Association of smoking with neurocognition, inflammatory and myeloid cell activation profiles in people with HIV on ART

Objective: People with HIV (PWH) experience excess comorbidities, including neurocognitive disorders, which are linked to inflammation, particularly monocyte-macrophage activation. Smoking contributes to morbidity and mortality in well-treated PWH. We investigated associations between smoking, neurocognitive function, and inflammation in PWH on ART. Design: We used baseline data on cognition and inflammation from a randomized treatment study among smoking and non-smoking PWH. Participants completed 4 neurocognitive tests (7 measures), with a composite score as the primary measure. Inflammatory markers were plasma sCD14, sCD163, and CCL2/MCP-1; %CD14+ monocytes expressing CD16, CD163, and CCR2; and %CD8+ T cells co-expressing CD38/HLA-DR. Exploratory analyses included a plasma cytokine/chemokine panel, hsCRP, neurofilament light chain (NFL) and monocyte transcriptomes by RNAseq. Results: We recruited 58 PWH (26 smokers, 32 non-smokers). Mean composite and individual neurocognitive scores did not differ significantly by smoking status except for the color shape task; smokers exhibited worse cognitive flexibility, with adjusted mean times 317.2 (95%CI 1.4, 632.9) msec longer than non-smokers. Smokers had higher plasma sCD14 than non-smokers (median(IQR) 1820(1678, 2105) versus 1551(1284, 1760) ng/ml, p=0.009). Other inflammatory markers were not significantly different between smokers and non-smokers. Monocyte transcriptomes showed several functions, regulators and gene sets that differed by smoking status. Conclusions: sCD14, a marker of monocyte activation, is elevated in PWH who smoke. While neurocognitive measures and other inflammatory markers did not generally differ, these data implicate smoking-related myeloid activation and monocyte gene dysregulation in the HIV/smoking synergy driving HIV-associated comorbidities.