The Effects of Lipoprotein Cholesterol Levels and Particle Sizes on HIV Cell Entry via gp41 C34: Insights from Mendelian Randomization Analysis

Background: The gp41 C34 peptide, which is part of the HIV envelope glycoprotein, is crucial for HIV entry into host cells because it facilitates membrane fusion and serves as a biomarker for viral replication. Lipoproteins, including HDL, LDL, IDL, VLDL, and chylomicrons, affect HIV infection via their cholesterol levels and particle sizes, but their causal relationships with HIV remain unclear. Methods: Utilizing the Mendelian randomization (MR) approach to infer causality, this study leverages genetic data from the UK Biobank (115,082 individuals) and the KORA cohort (997 individuals) to explore the causal relationships between 39 lipoprotein traits (cholesterol levels and subtype concentrations of different particle sizes) and gp41 C34 expression. The primary MR method employed was the random-effect inverse variance weighted (IVW) approach. To ensure robust and reliable causal inference, multiple sensitivity analyses, including weighted median, MR‒Egger regression, simple mode, weighted mode, and leave-one-out analyses, were conducted. Results : Elevated HDL cholesterol levels were significantly associated with reduced gp41 C34 expression (IVW: β = -0.61, SE = 0.186, p = 1.25e-4, FDR = 0.004), suggesting a protective role of HDL cholesterol in HIV infection. Higher HDL particle concentrations were also inversely associated with gp41 C34 expression (IVW: β = -0.549, SE = 0.202, p = 0.007, FDR = 0.032). Increased cholesterol levels in large HDL particles were significantly inversely related to gp41 C34 expression (IVW: β = -0.46, SE = 0.16, p = 0.004, FDR = 0.03). Similarly, higher concentrations of medium HDL particles were linked to lower gp41 C34 expression (IVW: β = -0.473, SE = 0.166, p = 0.005, FDR = 0.028). No significant causal relationships were found between gp41 C34 expression and the cholesterol levels or sizes of IDL, LDL, or VLDL particles or chylomicrons.Consequently, these lipoprotein particles are unlikely to influence gp41 C34 expression and HIV cell entry. Conclusion : HDL cholesterol and HDL particle concentrations, particularly large and medium HDL particles, play a protective role against HIV cell entry by reducing gp41 C34 expression. Other lipoprotein particles do not show significant causal relationships, indicating that specific lipid traits modulate HIV entry mechanisms. These findings enhance our understanding of the influence of lipoprotein traits on HIV infection and persistence.