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Rapid rebound of highly replication competent CXCR4-tropic HIV variant after allogeneic stem cell transplantation with C

This study investigates the rapid resurgence of a CXCR4-tropic HIV variant after allogeneic stem cell transplantation using CCR5Δ32 stem cells. The underlying mechanisms and implications for disease progression are poorly understood. Deep sequencing and phenotypic analyses are used to explore viral replication capacity and tropism.

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Rapid rebound of highly replication competent CXCR4-tropic HIV variant after allogeneic stem cell transplantation with C

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  1. 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

  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

  4. X4 X4 X4 X4 X4 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

  5. R5 R5 R5 R5 R5 R5 X4 X4 X4 X4 X4 Background: CXCR4 coreceptor usage and pathogenesis X4-tropic variants consequence of disease progression HIV disease progression: increase in immune activation decrease number of CD4 T cells 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. -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 Case description: Essen patient • clearly two distinct viral populations Verheyen et al. , CID, 2018

  9. -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 Case description: Essen patient • 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. -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 Case description: Essen patient • clearlytwodistinctviralpopulations • 100% of theviralsequencesdetectedafter SCT werepredictedtobe X4-tropic • dominant X4-tropic viralsequenceobservedafter SCT • -present prior to SCT • -present prior to treatment interuption • -why does itnotdominatebefore SCT, poorlyreplicating? Verheyen et al. , CID, 2018

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

  12. -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 Essen patient Replication capacity in PBMCs Luciferase activity (PBMCs) FPR 10.5 8.5 6.9 6.8 4.2 6.8 5.7 0.4 0.5 0.2 dominant variants pre-SCT minority variants pre-SCT minority variants after SCT Verheyen et al. , CID, 2018 dominant variant after SCT

  13. R5 R5 R5 R5 R5 R5 X4 X4 X4 X4 X4 Background: CXCR4 coreceptor usage and pathogenesis X4-tropic variants consequence of disease progression HIV disease progression: increase in immune activation decrease number of CD4 T cells Minority variant Translate to the setting of allogeneic SCT (CCR5Δ32) Maraviroc therapy!

  14. Viral evolution during MVC therapy Non-R5 (X4 FPR cutoff 10) Mc Govern et al, JAC, 2013

  15. Final remarks Conclusion • 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

  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 InstituteforImmunologyand Genetics, Kaiserslautern M Daumer University of Cologne R Kaiser

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