Immune exhaustion, Telomere and Immune Response Effects on DLco in HIV– The I’M TIRED-HIV Study

About This Grant

ABSTRACT People with HIV (PWH) are at a greater risk for chronic lung diseases compared to the general population, even with effective antiretroviral therapy (ART) and controlling for smoking and other risk factors. Diffusing capacity for carbon monoxide (DLCO) measures the ability of the lungs to transfer gas from inspired air to red blood cells. A reduced DLCO is the most common abnormality on pulmonary function testing (PFTs) in PWH and is associated with increased respiratory symptom burden and mortality. Our preliminary results show that 1) Using NanoString technology measuring 945 unique genes, a list of interferon pathway and inflammation genes are upregulated in PBMCs from PWH with impaired DLCO. 2) In spectral flow cytometry, cell surface expression of the Interferon γ -induced protein 10 (IP-10) receptor CXCR3 is lower in subsets of CD4 T cells and all CD8 T cell subtypes in PWH with impaired DLCO, including impaired DLCO with normal spirometry, a phenotype which we have termed iso↓DLCO, suggesting compromised type I T helper (Th1) CD4 function and CD8 T maturation defects. 3) In single cell RNAseq analysis, interferon α and γ pathways are upregulated in CD4 and CD8 cells, while TNF α signaling pathway is downregulated in CD4, CD8 and monocytes in PWH with impaired DLCO, suggesting immune exhaustion. 4) In bulk RNAseq analysis of cells from bronchoalveolar lavage (BAL), impaired DLCO is associated with an enriched oxidative phosphorylation pathway, potentially reflecting immune activation. 5) DLCO is positively correlated with telomere length in monocytes, suggesting that accelerated cellular aging/immune senescence in this specific cell type is associated with impaired DLCO. Taken together, these preliminary results support our central hypothesis that in PWH, immune exhaustion and senescence lead to defective immune functions and these defects contribute to impaired DLCO. These results lead us to propose that immune functional defects in circulating PBMCs (immune exhaustion, immune senescence, compromised Th1 function, CD8 differentiation defects, downregulation of TNFα pathway) lead to a systemic immune environment more permissive to fibrosis and endothelial dysfunction as mechanisms of impaired DLCO. We further propose that CD4, CD8 T cells and monocyte-derived macrophages (MDM) in BAL will have similar defects, and alveolar macrophages (AM) will have immune defects that decrease the ability to clear pathogen and toxin and promote pulmonary fibrosis and endothelial dysfunction. The specific aims are: Aim 1: To test the hypothesis that elevated levels of biomarkers of immune exhaustion in CD4, CD8 T cells and immune senescence in CD4, CD8 T cells and monocytes in PBMCs are associated with impaired DLCO, particularly iso↓DLCO. Aim 2: To test the hypothesis that CD4, CD8 T cells, and monocytes in PBMCs from PWH with impaired DLCO, particularly iso↓DLCO, have ex vivo functional defects. Aim 3: To test the hypothesis that biomarkers of exhaustion, senescence, and immune functional defects are associated with decline in lung function longitudinally (at 2 years). Both Aims 1&2 have a sub-aim to measure BAL samples to compare systemic vs. lung immune defects.