HIV induces airway basal progenitor cells to adopt an inflammatory phenotype

Abstract

Despite the introduction of anti-retroviral therapy, chronic HIV infection is associated with an increased incidence of other comorbidities such as COPD. Based on the knowledge that binding of HIV to human airway basal stem/progenitor cells (BC) induces a destructive phenotype by increased MMP-9 expression through MAPK signaling pathways, we hypothesized that HIV induces the BC to express inflammatory mediators that contribute to the pathogenesis of emphysema. Our data demonstrate that airway BC isolated from HAART-treated HIV+ nonsmokers spontaneously release inflammatory mediators IL-8, IL-1β, ICAM-1 and GM-CSF. Similarly, exposure of normal BC to HIV in vitro up-regulates expression of the same inflammatory mediators. These HIV-BC derived mediators induce migration of alveolar macrophages (AM) and neutrophils and stimulate AM proliferation. This HIV-induced inflammatory phenotype likely contributes to lung inflammation in HIV+ individuals and provides explanation for the increased incidence of COPD in HIV+ individuals.

Lung function declines more rapidly in treated HIV-positive people than in HIV-negative people

“…This has been achieved in cross-sectional studies, most recently with the demonstration that airway basal stem (progenitor) cells isolated from virally suppressed HIV-positive but not HIV-negative non-smokers spontaneously release inflammatory mediators. 10 Thus, the study demonstrated that HIV is associated with faster lung function decline independent of smoking or legacy effects from before initiation of antiretroviral therapy, and further supports a role of chronic immune activation in this association. The phenotypic difference between declines in HIV-related pulmonary function and declines related to smoking provide further support that the evidenced effects on pulmonary health were driven largely by HIV status.…”

Impaired differentiation of small airway basal stem/progenitor cells in people living with HIV

“…PLWH on HAART therapy have chronic lung inflammation 48 – 55 , contributing to HIV-associated aging, lung injury and tissue damage 2 , 21 – 23 , 50 , 53 , 55 , 56 . Our recent studies demonstrate that HIV binding to airway BC increased secretion of MMP-9 and inflammatory mediators 27 , 28 and BC from PLWH showed increased release of IL-8 IL-1β, ICAM-1 and GM-CSF 27 , 28 . These mediators and proteases such as MMPs are collectively known as senescence associated secretory phenotypes (SASP) 57 , 58 .…”

“…Other possible mechanisms of HIV-associated lung aging include direct effect of HIV or viral proteins and opportunistic infections 2 , 23 , 47 . Our prior studies demonstrated that HIV can induce BC to express inflammatory mediators and MMP-9 27 , 28 . We demonstrate that disordered epithelium observed in PLWH is closely associated with BC senescence due to the adverse effects of HAART on BC.…”

“…Human airway basal cells (BC) function as the stem/progenitor cells of the human small airway epithelium (SAE), responsible for maintaining the correct proportions of ciliated and secretory cells that function as the mucociliary component of lung host defense 24 – 26 . Our previous studies showed that HIV binding to BC induces the BC to acquire destructive and inflammatory phenotypes, with increased expression of matrix metalloproteinase-9 (MMP-9) and release of inflammatory mediators, contributing to the tissue destruction and chronic inflammation that characterizes the HIV + lung 27 , 28 . In addition, BC from PLWH have increased release of inflammatory mediators 28 .…”

“…Our previous studies showed that HIV binding to BC induces the BC to acquire destructive and inflammatory phenotypes, with increased expression of matrix metalloproteinase-9 (MMP-9) and release of inflammatory mediators, contributing to the tissue destruction and chronic inflammation that characterizes the HIV + lung 27 , 28 . In addition, BC from PLWH have increased release of inflammatory mediators 28 . Given these altered BC phenotypes, we hypothesized that BC from PLWH may also have altered differentiation capacity and senescence-associated phenotypes, resulting in the disordered airway epithelium observed in PLWH.…”