HIV gp120 in the Lungs of Antiretroviral Therapy–treated Individuals Impairs Alveolar Macrophage Responses to Pneumococci
Year: 2018
Type: article
Abstract: Rationale People living with HIV are at significantly increased risk of invasive pneumococcal disease, despite long-term antiretroviral therapy (ART). The mechanism explaining this observation remains undefined. Objectives To determine if apoptosis-associated microbicidal mechanisms, required to clear intracellular pneumococci that survive initial phagolysosomal killing, are perturbed. Methods Alveolar macrophages (AM) were obtained by BAL from healthy donors or HIV-1–seropositive donors on long-term ART with undetectable plasma viral load. Monocyte-derived macrophages (MDM) were obtained from healthy donors and infected with HIV-1BaL or treated with gp120. Macrophages were challenged with opsonized serotype 2 Streptococcus pneumoniae and assessed for apoptosis, bactericidal activity, protein expression, and mitochondrial reactive oxygen species (mROS). AM phenotyping, ultrasensitive HIV-1 RNA quantification, and gp120 measurement were also performed in BAL. Measurements and Main Results HIV-1BaL infection impaired apoptosis, induction of mROS, and pneumococcal killing by MDM. Apoptosis-associated pneumococcal killing was also reduced in AM from ART-treated HIV-1–seropositive donors. BAL fluid from these individuals demonstrated persistent lung CD8+ T lymphocytosis, and gp120 or HIV-1 RNA was also detected. Despite this, transcriptional activity in AM freshly isolated from people living with HIV was broadly similar to healthy volunteers. Instead, gp120 phenocopied the defect in pneumococcal killing in healthy MDM through post-translational modification of Mcl-1, preventing apoptosis induction, caspase activation, and increased mROS generation. Moreover, gp120 also inhibited mROS-dependent pneumococcal killing in MDM. Conclusions Despite ART, HIV-1, via gp120, drives persisting innate immune defects in AM microbicidal mechanisms, enhancing susceptibility to pneumococcal disease.
Institutions: Sheffield Teaching Hospitals NHS Foundation Trust, University of Sheffield, University of Liverpool, National Institute for Health and Care Research, NIHR Southampton Biomedical Research Centre, University of Southampton, University College London, Centre for Inflammation Research, University of Edinburgh
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: World Health Organization, Tulane University, National Institute for Health and Care Research, University College London Hospitals NHS Foundation Trust, National Institutes of Health, Medical Research Council, NIHR Sheffield Clinical Research Facility, National Institute of Allergy and Infectious Diseases
Awards: Integrated multi-dimensional molecular organ imaging, A genetically modified nasopharyngeal commensal as a platform for human bacteriotherapy, Optimising Innate Host Defence to Combat Antimicrobial Resistance, Pathfinder:Experimental Human Challenge with Genetically Modified Commensals to Investigate Respiratory Tract Mucosal Immunity and Colonisation, NIHR Senior Investigator Award, G8765071762
OpenAlex ID: W2783545767