p24 (CA) p2 p7 p1 p6-gag p1
p24 (CA) p2 p7
Heider et al. (2010)
CS p24/p2 (alpha-Helix)