The Interplay Between Host Genetic Variation, Viral Replication, and Microbial Translocation in Untreated HIV-Infected Individuals

Abstract

Systemic immune activation, a major determinant of human immunodeficiency virus (HIV) disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. Although human genetic variants influencing HIV load have been identified, it is unknown how much the host genetic background contributes to interindividual differences in other determinants of HIV pathogenesis such as gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty acid-binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble CD14 (sCD14), a marker of lipopolysaccharide bioactivity and microbial translocation. We also assessed the correlations between HIV load, sCD14, and I-FABP. Although we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infection.

Keywords: HIV; I-FABP; genome-wide association study; host genomics; immune activation; microbial translocation; sCD14.

Figure 1.

No single-nucleotide polymorphisms are significantly associated with intestinal fatty acid–binding protein (I-FABP) or soluble CD14 (sCD14) plasma levels. Manhattan plots show the distribution of results for the 2 genome-wide association studies, for I-FABP (A) and sCD14 (B) plasma levels. Horizontal axes represent human chromosomes in linear order; vertical axes, association strengths as −log₁₀ P values.

Figure 2.

Intestinal fatty acid–binding protein (I-FABP) and human immunodeficiency virus (HIV) load at set point are independently associated with soluble CD14 (sCD14). Correlations are shown between plasma levels of I-FABP and sCD14 (P = 7.1 × 10⁻¹⁶; r² = 0.09) (A), sCD14 and HIV load (P = 7.1 × 10⁻⁸; r² = 0.04) (B), and I-FABP and HIV load (P = .2; r² < 0.01) (C).