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Control of the HIV-1 DNA Reservoir Is Associated In Vivo and In Vitro with NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells.

Control of the HIV-1 DNA Reservoir Is Associated In Vivo and In Vitro with NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells.
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Marras F, Casabianca A, Bozzano F, Ascierto ML, Orlandi C, Di Biagio A, Pontali E, Dentone C, Orofino G, Nicolini L, Taramasso L, Magnani M, Marincola FM, Wang E, Moretta L, De Maria A,


Marras F, Casabianca A, Bozzano F, Ascierto ML, Orlandi C, Di Biagio A, Pontali E, Dentone C, Orofino G, Nicolini L, Taramasso L, Magnani M, Marincola FM, Wang E, Moretta L, De Maria A, (click to view)

Marras F, Casabianca A, Bozzano F, Ascierto ML, Orlandi C, Di Biagio A, Pontali E, Dentone C, Orofino G, Nicolini L, Taramasso L, Magnani M, Marincola FM, Wang E, Moretta L, De Maria A,

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Journal of virology 2017 09 27() pii JVI.00647-17
Abstract

The size of lentiviral DNA reservoirs reflects effectiveness of immune responses against lentiviruses. So far, abundant information has been gathered on the control of HIV-1 replication, Understanding of innate mechanisms contributing to containment of HIV-DNA reservoir, however, are only partly clarified and are relevant to guide interventions for reservoir containment or eradicationWe studied the contribution of Natural Killer (NK) cell functional features in HIV patients either controlling replication either spontaneously (HIC) or after progression and antiretroviral treatment (PP). An inverse correlation between HIV-DNA copy numbers (either total or integrated) in circulating CD4(+) cells and NK cell function were observed. Induced IFN-γ production and NKp46/NKp30 activating receptor-induced expression correlated inversely with reservoir size. The correlation was present not only when considering a homogeneous cohort of HIC patients, but also when PP patients were included in the analysis. Adaptive (NKG2C(+)CD57(+)) NK cell features were not associated with reservoir size. However a distinct set of 370 differentially expressed transcripts was found to underlie functional differences in NK cells controlling HIV-DNA reservoir size. In proof-of-principle in vitro experiments of CD4(+) cell infection with HIV-1, purified NK cells with the above functional/transcriptional features displayed a 10- and 30-fold higher ability to control HIV replication and DNA burden in vitro, respectively, compared to other NK cells.Thus, NK cells with a specific functional and transcriptional signature contribute to control of HIV reservoir in CD4(+) cells. Their selection, expansion and/or adoptive transfer may support strategies to eradicate HIV-1 infection or to safely deescalate antiretroviral treatment.IMPORTANCE The most relevant feature of HIV-1 infection is represented by its DNA reservoir size in the body that guarantees lifelong infection and resumption of virus replication after antiretroviral treatment interruption. So far, there has been little success in the identification of factors contributing to HIV-1 reservoir containment.Here, by studying quantitative total and integrated HIV-1 DNA and NK cells in HIV-1 patients with both progressive and non-progressive disease, we observed that inducible IFN-γ and Natural Cytotoxicity Receptor (NCR) expression in a specific subset of NK cells with characteristic transcriptional signature represents a correlate for HIV-1 reservoir control. This represents an advance in our understanding of mechanism(s) that control lentivirus reservoir. Monitoring, selection, expansion and adoptive transfer of these NK cells could allow monitoring treatment efficacy, likelihood of reservoir control and could support protocols for HIV-1 eradication.

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