Virological failure to Protease inhibitors in Monotherapy is linked to the presence of signature mutations in Gag without changes in HIV-1 replication

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1 Virological failure to Protease inhibitors in Monotherapy is linked to the presence of signature mutations in Gag without changes in HIV-1 replication Oscar Blanch-Lombarte Rome, 7-9 June, 2017 European Meeting on HIV & Hepatitis

2 Contribution of Gag mutations to PI susceptibility Mutations Protease Cleavage sites Structural proteins Gag PI Monotherapy Why do PIs fail? p17 p24 p2 p7 p1 p6 Protease CypA binding loop

3 Contribution of Gag mutations to PI susceptibility Mutations Protease CSM Structural proteins Gag PI Monotherapy p17 p24 p2 p7 p1 p6 Protease Why do patients with good adherence and treated with boosted PIs develop virological failure to the treatment without mutations in the protease? AIM: to identify HIV-1 mutational patterns involved in virological failure through the characterization of Gag and protease genes

4 Patients selection criteria Study Subjects 511 Discarded 520 patients who received LPV/r or DRV/r monotherapy 9 patients with VF on LPV/r or DRV/r monotherapy Selection criteria: 1) Initiation of PI monotherapy as ARTsimplification strategy with DRV/r or LPV/r 2) No previous PI-exposure known 3) Sustained virological suppression (<50 copies/ml) for at least 6 months from treatment initiation Criteria of virological failure: Two viral loads >50 copies/ml 7 patients with one cross-sectional sample in VF 2 patients with two longitudinal samples in VF 7 plasma samples to amplify full-length Gag-PR 4 plasma samples to amplify full-length Gag-PR 2 Gag-PR amplification failed 5 Gag-PR successfully amplified 4 Gag-PR successfully amplified

5 CD4 + T-lymphocytes/ml Clinical follow-up and Sampling Pt1 LPV/r Pt2 LPV/r T1 Pt3 LPV/r Pt4 DRV/r T2 T1 T1 T1 T2 Pt5 LPV/r T1 Pt6 DRV/r Pt7 LPV/r Pt8 LPV/r T1 T1 T1 Viral load (RNA copies/ml) Pt9 LPV/r T1 Weeks after treatment initiation

6 Virological failure to DRV/r or LPV/r occurs in absence of protease drug resistance mutations Gag p17 p24 p2 p7 p1 p6 Protease Sequencing and direct comparison with HXB2 Patients Time ARV Protease Resistance associated mutations Other mutations Pt1 T1 LPV/r - K20T Pt2 T1 LPV/r - - Pt3 Pt4 T1 LPV/r - - T2 LPV/r - - T1 DRV/r - - T2 DRV/r - A71V Pt5 T1 LPV/r - L10V Pt6 T1 DRV/r - - Pt7 T1 LPV/r - -

7 Gag p17 p24 p2 p7 p1 p6 Protease Patients Time ARV p17 p17/p24 p24 p24/p2 p2 p2/p7 p7 p7/p1 p1/p6 p6 E12D, R15K, K30Q, S67A, S465F, Q476P, A146P, S148T, V215M, T242N, Q386P, Pt1 T1 LPV/r R76K, L78V, R91K, K95R, K481Q, L483K, N252S, R286K, T303V, E312D K411R K103R, N126R Y484S, S498* Pt2 T1 LPV/r Pt3 Pt4 V7L, E12K, R15Q, K18R, K28Q, K30R, I34L, L61I, G62Q, R76K, T81A, T84V, E93D, S111I T1 R15K, K30R, E93D, K113Q - T2 R15K, K30R, E93D, K113Q - T1 T2 LPV/r DRV/r Pt5 T1 LPV/r p17 p24 p2 p7 p6 K28Q, E55G, R76K, E93D, K95R, K113Q, T122P, H124K K28Q, E55G, G62E, R76K, R91K, E93D, K95R, K113Q, T122P, H124K E12K, R15K, K18R, K26N, K30R, S54A, E55D, R58K, G62E, Q69K, V82I, A83S, Q90K, R91N, E93D, K95T, E99A - E312D - N372G V159I, S165N, Q199E, E203D, I223V, G248A, N252S, E260D, T280V, R286K, S310T, G357S V159I, S165N, V168I, Q199E, E203D, I223V, G248A, N252S, E260D, T280V, R286K, S310T, G357S - V370A - V370A - L268M, R286K, A326S L268M, R286K, A326S S173T, E203D, V215M, M228I, G248T, N252S, P255A, T280V, E312D, A340G, M347S S373P, T375L, M377L A374S, T375V, I376M A374S, T375V, I376M R380K, N382H T375A R380K, N382H - V370M I376P I389T, R406K I389T, K411R I389T, K411R R387K, K388R R387K, K388R I389T, V390I, T401L, K411R, R429K - - S465F, T471I, E477D, P478S, R490K - - T456S, S465L - - T456S, S465L S451N R429K, K436R - T456I, S465F, E477G, I479T T456I, S465F, E477G, I479T T456S, E460A, R464K, S465F, T470A, I479P, D480E Pt6 T1 DRV/r E12K, R76K, R91G, K95R, K103R, K110C, Q117L - I147L, V159I, S173T, I223V, G248A, N252S, T280V, R286K, E312D, G357S - V370A S373P, M378V I389T, K418R, D425E - - S465F, E477G, P478T, L483I, L486W Pt7 T1 LPV/r D121N N131H A179T, A209T, T318K - - R380K R384G, E398Q I437V - S465F, R490K

