LBPE06 - Poster Exhibition
Immunological correlates of HIV-1 DNA decline during latency reversal with panobinostat in patients on suppressive cART
M. Tolstrup1,2, S. Vigano3, R. Olesen1, C. Brinkmann1, M. Buzon3, L. Østergaard1,2, T. Rasmussen1,2, M. Lichterfeld3, O. Søgaard1,2
1Aarhus University Hospital, Department of Infectious Diseases, Aarhus, Denmark, 2Aarhus University, Institute of Clinical Medicine, Aarhus, Denmark, 3Ragon Institute, MGH, MIT and Harvard University, Boston, United States
Background: Reversing HIV-1 latency is a possible strategy to reduce the HIV-1 reservoir, but elimination of latently infected cells likely depends on immune mechanisms. In a clinical trial that included 15 HIV-patients, 8 weeks of cyclic therapy with the HDACi panobinostat, significantly increased HIV-1 transcription and plasma HIV-1 RNA. At cohort level, HIV-1 DNA did not change but persistent reductions in total HIV-1 DNA were observed in some patients. Here, we report associations between changes in HIV-1 DNA during panobinostat treatment and 1) viral rebound during analytical treatment interruption (ATI); and 2) immune effector characteristics.
Methods: During ATI, viral load and CD4 T cell counts were monitored twice weekly. Total and integrated HIV-1 DNA in CD4 T cells was determined using digital droplet PCR. HIV-1-specific CD8 T cells were analyzed using interferon-γ elispots with an individual HLA-class I-matched library of epitopic peptides. Frequencies and phenotypic characteristics of NK cells, T cells, as well as regulatory T cells were determined before, during, and after panobinostat treatment using multiparametric flow cytometry.
Results: Viral rebound occurred in all ATI participants (n=9) with a median time to viral rebound >1,000 copies/ml of 17 days (range 14-56). Time to viral rebound correlated significantly with reductions in both total (p=0.0003) and integrated HIV-1 DNA (p=0.018) during panobinostat treatment. The breadth and magnitude of HIV-1-specific CD8 T cell responses to HIV peptides expanded significantly during panobinostat treatment, but this was not correlated to changes in HIV-1 DNA. However, low baseline levels of PD-1 expressing CD8 T cells strongly predicted a sustained decrease in HIV-1 DNA levels (p=0.001). Further, declining HIV-1 DNA levels during panobinostat treatment were associated with increasing proportions of activated (CD69+) NK cells (p=0.04) and decreasing expression of the inhibitory NK cell marker NKG2A (p=0.001). Levels of PD-1 on CD4 T cells as well as expression of inhibitory molecules CTLA-4 and CD39 on regulatory T cells were not associated with HIV-1 DNA changes.
Conclusions: In this exploratory analysis, we identified key innate and adaptive immune effector characteristics that correlated with HIV-1 DNA changes during latency reversal. Combining panobinostat with immunotherapy may result in improved elimination of the HIV-1 reservoir.
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