Collini, PJ;
Bewley, MA;
Mohasin, M;
Marriott, HM;
Miller, RF;
Geretti, A-M;
Beloukas, A;
... Dockrell, DH; + view all
(2018)
HIV gp120 in Lungs of ART-treated Individuals Impairs Alveolar Macrophage Responses To Pneumococci.
American Journal of Respiratory and Critical Care Medicine
, 197
(12)
pp. 1604-1615.
10.1164/rccm.201708-1755OC.
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Abstract
RATIONALE: People living with HIV (PLWH) are at significantly increased risk of invasive pneumococcal disease, despite long-term antiretroviral therapy (ART). The mechanism explaining this observation remains undefined. OBJECTIVES: We hypothesized apoptosis-associated microbicidal mechanisms, required to clear intracellular pneumococci that survive initial phagolysosomal killing, are perturbed. METHODS: Alveolar macrophages (AM) were obtained by bronchoalveolar lavage (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 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-cell lymphocytosis, and gp120 or HIV-1 RNA was also detected. Despite this, transcriptional activity in AM freshly isolated from PLWH 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.
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