Bacterial pneumonia remains one of the most common complications of HIV infections. In spite of our growing understanding of the pathogenesis of the immune deficiency associated with HIV infection, the factors that predispose HIV+ individuals to pneumonia remain obscure. For example, the risk of pneumonia for HIV infected individuals is 6 fold higher than for HIV-individuals. This risk can only partially be explained by lower blood CD4 counts. Our preliminary experiments demonstrate that the lung CD4 counts remain normal in the face of falling peripheral counts when compared to HIV uninfected subjects. However, CD8+ lymphocytes are markedly increased in the lung, a hallmark of HIV infection. These cytotoxic CD8+ lymphocytes (CTLs) are believed to function to suppress viral replication. In this context, the primary defense against bacterial infections in the lung is provided by alveolar macrophages which are also the prime source of HIV in the lung. Since macrophage HIV infection is enhanced by inflammatory events, we have hypothesized that 1) initiation of antibacterial function by lung macrophages induces local HIV replication, and 2) as a consequence of this increase in viral burden, lung CTLs may be signaled to suppress this viral replication. This suppression of virus may in the process suppress macrophage antibacterial function. We therefore, propose to test these hypotheses by studying the macrophage's ability to phagocytose opsonized particles. We will evaluate lung macrophages from HIV infected individuals and normal controls to test whether opsonized phagocytosis induces viral replication in the macrophage. As a corollary we will determine whether CTLs can impair macrophage phagocytosis. These in vitro experiments will be corroborated by studies of lung macrophages taken at the time of bacterial pneumonia. Together these experiments will improve our understanding of how the innate immune defense against bacteria is affected by attempts to suppress HIV in macrophages.
| Wewers, Mark D; Lemeshow, Stanley; Lehman, Amy et al. (2005) Lung CD4 lymphocytes predict survival in asymptomatic HIV infection. Chest 128:2262-7 |
| Fahy, Ruairi J; Lichtenberger, Frank; McKeegan, Christine B et al. (2003) The acute respiratory distress syndrome: a role for transforming growth factor-beta 1. Am J Respir Cell Mol Biol 28:499-503 |
| Bhatt, Nitin Y; Kelley, Todd W; Khramtsov, Valery V et al. (2002) Macrophage-colony-stimulating factor-induced activation of extracellular-regulated kinase involves phosphatidylinositol 3-kinase and reactive oxygen species in human monocytes. J Immunol 169:6427-34 |
| Fahy, R J; Diaz, P T; Hart, J et al. (2001) BAL and serum IgG levels in healthy asymptomatic HIV-infected patients. Chest 119:196-203 |
