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Monique Nijhuis University Medical Center Utrecht, the Netherlands

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1 Monique Nijhuis University Medical Center Utrecht, the Netherlands
Rapid rebound of a highly replication competent preexisting CXCR4-tropic HIV variant after allogeneic stem cell transplantation with CCR5Δ32 stem cells Monique Nijhuis University Medical Center Utrecht, the Netherlands

2 Disclosure sheet No (potential) conflict of interest None
For this meeting possible relevant relations with companies Company names: Sponsorships or research funds Honorarium or other (financial) compensation Stakeholder Other relationship, namely …

3 Background: HIV co-receptors are important determinants for cell tropism
Tropism CD4 Co-receptor Cells M-tropic HIV low CCR5 macrophages, microglia T-tropic HIV (slow, NSI) high CCR5 T memory cells T-tropic HIV (rapid, SI) high CCR5-CXCR4 T naïve and memory cells X4 usage observed in about 50% of untreated patients and associated with progression The underlying mechanisms are poorly understood and it is unclear whether evolution towards X4 usage is the cause or the consequence of disease progression Before we start on the impact of coreceptor usage on stem cell transplantation, i would like to take one step back.

4 Background: CXCR4 coreceptor usage and pathogenesis
X4-tropic variants cause disease progression HIV disease progression: increase in immune activation decrease number of CD4 T cells X4 X4 X4 X4 X4 Before we start on the impact of coreceptor usage on stem cell transplantation, i would like to take one step back.

5 Background: CXCR4 coreceptor usage and pathogenesis
X4-tropic variants consequence of disease progression R5 R5 HIV disease progression: increase in immune activation decrease number of CD4 T cells X4 R5 R5 R5 R5 X4 Before we start on the impact of coreceptor usage on stem cell transplantation, i would like to take one step back. Minority variant Translate to the setting of allogeneic stem cell transplantation (CCR5Δ32)

6 Background: Stem cell transplantation (CCR5Δ32)
Berlin Patient: diagnosed with AML and transplanted with CCR5Δ32 donor cells1 Transplanted in 2007 and off ART ever since Only person cured of HIV infection Prior to SCT a minority population predicted to use the CXCR4 coreceptor Phenotypic analyses demonstrated that these variants were still dependent on CCR5 for viral replication2 One other case reported of a patient transplanted with CCR5Δ32 donor cells stopping ART Essen patient: diagnosed with anaplastic large-cell lymphoma and transplanted with CCR5Δ32 donor cells3 27 year old HIV-1 infected patient transplanted in 2012 Successful engraftment Treatment interruption 7 days before transplantation 1Hutter et al, NEJM, 2008; 2Symons, CID, 2014; 3Kordelas et al, NEJM, 2014

7 Case description: Essen patient
ART was stopped 7 days before SCT and resumed 3 weeks after SCT Patient died a year later due to relapse of the T cell lymphoma (ART stopped) Longitudinal deep sequence analyses of viral envelope to get insight the viral rebound Kordelas, NEJM, 2014

8 Case description: Essen patient
-287d/RNA/V03 -103d/DNA/V02 -103d/DNA/V11 -103d/RNA/V03 -103d/RNA/V04 -103d/RNA/V01 -103d/RNA/V05 -103d/RNA/V02 -18d/DNA/V05 -103d/DNA/V04 -103d/DNA/V10 -287d/RNA/V01 -103d/DNA/V01 -103d/DNA/V08 -18d/DNA/V06 -18d/DNA/V04 -18d/DNA/V02 -18d/DNA/V03 -287d/RNA/V02 -18d/DNA/V01 -103d/DNA/V03 -103d/DNA/V09 -18d/DNA/V07 -103d/DNA/V07 -103d/DNA/V06 -287d/RNA/V04 +373d/RNA/V06 +20d/RNA/V01 +373d/RNA/V02 -103d/DNA/V05 +373d/DNA/V01 +373d/RNA/V03 +373d/RNA/V08 +20d/RNA/V02 +373d/RNA/V01 +373d/RNA/V05 +373d/DNA/V02 +373d/DNA/V03 +373d/RNA/V04 +373d/RNA/V07 0.01 clearly two distinct viral populations Verheyen et al. , CID, 2018

9 Case description: Essen patient
-287d/RNA/V03 -103d/DNA/V02 -103d/DNA/V11 -103d/RNA/V03 -103d/RNA/V04 -103d/RNA/V01 -103d/RNA/V05 -103d/RNA/V02 -18d/DNA/V05 -103d/DNA/V04 -103d/DNA/V10 -287d/RNA/V01 -103d/DNA/V01 -103d/DNA/V08 -18d/DNA/V06 -18d/DNA/V04 -18d/DNA/V02 -18d/DNA/V03 -287d/RNA/V02 -18d/DNA/V01 -103d/DNA/V03 -103d/DNA/V09 -18d/DNA/V07 -103d/DNA/V07 -103d/DNA/V06 -287d/RNA/V04 +373d/RNA/V06 +20d/RNA/V01 +373d/RNA/V02 -103d/DNA/V05 +373d/DNA/V01 +373d/RNA/V03 +373d/RNA/V08 +20d/RNA/V02 +373d/RNA/V01 +373d/RNA/V05 +373d/DNA/V02 +373d/DNA/V03 +373d/RNA/V04 +373d/RNA/V07 0.01 clearly two distinct viral populations 100% of the viral sequences detected after SCT were predicted to be X4-tropic Verheyen et al. , CID, 2018

