Share
Title
Long-term protection against HIV infection after discontinuation treatment with ponatinib for 1 year
Presenter
Mario Manzanares
Authors
M. Manzanares1, F. Ramos-Martín1, G. Casado-Fernández1,2,3, M. Torres1, C. Sánchez-Menéndez1,4, E. Mateos1, L. Vigón1, S. Rodríguez-Mora1,3, V. García-Gutiérrez4, V. Planelles5, M. Coiras1,3
Institutions
1Instituto de Salud Carlos III, Immunopathology Unit-National Center of Microbiology, Majadahonda, Spain, 2Universidad de Alcalá, Faculty of Sciences, Madrid, Spain, 3Biomedical Research Center Network in Infectious Diseases (CIBERINFEC), Madrid, Spain, 4Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Hematology and Hemotherapy Service, Madrid, Spain, 5University of Utah School of Medicine, Division of Microbiology and Immunology, Department of Pathology, Salt Lake City, United States

BACKGROUND: PLWH on ART and dasatinib show reduced reservoir size resistant to reactivation. We evaluated if treatment with ponatinib for 1 year may protect CD4 from HIV infection and if this protection was maintained during treatment-free remission (TFR).
METHODS: 12 participants with chronic myeloid leukemia (CML) of NCT04043676 were recruited. They were on treatment with imatinib for 14 (IQR 5.25-15.75) before discontinuation and then received 1 year-consolidation treatment with ponatinib 15mg/day. Blood samples were collected before starting ponatinib, after 1 year-treatment, and 3, 6 and 12 months after discontinuation. PBMCs were infected with NL4-3_wt 72h. HIV-p24, pSAMHD1, CD4 memory and cytotoxic cell populations were analyzed by flow cytometry. PBMCs antiviral activity was evaluated by measuring caspase-3 activity in NL4.3_wt-infected TZM-bl cells.
RESULTS: 1) 8 participants (66.6%) did not relapse from CML 12 months after ponatinib interruption (Non-relapsed); 4 participants (33.3%) relapsed after 5,5 months (IQR 4,25-6,75) of ponatinib interruption (Relapsed). 2) CD4 were susceptible to HIV infection in all participants while treatment with imatinib; 1 year-treatment with ponatinib reduced 5.75-fold HIV infection (Figure 1) and this protection was maintained 6 (p=0.0313) and 12 months (p=0.0313) during TFR in Non-relapsed, which correlated with pSAMHD1 interference. 3) After CML relapse and imatinib reintroduction, all CD4 memory subpopulations regained susceptibility to HIV replication, including TEM (>3.79-fold;p=0.0485) and TEMRA (>4.93-fold;p=0.0317). 4) Antiviral cytotoxicity increased 4.22-fold (p=0.0156) in PBMCs from Non-relapsed after 1-year of ponatinib and remained enhanced for 12 months of TFR. 5) NK cells increased 1.86-fold (p=0.0061) after 1-year on TFR in Non-relapsed, with 3.51-fold (p=0.0476) increased degranulation capacity.


CONCLUSIONS: One-year treatment with ponatinib preserved SAMHD1 in CD4 and induced sustained cytotoxic effect, impeding HIV infection and reservoir formation. Antiviral protection was maintained 12 months during TFR in correlation with sustained antileukemic response. Short-term intensification treatment with dasatinib or ponatinib could be used for HIV cure strategies.

Download the e-Poster (PDF)