Immune activation correlates with and predicts CXCR4 co-receptor tropism switch in HIV-1 infection
Bridgette J. Connell, Lucas E. Hermans, Annemarie M. J. Wensing, Ingrid M. M. Schellens, P Schipper, Petra M. van Ham, Dorien T. C. M. de Jong, Sigrid A. Otto, Tholakele Mathe, Robert Moraba, José A. M. Borghans, Maria A. Papathanasopoulos, Zita Kruize, François Venter, Neeltje A. Kootstra, Hugo Tempelman, Kiki Tesselaar, Monique Nijhuis
Abstract
Abstract HIV-1 cell entry is mediated by binding to the CD4-receptor and chemokine co-receptors CCR5 (R5) or CXCR4 (X4). R5-tropic viruses are predominantly detected during early infection. A switch to X4-tropism often occurs during the course of infection. X4-tropism switching is strongly associated with accelerated disease progression and jeopardizes CCR5-based HIV-1 cure strategies. It is unclear whether host immunological factors play a causative role in tropism switching. We investigated the relationship between immunological factors and X4-tropism in a cross-sectional study in HIV-1 subtype C (HIV-1C)-infected patients and in a longitudinal HIV-1 subtype B (HIV-1B) seroconverter cohort. Principal component analysis identified a cluster of immunological markers (%HLA-DR + CD4 + T-cells, %CD38 + HLA-DR + CD4 + T-cells, %CD38 + HLA-DR + CD8 + T-cells, %CD70 + CD4 + T-cells, %CD169 + monocytes, and absolute CD4 + T-cell count) in HIV-1C patients that was independently associated with X4-tropism (aOR 1.044, 95% CI 1.003–1.087, p = 0.0392). Analysis of individual cluster contributors revealed strong correlations of two markers of T-cell activation (%HLA-DR + CD4 + T-cells, %HLA-DR + CD38 + CD4 + T-cells) with X4-tropism, both in HIV-1C patients (p = 0.01;p = 0.03) and HIV-1B patients (p = 0.0003;p = 0.0001). Follow-up data from HIV-1B patients subsequently revealed that T-cell activation precedes and independently predicts X4-tropism switching (aHR 1.186, 95% CI 1.065–1.321, p = 0.002), providing novel insights into HIV-1 pathogenesis and CCR5-based curative strategies.