Determining the role of HIV-DNA in relation to activated monocytes in the development of HIV-associated neurocognitive disorders
Determining the role of HIV-DNA in relation to activated monocytes in the development of HIV-associated neurocognitive disorders
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2010-12
Authors
Agsalda, Melissa Anne
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[Honolulu] : [University of Hawaii at Manoa], [December 2010]
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Abstract
There has been an increase in the prevalence of HIV-associated neurocognitive disorders (HAND) in spite of effective antiretroviral therapy (ART). It is believed that activated monocytes, CD14+/16+, are involved in the HAND pathogenesis through trafficking of HIV into the central nervous system (CNS). Once inside, CD14+/16+ cells initiate inflammation resulting in neuronal damage. Monocytes are also able to harbor HIV and serve as viral reservoirs, which are identified by presence of HIV DNA. These concepts are supported by findings in our lab where individuals with HAND have higher HIV DNA copy numbers in circulating CD14+/16+ cells compared to other cell subsets. The goal of this study is to characterize HIV DNA in these cells from other compartments through experiments on cerebrospinal fluid (CSF) and archival CNS tissue. The overall hypothesis is HIV DNA levels in cell subsets correspond to observations in the periphery. We also posit that insertional mutagenesis may be involved in neuropathogenesis through disruption of genes that may drive inflammation and neuronal apoptosis. Thus, HIV integration studies were done to determine genes that within and around the integration sites in the various CSF subsets.
Results of HIV DNA levels in the CSF cell subsets were in contrast to levels reported in the periphery. Non-activated monocytes, CD14+/16-, contained the highest levels of HIV DNA regardless of neurocognitive status. This suggests that CSF viral reservoirs may be present that serve as sanctuaries for HIV evolution and compartmentalization. Conversely, the highest levels of HIV DNA were found in CD14+/16+ in HIV-encephalitis brain sections, which may reflect ongoing inflammation that might be occurring. Furthermore, common CSF integration sites were found within genes that were involved in apoptosis, macrophage behavior, and transcriptional regulation; all of which could promote HAND. The studies included the use of a unique flow cytometry technique that was shown to be comparable to our current quantitative real-time PCR assay to detect HIV DNA. The information obtained through these studies sets the stage for the focus of future studies and provide additional molecular tools to monitor the involvement of monocytes throughout the progression of HAND.
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Ph.D. University of Hawaii at Manoa 2010.
Includes bibliographical references.
Includes bibliographical references.
Keywords
HIV-DNA,
neurocognitive disorder
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Theses for the degree of Doctor of Philosophy (University of Hawaii at Manoa). Cell and Molecular Biology.
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