The air system design requirements for a higher reactivity gasoline fuel (RON70) operating under partially premixed combustion (PPC) in a heavy duty diesel engine was investigated in this study using a 1-D engine system model coupled with 3-D computational fluid dynamics (CFD) analysis. The production engine has a geometric compression ratio of 17.3 and the air system hardware consists of a single stage variable geometry turbine (VGT) with a high pressure exhaust gas recirculation (HP-EGR) loop. The analysis was conducted at six key engine operating points selected from the heavy-duty supplemental emissions test (SET) cycle, i.e. A75, A100, B25, B50, B75, and C100. The engine-out NOx emission target was 1 g/hp-hr to explore the potential of reaching 0.02 g/hp-hr tailpipe NOx emission level with an engine-out particulate matter (PM) target of 0.01 g/hp-hr. Closed-cycle 3-D CFD combustion simulation was conducted across the six engine operating points to identify the proper combustion recipe that delivers high fuel efficiency while keeping the NOx and PM within the targets. The air system boundary conditions and combustion heat release profiles were then provided to a validated 1-D GT-Power engine model for air system development and performance evaluation. The requirement to simultaneously deliver high EGR rates with sufficient boost under PPC operation imposed a challenge on the air-system development. Namely, to transfer the efficiency benefit from combustion (i.e., gross indicated thermal efficiency) to an improvement in the brake thermal efficiency (BTE) by appropriately managing the pumping loss incurred by the air system. In this study we investigated two different air-system configurations: (A) a single-stage turbocharger w/ HP-EGR loop and (B) a two-stage turbocharger w/ HP-EGR loop. Several high efficiency turbocharger maps were examined to meet the PPC air-system boundary requirements. Based on the 1-D engine modeling results, both single-stage and two-stage turbocharger solutions were identified that met the air-system requirements of an engine-out NOx target of 1g/hp-hr across the operating points investigated. Moreover, a detailed energy balance analysis showed that both of the proposed air system configurations led to a BTE improvement compared to the baseline diesel combustion with the stock engine air system hardware. When comparing the two air system configurations, the single-stage turbocharger had lower pumping losses, but required higher peak efficiency for the compressor. In contrast, the two-stage turbocharger was less demanding on peak efficiency for the high pressure compressor, but at the expense of higher pumping losses.