European Clinical Data on HIV-1 Coreceptor Usage and Genotypic - - PowerPoint PPT Presentation

European Clinical Data on HIV-1 Coreceptor Usage and Genotypic Identification of Tropism in HIV-2

Matthias Döring

Max Planck Institute for Informatics

May 8, 2015

Coreceptors are crucial for HIV-1 cell entry

Delhalle et al, Int. J. Mol. Sci. 2011 May 8, 2015 2

EucoHIV: European HIV coreceptor study panel

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Goals

Clinical significance of coreceptor usage Validation of geno2pheno [coreceptor]

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EucoHIV: European HIV coreceptor study panel

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Data

Twenty clinical centers in Europe Measurements from more than 450 patients:

Required

– Viral load – Tropism

Optional

– CD4 cell count – V3 sequence – Env sequence

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Criteria for selecting patient records

Measurement Cutoff (viraemic) Cutoff (suppressed) V3/Tropism ≤ 12 weeks earlier Viral load ≤ 24 weeks ≤ 24 weeks CD4 count ≤ 16 weeks earlier

All cutoffs are with regard to therapy start

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Overview of the data set

Ethnicities Viral subtypes

50 100 150 A A (01_AE), A (A1) A/E A1 B B,D C CRF 01_AE CRF 02_AG CRF 05_DF CRFAG D F1 Groupe M Groupe M, PR:F/RT:B U non B urf,D urf,D,CRF

Subtype count

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Overview of the data set

Treatment status Therapy-experienced

Previous antiretroviral therapy Suppressed VL: < 50 cps/ml Detectable VL: ≥ 50 cps/ml

Therapy-naive

First-line treatment

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Treatment status and immune status of patients

Baseline CD4 counts

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Virologic response to Maraviroc

Approach

• 1. Use geno2pheno[coreceptor]

to compute FPRs

• 2. Classify as

by applying different FPR cutoffs: German guidelines: 15% GB guidelines: 5.75% EU guidelines: 10%/20%

Change in viral loads from baseline

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Virologic response to Maraviroc

Status-specific change in viral loads

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Immune response

Overall rate of immunologic success

0.2 0.3 0.4 0.5 0.6 0.7 2 4 6 8 12 16 20 24 32 40 48

Time [Weeks] Ratio of patients with CD4 > 400 cells

Method Pheno/g2p_FPR=15_R5 Pheno/g2p_FPR=15_X4 g2p_FPR=15_R5 g2p_FPR=15_X4 g2p_FPR=5.75_R5 g2p_FPR=5.75_X4 g2p_FPR=EU_R5 g2p_FPR=EU_X4

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Therapy success

Success criteria

VL < 50 cps/ml CD4 ≥ 400 cells/µl

Combined outcomes

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HIV-2 coreceptor usage and MVC

Background

Fewer treatment options available Treatment with MVC is an

• ption (Armstrong-James,

2010)

Motivation

No genotypic tool for HIV-2 coreceptors Major determinant: V3 loop, but V1 and V2 also important (Santos-Costa, 2014) Rules for V3 loop exist (Visseaux, 2012)

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Statistical learning on the HIV-2 V3 loop sequence

Data Set

Pairs of sequences and phenotypic annotation of tropism R5 X4-capable Total 89 49 138

Model

Support Vector Machine Input: V3 amino acid sequences Output: FPR for an X4-capable prediction

Results

Performance: balanced accuracy of 0.897 Interpretability: FPRs and positions in V3

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Positional weights highlight important amino acids

L F Q R H K Y V I R K Q R V I S R K P S F T M Q N K R K A E K M G H Y I L F H K T V I

R5 X4

−0.3 0.0 0.3 18 19 23 INS(1)_24 28 24 22 13 11 27 2 10 15 INS(1)_22 INS(2)_22 14 20 8 12

Position Weight

AA A E F G H I K L M N P Q R S T V Y

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Summary and conclusions

EucoHIV

First, large European data set on tropism and MVC treatment MVC improved both, virologic and immune status considerably

HIV-2 Coreceptor Identification

Most important region: V3 loop Individual positions are highly predictive Genotypic prediction of tropism is possible – Interpretable – High accuracy

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Thank you for your attention and thanks to . . .

Thomas Lengauer and Nico Pfeifer The EucoHIV steering committee – Charles Boucher – Anna Maria Geretti – Rolf Kaiser – Maurizio Zazzi – Anne-Mieke Vandamme Viiv Nuno Taveira and Pedro Borrego

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