Background and Aims: HIV infection increases autoantibodies against apolipoprotein A1 (AAA1). We investigated their possible relationship with high-density lipoproteins (HDL) particle proteome and subfractions.

Methods: This case-control study consisted in three groups: healthy volunteers (n=50), people living with HIV (PLWH) on antiretroviral therapy (ART) (n=50), PLWH ART-naïve (n=44), in whom AAA1, HDL proteome and subfractions were characterized. AAA1 serum levels were assessed with an in-house immunoassay. Proteome profiling was performed using LC-MS/MS (DIA). HDL particle subfractions were analysed using the Lipoprint® system, and inflammatory biomarkers were measured using the Meso Scale Discovery® platform. Framingham risk score (FRS), carotid intima thickness (cIMT) and flow-mediated dilation (FMD) were determined individually.

Results: PLWH on ART revealed the highest significant modulations in HDL particles: 37 HDL features were modified compared to 18 in PLWH ART-naïve and 8 in healthy volunteers. In PLWH with ART, AAA1 was associated with proteins related of HDL metabolism and dysfunction, such as decreased apolipoprotein AII, apolipoprotein CIII, lecithin cholesterol acyltransferase or paraoxonase-1. This latter was negatively correlated with levels of circulating VCAM-1 and ICAM-1. In PLWH ART-naïve, AAA1 was associated with higher HDL content of phospholipid transfer protein and with larger HDL particles. In healthy volunteers, AAA1 was associated with higher serum amyloid A protein content in HDL, which was positively correlated with circulating c-reactive protein levels. None of HDL proteome signatures, AAA1 seropositivity were found to be associated with FRS, cIMT or FMD in any subgroups.

Conclusions: These results indicate that AAA1 response is associated with HDL proteome signatures known to be associated with HDL dysfunction or metabolism. In PLWH ART-naïve AAA1 were associated with larger HDL subfractions, controversially associated with cardiovascular risk. These results highlighted that group-specific HDL profiles are differentially associated with AAA1. Knowing whether these would translate in changes of HDL functions and atherosclerosis burden in HIV patients warrants further investigations.