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Title: The modulation of macrophage apoptosis by HIV-1 during Streptococcus pneumoniae infection
Author: Collini, Paul
ISNI:       0000 0004 5348 9997
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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Invasive pneumococcal disease (IPD) causes significant global morbidity and mortality. IPD is also more common in HIV-1-seropositive individuals. Although anti-retroviral therapy (ART) has transformed the outlook of HIV-1 infection, IPD remains up to 30 times more common. The currently available strategies against IPD, vaccination and antimicrobial therapy, have had only modest impact and are less effective in HIV-1. New approaches based on a better understanding of the underlying immunology of these two diseases are needed. A programme of host-mediated macrophage apoptosis ensures killing of pneumococci when canonical phagolysosomal killing capacity is exhausted. HIV-1 is associated with resistance of macrophages to apoptosis. I hypothesised that HIV-1 mediated resistance to S. pneumoniae associated macrophage apoptosis resulting in reduced bacterial killing. I measured the effect of HIV-1 and the HIV-1 antigen gp120 on rates of macrophage apoptosis and bacterial survival in vitro following challenge with S. pneumoniae. Macrophages were derived from monocytic cell lines U937 and U1 (latently infected with HIV-1) or primary human monocytes or alveolar macrophages (AM) were harvested from the lungs of HIV-1-seropositive individuals naive to, or receiving ART and controls by bronchoalveolar lavage (BAL). I also measured the levels of anti-apoptotic Mcl-1 and mitochondrial superoxide following pneumococcal challenge. Additionally, I characterized and compared the T lymphocytes subsets and AM phenotype from the BAL fluid of each group. I found that HIV-1 infection is associated with reduced macrophage apoptosis, a persistence of Mcl-1 expression, altered mitochondrial superoxide generation and decreased bacterial killing following pneumococcal challenge. Altered apoptosis was observed even with low rates of in vitro HIV-1 infection and in AM from virally suppressed, HIV-1 ART treated individuals. gp120 alone was sufficient to mediate these effects. There was a CD8 T cell predominant lymphocytosis in the BAL of HIV-1-seropositive individuals and, in some cases, evidence of ongoing HIV-1 replication in AM, despite ART. These observations demonstrate that apoptosis-associated killing of S. pneumoniae is impaired in HIV-1 infection, potentially through altered Mcl-1 expression and ROS generation. Importantly this defect appears to persist in the alveolar macrophages of virally suppressed HIV-1-seropositive individuals on ART and is associated with an altered T lymphocyte environment in the lung. It is likely that these immune defects contribute to the increased risk of IPD in the HIV-1-seropositive population.
Supervisor: Dockrell, D. H. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available