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 für Virologie Universitätsklinikum Essen

Background: HIV-1 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 HAART (Highly active antiretroviral therapy)

HIV-1 replication and antiretroviral treatment maturation entry assembly and budding translation reverse transcription transcription integration

Antiretroviral drugs TDF+FTC 3TC+ABC AZT+3TC +DGV/c AZT+3TC+ABC TDF+FTC +RPV AZT+3TC TDF+FTC +EFV NFV ATV IDV TPV MV SQV APV C RAL DGV EFV FPV d4T RTV LPV/r DRV EVG ddC NVP DLV T-20 RPV ETV AZT ddI 3TC ABC TDF FTC 1980 1990 2000 2010

Antiretroviral drugs TDF+FTC 3TC+ABC AZT+3TC +DGV/c TDF+FTC +RPV TDF+FTC +EFV ATV DGV EFV /r LPV/r DRV EVG RPV 3TC ABC TDF FTC 1980 1990 2000 2010

Antiretroviral drugs Is everything solved? Is happiness allround? 2030 2020

HIV-1 entry - inhibitors Book: HIV2011 Coreceptor Fusion Attachment blocker inhibitor inhibitor (maraviroc) (T-20)

Attachment Inhibitor BMS-448043: proof of concept BMS-626529: 2. generation drug BMS-663068: pro-drug Thompson et al. CROI 2015, Seattle

Attachment Inhibitor Langley et al. Proteins 2015: 83: 331-350

Attachment Inhibitor C2 C3 C4 C5 C1 Microbiologybook.org R Hunt University of South Carolina School of Medicine Resistance-associated mutations (gp160): L116Q C1 A204D, A281V C2 S375H C3 Zhou et al. M426L, M434I C4 JAC 2014 M475I C5 69: 573-581

Attachment Inhibitor 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 Zhou et al. JAC 2014: 69: 573-581

HIV-1 (Maturation) HIV-1 Assembly, Budding, and Maturation. Sundquist and Kräusslich. Cold Spring Harb Perspect Med 2012

Protease - substrat - drugs precursor proteins (Gag and Gag-Pol) virale protease protease-inhibitor

Maturation inhibitor 1. phase: p17 (MA) p24 (CA) p2 p7 p1 p6-gag 2. phase: p17 (MA) p24 (CA) p2 p7 p1 p6-gag X 3. phase: p24 (CA) p2 p7 p1

Maturation inhibitor CS p24/p2 (alpha-Helix) Heider et al. (2010)

Maturation inhibitor Bevirimat

Maturation inhibitor

Maturation inhibitor

geno2pheno (gag)

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