455. HIV-1 modulates macrophage death responses to S. pneumoniae infection
Session: Poster Abstract Session: HIV Pathogenesis and Immunity
Friday, October 21, 2011
Room: Poster Hall B1

Background:

Invasive pneumococcal disease (IPD) is more common in HIV-1 infected individuals. The risk of IPD is only partly reversed following reconstitution of CD4 cells with antiretroviral therapy and is independently associated with HIV-1 viraemia, implicating HIV-1 in disrupting immune defenses against S. pneumoniae (Spn) beyond T cell mediated immunity.  Timely macrophage (Mφ) apoptosis is critical to the early resolution of Spn infection in the lung, yet with HIV are found to exhibit prolonged survival and resistance to apoptosis. We investigated whether HIV-1 infection alters the apoptotic response to Spn.

Methods:

Two models of alveolar Mφ +/- HIV infection were used, the promonocytic cell line U937 v its HIV-1 expressing clonal derivative U1 and monocyte derived macrophages (MDM) from HIV-1 infected individuals v uninfected controls. Each was challenged with opsonised type 2 Spn (D39) or mock infected (MI) and apoptosis measured over 20 hours by cell cycle hypodiploid peak analysis, caspase-3 activity and imaging for changes in nuclear morphology.

Results:

HIV-1 is associated with greater background apoptosis in both models. In differentiated U1 v U937, mean hypodiploid proportions were 26.8% and 16.1% respectively. However, HIV-1 was associated with a smaller increment in apoptosis following Spn challenge of 11.0% v 15.3% at 16 hrs and 10.3% v 23.2% at 20 hrs (p<0.005) respectively. Analysis of nuclear morphology yielded similar results. Caspase activity increased in U937 but decreased in U1 post Spn. For MDM from HIV viraemic subjects/controls hypodiploid increments at 16 hrs were 5.4% and 16.1% respectively.

Conclusion:

In these models, HIV-1 was associated with greater constitutive apoptosis but, following Spn challenge, reduced induction of macrophage apoptosis. In addition, the response to Spn in HIV involved a caspase-3 independent death process. HIV-1 infection may result in a macrophage phenotype that either resists apoptosis or defaults to alternative death pathways in response to Spn. This would undermine the bactericidal and anti-inflammatory advantage gained by normal macrophage apoptosis in response to Spn and may contribute to susceptibility to pneumococcal pneumonia among HIV-1 infected individuals.

 


Subject Category: H. HIV/AIDS and other retroviruses

Paul Collini, MBChB , Infection & Immunity, University of Sheffield, Sheffield, United Kingdom and David Dockrell, MD, Infection and Immunity, University of Sheffield Medical School, Sheffield, United Kingdom

Disclosures:

P. Collini, None

D. Dockrell, None

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