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HIV gp120 in Lungs of ART-treated individuals impairs alveolar macrophage responses to pneumococci

HIV gp120 in Lungs of ART-treated individuals impairs alveolar macrophage responses to pneumococci
HIV gp120 in Lungs of ART-treated individuals impairs alveolar macrophage responses to pneumococci

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, ultra-sensitive 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-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.

Journal Article
1073-449X
1604-1615
Collini, Paul J.
4a93e099-0be4-4841-ac9a-ab65baa1e4ce
Bewley, Martin A.
1412f184-67e0-4fe7-8692-db253d411471
Mohasin, Mohamed
a0667d9b-e09a-4568-b223-80d5a3840ebd
Marriott, Helen M.
34ca8904-d637-4081-b34c-12be45ecef9f
Miller, Robert F.
7d4c5365-a2ca-4a7c-9017-03da278aa03b
Geretti, Anna-Maria
8d3987ff-898e-45fa-8f77-d722e8fa848f
Beloukas, Apostolos
8ad81553-12f1-47a6-854c-a1d6317c4368
Papadimitropoulos, Athanasios
4f058899-9111-44fa-b707-1fa8ad94d3c3
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Noursadeghi, Mahdad
c86534b2-c59d-4f43-8af4-48ecba03b5ee
Dockrell, David H.
a068c9bf-35b8-4c10-8f91-58639cfeca0b
Collini, Paul J.
4a93e099-0be4-4841-ac9a-ab65baa1e4ce
Bewley, Martin A.
1412f184-67e0-4fe7-8692-db253d411471
Mohasin, Mohamed
a0667d9b-e09a-4568-b223-80d5a3840ebd
Marriott, Helen M.
34ca8904-d637-4081-b34c-12be45ecef9f
Miller, Robert F.
7d4c5365-a2ca-4a7c-9017-03da278aa03b
Geretti, Anna-Maria
8d3987ff-898e-45fa-8f77-d722e8fa848f
Beloukas, Apostolos
8ad81553-12f1-47a6-854c-a1d6317c4368
Papadimitropoulos, Athanasios
4f058899-9111-44fa-b707-1fa8ad94d3c3
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Noursadeghi, Mahdad
c86534b2-c59d-4f43-8af4-48ecba03b5ee
Dockrell, David H.
a068c9bf-35b8-4c10-8f91-58639cfeca0b

Collini, Paul J., Bewley, Martin A., Mohasin, Mohamed, Marriott, Helen M., Miller, Robert F., Geretti, Anna-Maria, Beloukas, Apostolos, Papadimitropoulos, Athanasios, Read, Robert C., Noursadeghi, Mahdad and Dockrell, David H. (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), 1604-1615. (doi:10.1164/rccm.201708-1755OC).

Record type: Article

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, ultra-sensitive 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-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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Accepted/In Press date: 23 January 2018
e-pub ahead of print date: 24 January 2018
Published date: 15 June 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 422255
URI: http://eprints.soton.ac.uk/id/eprint/422255
ISSN: 1073-449X
PURE UUID: 4b064b67-99d7-4087-9958-f55ed4dae575
ORCID for Robert C. Read: ORCID iD orcid.org/0000-0002-4297-6728

Catalogue record

Date deposited: 19 Jul 2018 16:30
Last modified: 26 Nov 2021 05:28

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Contributors

Author: Paul J. Collini
Author: Martin A. Bewley
Author: Mohamed Mohasin
Author: Helen M. Marriott
Author: Robert F. Miller
Author: Anna-Maria Geretti
Author: Apostolos Beloukas
Author: Athanasios Papadimitropoulos
Author: Robert C. Read ORCID iD
Author: Mahdad Noursadeghi
Author: David H. Dockrell

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