The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers

FUNDING. Instituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation.BACKGROUND. Persistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure. METHODS. The characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq). RESULTS. PCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs. CONCLUSIONS. These results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.Instituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127, PI22/01796)Gilead Fellowships (GLD22/00147)NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHEBill and Melinda Gates Foundatio

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers.

BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).RESULTSPCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONSThese results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.FUNDINGInstituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation

Fabrication and characterization of CeO2 pellets for simulation of nuclear fuel

Cerium Oxide, CeO, has been shown as a surrogate material to understand irradiated Mixed Oxide (MOX) based matrix fuel for nuclear power plants due to its similar structure, chemical and mechanical properties. In this work, CeO pellets with controlled porosity have been developed through conventional powder-metallurgy process. Influence of the main processing parameters (binder content, compaction pressure, sintering temperature and sintering time) on porosity and volumetric contraction values has been studied. Microstructure and physical properties of sintered compacts have also been characterized through several techniques. Mechanical properties such as dynamic Young's modulus, hardness and fracture toughness have been determined and connected to powder-metallurgy parameters. Simulation of nuclear fuel after reactor utilization with radial gradient porosity is proposed

Processing and characterization of surrogate nuclear materials with controlled radial porosity

Irradiated fuel pellets present radial gradient porosity. CeO has been proven as a surrogate material to understand irradiated mixed oxide (MOX) due to its similar structural and mechanical properties. A novel compaction device was developed to produce CeO cylindrical pellets with controlled radial porosity. Three blends of CeO with different binder contents (0.5, 3 and 7.5 vol.% of ethylene-bis-stearamide, EBS) were prepared and used to obtain three different porosities for the core, intermediate and outer rings of pellets, respectively. Different compaction pressures were employed in each region to get the intended porosities. The whole pellet was subjected to a heating rate up to 500 °C to remove the EBS binder. Finally, a pressureless sintering step was performed at 1700 °C for 4 h. A microstructural characterization was performed in the three areas, including grain size and porosity. Mechanical properties like hardness, fracture toughness and tribo-mechanical response, as scratch resistance, were also determined. Pellets fabricated from this device have shown microstructural and mechanical properties with a good correlation to those of irradiated nuclear fuel

Diseño, procesado y caracterización, procesado y caracterización de materiales con porosidad radial controlada para aplicaciones nucleares

Las pastillas de combustible irradiado presentan un gradiente de porosidad radial como consecuencia de la presencia de gas He y otros productos de fisión que modifican su microestructura. El óxido de Cerio, CeO2, ha mostrado ser un material de características similares a los óxidos utilizados como combustible en los reactores nucleares. El objetivo de este trabajo es la implementación de un dispositivo de compactación novedoso para obtener pastillas de CeO2 con una porosidad radial controlada. Se emplean presiones de compactación de 460 y 700 MPa y contenidos de cera EthyleneBis-Stearamide (EBS) de 0.5, 3 and 7.5% vol., para obtener tres zonas diferentes en la pastilla. Finalmente, todo el conjunto es sometido al mismo protocolo de eliminación de EBS (una tasa de calentamiento de 5ºC/min manteniendo la pastilla 4 horas a 500ºC) y de sinterización (1700ºC, 4h, aire). La caracterización microestructural incluye la porosidad y el tamaño de grano, caracterizadas en las tres zonas. Las propiedades tribo-mecánicas incluyen la microfractura por indentación (KIc) y la resistencia al rayado (carga constante).Irradiated fuel pellet present a radial gradient porosity as a result of the occurrence of He gas and other fission products that modify its nuclear fuel microstructure. Cerium Oxide, CeO2, has been shown as a surrogate material to understand irradiated Mixed Oxide (MOX) based matrix fuel for nuclear power plants due to its similar characteristics. The aim of this work is the implementation of a novel compaction device to produce CeO2 pellets with a radial controlled porosity. Compaction Pressures of 460 and 700 MPa have been employed and binder contents, Ethylene-Bis-Stearamide (EBS), of 0.5, 3 and 7.5% vol. in order to obtain three different areas in the pellet. Finally, the whole pellet is subjected to the same protocol in order to eliminate EBS (heating rate of 5ºC/min up to 4h at 500ºC) and a sinterization process at 1700ºC for 4 hours in air. Microstructure characterization includes grain size and porosity, being characterized in the three areas. Tribo-mechanical properties such as scratch resistance (constant load), dynamic Young’s modulus, hardness and indentation microfracture (KIc) have also been determined