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Abstract
Macrophages adapt their functional characteristics, as the needs of the local environment changes with compounding signals. Both monocytes and macrophages (M/MΦ) can be activated by an inflammatory insult, and have an impressive arsenal of over a hundred different secreted substances that regulate surrounding cells, or act as direct effectors. Cellular activation is a vital factor for HIV-1 infection, because CCR5 and CXCR4 expression make the conditions optimal for HIV-1 entry and replication.
HIV-1 integration occurs as a necessary step in the life cycle allowing for replication and transcription of the viral genome to take place. While HIV-1 is thought to integrate randomly, more recent studies have suggested that integration occasionally occurs in a less random fashion. HIV-1 infection and/or integration takes place in M/MΦ, which may be a common pathogenic link to HIV-1 associated diseases such as malignancies and neurological disorders.
HIV-1 infected individuals are at risk for developing cancers. A common element among lymphomas is the inability to control a pathogen that acts as an ongoing immune activator. Thus, an increased risk of HIV-1 associated malignancies may result from immunodeficiency, increased immune activation and possibly HIV-1 insertional mutagenesis. While there are data to show that non-random HIV-1 integration may occur, our goal was to identify preferential genomic sites where HIV-1 integration might be targeted leading to oncogenesis.
M/MΦ serve as HIV-1 reservoirs and may indirectly lead to HIV-associated dementia (HAD) via neurotoxic cytokine/chemokine production. It remains unknown if peripheral M/MΦ are responsible for both circulating and cerebral spinal fluid (CSF) cytokines/chemokines. Our objective was to determine the relationship between cytokines in the periphery and the CNS among HAD patients. Different cytokines from plasma, CSF, and cultured peripheral M/MΦ supernatants were identified in subjects with HAD versus those with normal cognition, suggesting unique pathways leading to cytokine/chemokine release in the periphery versus the brain region. This may have implications in delineating a cause and effect in HAD pathogenesis. The focus of this dissertation is the role that activated macrophages play in HIV-1 pathogenesis.