8 Presence of previously described Gag mutations We identified previously described mutations associated to resistance or exposure of PIs in CSM and in Gag structural regions p17 p24 p2 p7 p1 p6 E12K b (33%) R76K a,c (55%) T81A a,c (1%) V370A a (33%) K436R a,b,c (1%) I437V a,b,c (1%) I389T a (44%) S451N a (1%) Mutations CSM Structural proteins a Mutations associated with exposure to PI in vivo b Mutations associated with exposure to PI in vitro c Mutations associated with PI resistance

9 Novel Gag mutations identified by VESPA Are those mutations generated by PI treatment or are mutations naturally as polymorphism? Mutations at positions K95R, E203D, V215M and R286K were statistically more prevalent in PIs treatment patients than naïve sequences * p<0.01 (*) p< (***) * *** * p17 p24 p2 p7 p1 p HIV-1 subtype B treatment naïve sequences of Gag (Los Alamos sequence database)

10 Methods Cloning of recombinant virus cdna Gag-PR from our patients Generation of Gag-protease viral stocks Recombinant virus Gag-Pol Consensus B HXB P83.10-GFP GFP gene 3 HIV genome Electroporation Replication kinetics Harvest virus Pt4 Viral replication (Slope)

11 Mutations in HIV-1 Gag do not affect viral replication ** ** *** ** p<0.001 (**) p< (***) *** *** *** *** I54V and V82A in PR (mutations that affect replication as previously described)

12 Patients ARV Pt3 LPV/r Pt1 LPV/r Pt4 DRV/r Pt6 DRV/r Drug susceptibility to LPV and DRV LPV (nm) T1 T2 T1 T1 T2 T1 Pt3 Pt1 Pt4 Pt6 DRV (nm) T1 T2 T1 T1 T2 T1 Pt3 Pt1 Pt4 Pt6

13 Take Home Messages We identified previously described mutations in Gag associated to resistance or exposure to PIs in patients with VF in monotherapy. Gag CSM K436R (1%), I437V (1%) and S451N (1%) Structural regions of Gag R76K (55%), I389T (44%), E12K (33%), V370A (33%) and T81A (1%) Although we have limited number of patients, VESPA provided a novel signature pattern of mutations in Gag including residues K95R, E203D, V215M and R286K. Most of the virus in patients with VF in PI monotherapy preserved their replication. We identified recombinant virus with reduced susceptibility to LPV and DRV treatment during VF. Gag mutations were directly involved in PIs monotherapy in the absence of protease resistance mutations. However, additional studies are needed to identify the specific sites involved in PI resistance.

14 VIRus Immune Escape and VACcine Group Oscar Blanch-Lombarte Alba Ruiz Esther Jiménez-Moyano Ruth Peña Marta Colomer Clara Francés Àuria Eritja Julia G Prado P31 José Ramón Santos Roger Paredes Bonaventura Clotet Duncan Njenda Ujjwal Neogi

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