Potential drivers
A bird’s eye view of potential – and likely interrelated – mechanisms for chronic lung disease includes chronic immune activation that impairs innate and adaptive immune pathways; chronic inflammation systemically and in the lung despite viral suppression; persistence of the virus in latent reservoirs in the lung, particularly in alveolar macrophages and T cells; HIV-related proteins contributing to oxidative stress; accelerated cellular aging; dysbiosis; and ongoing injury from inhaled toxins.
All are described in the literature and are being further explored. “It’s likely that multiple pathways are playing a role,” said Dr. Crothers, “and it could be that the balance of one to another leads to different manifestations of disease.”
Biomarkers that have been elevated and associated with different features of chronic lung disease – such as airflow obstruction, low DLCO, and emphysema – include markers of inflammation (e.g., C-reactive protein, interleukin-6), monocyte activation (e.g., soluble CD14), and markers of endothelial dysfunction, she noted in a 2021 commentary marking 40 years since the first reported cases of acquired immunodeficiency syndrome.
In her laboratory, Dr. Leung is using new epigenetic markers to look at the pathogenesis of accelerated aging in the lung. By profiling bronchial epithelial brushings for DNA methylation and gene expression, they have found that “people living with both HIV and COPD have the fastest epigenetic age acceleration in their airway epithelium,” she said. The findings “suggest that the HIV lung is aging faster.”
They reported their findings in 2022, describing methylation disruptions along age-related pathways such as cellular senescence, longevity regulation, and insulin signaling.
Dr. Leung and her team have also studied the lung microbiome and found lower microbial diversity in the airway epithelium in patients with HIV than those without, especially in those with HIV and COPD. The National Institutes of Health–sponsored Lung HIV Microbiome Project found that changes in the lung microbiome are most pronounced in patients who haven’t yet initiated ART, but research in her lab suggests ongoing suppression of microbial diversity even after ART, she said.
Dr. Morris is particularly interested in the oral microbiome, having found through her research that changes in the oral microbiome in PWH were more related to impaired lung function than alterations in the lung and gut microbiome. “That may be in part because of the way we measure things,” she said. “But we also think that the oral microbiome probably seeds the lung [through micro-aspiration].” A study published in 2020 from the Pittsburgh site of the MACS described alterations in oral microbial communities in PWH with abnormal lung function.
Preliminary research suggests that improved dental cleaning and periodontal work in PWH and COPD may influence the severity of COPD, she noted.
“We don’t see as much of a signal with the gut microbiome [and HIV status or lung function], though there could still be ways in which gut microbiome influences the lung,” through systemic inflammation, the release of metabolites into the bloodstream, or microbial translocation, for instance, she said.
The potential role of translocation of members of the microbiome, in fact, is an area of active research for Dr. Morris. Members of the microbiome – viruses and fungi in addition to bacteria – “can get into the bloodstream from the mouth, from the lung, from the gut, to stimulate inflammation and worsen lung disease,” she said.