Background
A virulent HIV-1 subtype B clade (VB) first reported in 2022 (Wymant et al. 2022), is linked to higher viral loads (VL), faster CD4+ T-cell decline, and greater transmissibility. This presents significant challenges for clinical management due to its faster disease progression. The study aims to elucidate the effects of VB on clinical outcomes and host proteomic profiles.
Methods
Viral genetic analysis was performed on 1,895 people living with HIV (PLWH) on ART from the 2000HIV cohort using partial env and pol sequencing of gDNA samples extracted from CD4+ T-cells. Phylogenetic analysis using IQ-TREE (subtype B), confirmed the presence of VB. The profiling of 2,367 proteins was assessed using proximity extension assay technology (OLINK proteomics). Associations of VB with clinical parameters were assessed using the Wilcoxon Rank-Sum Test. Differential protein expression analysis between VB and non-VB was performed using a linear regression model adjusting for covariates such as age, smoking status, and other factors that accounted for at least 3% of the variance in the plasma proteome.
Results
The VB was confirmed in 32 participants (male, diagnosed between 2004-2019, median ART duration before sampling: 9.93 years). Tropism profiles were R5 (n=22), X4 (n=3), and mixed-tropic (n=2) (Fig1A). VB participants had higher pre-cART VL(p=0.00099) and zenith VL (p =0.013), and more rapid CD4+ T-cell decline. Proteomic analysis revealed significant differential expression in 10 out of 2,376 proteins between VB and non-VB post-ART (Fig1B). Some of these proteins are already known to be involved in HIV progression. Notably, IDO1, an important player in tryptophan metabolism and immune regulation, was upregulated, potentially contributing to heightened immune dysregulation in VB. Additionally, IL-1B and ARF6 were upregulated, suggesting a more severe inflammatory response and modulation of crucial HIV life cycle processes, respectively. In contrast, TREH, a protein involved in carbohydrate metabolism, was downregulated which may indicate metabolic disturbances. Trehalose, TREH’s substrate, was shown to inhibit HIV post-entry by modulating autophagy, possibly affecting viral replication.
Conclusions
VB is linked to more severe clinical outcomes and distinct proteomic changes, especially in immune response, inflammation, and metabolism, which may contribute to the clade’s aggressiveness. Despite a decade of ART, proteomic profile changes persist in individuals with VB.