10 Case description: Essen patient
-287d/RNA/V03 -103d/DNA/V02 -103d/DNA/V11 -103d/RNA/V03 -103d/RNA/V04 -103d/RNA/V01 -103d/RNA/V05 -103d/RNA/V02 -18d/DNA/V05 -103d/DNA/V04 -103d/DNA/V10 -287d/RNA/V01 -103d/DNA/V01 -103d/DNA/V08 -18d/DNA/V06 -18d/DNA/V04 -18d/DNA/V02 -18d/DNA/V03 -287d/RNA/V02 -18d/DNA/V01 -103d/DNA/V03 -103d/DNA/V09 -18d/DNA/V07 -103d/DNA/V07 -103d/DNA/V06 -287d/RNA/V04 +373d/RNA/V06 +20d/RNA/V01 +373d/RNA/V02 -103d/DNA/V05 +373d/DNA/V01 +373d/RNA/V03 +373d/RNA/V08 +20d/RNA/V02 +373d/RNA/V01 +373d/RNA/V05 +373d/DNA/V02 +373d/DNA/V03 +373d/RNA/V04 +373d/RNA/V07 0.01 clearly two distinct viral populations 100% of the viral sequences detected after SCT were predicted to be X4-tropic dominant X4-tropic viral sequence observed after SCT -present prior to SCT -present prior to treatment interuption -why does it not dominate before SCT, poorly replicating? Verheyen et al. , CID, 2018

11 Methods: Investigate viral replication capacity and tropism (Tropchase)
Deep sequencing data of viral gp120-V3 region Phenotypic analyses of patient derived sequences Patient V3 patientV3-HXB2 BgmBI NheI ΔV3 HXB2 cbal, R5-predicted patient derived variant cHXB2, X4-predicted patient derived variants In vitro replication capacity In vitro co-receptor usage Symons et al, CID 2014

12 Essen patient Verheyen et al. , CID, 2018 dominant variant after SCT
-287d/RNA/V03 -103d/DNA/V02 -103d/DNA/V11 -103d/RNA/V03 -103d/RNA/V04 -103d/RNA/V01 -103d/RNA/V05 -103d/RNA/V02 -18d/DNA/V05 -103d/DNA/V04 -103d/DNA/V10 -287d/RNA/V01 -103d/DNA/V01 -103d/DNA/V08 -18d/DNA/V06 -18d/DNA/V04 -18d/DNA/V02 -18d/DNA/V03 -287d/RNA/V02 -18d/DNA/V01 -103d/DNA/V03 -103d/DNA/V09 -18d/DNA/V07 -103d/DNA/V07 -103d/DNA/V06 -287d/RNA/V04 +373d/RNA/V06 +20d/RNA/V01 +373d/RNA/V02 -103d/DNA/V05 +373d/DNA/V01 +373d/RNA/V03 +373d/RNA/V08 +20d/RNA/V02 +373d/RNA/V01 +373d/RNA/V05 +373d/DNA/V02 +373d/DNA/V03 +373d/RNA/V04 +373d/RNA/V07 0.01 dominant variant after SCT Luciferase activity (PBMCs) dominant variants pre-SCT FPR minority variants minority variants after SCT Replication capacity in PBMCs Verheyen et al. , CID, 2018

13 Background: CXCR4 coreceptor usage and pathogenesis
X4-tropic variants consequence of disease progression R5 R5 HIV disease progression: increase in immune activation decrease number of CD4 T cells X4 R5 R5 R5 R5 X4 Before we start on the impact of coreceptor usage on stem cell transplantation, i would like to take one step back. Minority variant Translate to the setting of allogeneic SCT (CCR5Δ32) Maraviroc therapy!

14 Viral evolution during MVC therapy
Becomes clear that in these patients X4 tropic viruses were present and are dominating the viral population once the R5 tropic viruses are inhibited by mvc. It also becomes clear that under these circumstances the X4 viruses have no apparant in vivo fitness defect which is reflected by the fact that the viral load does not change very much in three of the four patients Non-R5 (X4 FPR cutoff 10) Mc Govern et al, JAC, 2013 14

15 Conclusion Final remarks
Highly replication competent X4-tropic virus may be present as a minority variant in a R5-tropic viral population and dominate the viral population: Maraviroc therapy Stem cell transplantation using CCR5Δ32 stem cells (Essen patient) Implications for patients transplanted with CCR5Δ32 planned ATI Implications for gene therapy studies focus on CCR5 In-dept HIV co-receptor analyses (TropChase; IciStem): viral escape Marschner

16 Acknowledgements All the study participants
Translational Virology, UMCU J Symons University Hospital Duisburg-Essen J Verheijen, A Thielen, N Lubke, M Dirks, M Widera, U Dittmer, L Kordales, S Esser Institute for Immunology and Genetics, Kaiserslautern M Daumer University of Cologne R Kaiser

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