Assistant Professor of Pathology
Chief of Service Pathology
Division of Comparative Pathology

Dr. Westmoreland's primary research interests have been the neuropathogenesis of SIV in the rhesus macaque as a model of HIV encephalitis and AIDS dementia, pediatric neuropathogenesis of SIV, CNS viral entry, and SIV-associated neuronal dysfunction. She has examined the roles of chemokine receptors in leukocyte trafficking to the brain, CNS development, and in neuronal and glial dysregulation and injury associated with SIV.

Although HIV and SIV do not infect neurons, neuronal injury, dysfunction, and death are significant causes of neurological impairment in AIDS patients. Similar to HIV infection of the CNS in adult humans, approximately 30% of SIVmac251-infected rhesus macaques develop SIV encephalitis (SIVE), characterized by perivascular accumulation of macrophages and multinucleated giant cells. Although neurons are not productively infected, many express functional chemokine receptors, including CCR5 and CXCR4, which serve as cofactors for HIV and SIV infection. These receptors can mediate damaging signals by gp120, which has been shown to signal through CCR5 and CXCR4 on CD4-negative neurons in culture and cause calcium flux or apoptosis. We have demonstrated that CCR5 and CXCR4 neuronal expression increases during development from birth to 9 months of age in the rhesus. In addition, CCR5 expression in cortical neurons emerged as a bimodal or differential expression pattern where large pyramidal neocortical neurons expressed much higher levels of CCR5 than did neighboring neurons. This differential expression of chemokine receptors in neurons may contribute to the selective vulnerability of subpopulations of neurons observed in HIV and SIV neuropathogenesis. In brain from SIV-infected macaques with encephalitis, there is also increased expression of CCR5 in glia and alterations of CCR5 and CXCR4 expression in neurons. The dynamic neuronal expression pattern of these two chemokine receptors suggests that members of this class of seven-transmembrane receptors have multiple complex functions, many of which are still unknown.

SIV strains, in general, utilize CCR5, but there is differential utilization of CCR5 by macrophage and T cell tropic strains of SIV. Recent evidence indicates that gp120 of certain strains of HIV and many strains of SIV are able to interact directly with chemokine receptors independent of CD4. In studies with collaborators, we have demonstrated that SIV brain isolates contain CD4-independent strains that are R5- or R5X4-utilizing. These virions and viral gp120 can interact directly with chemokine receptors on CD4-negative cells, including neurons, resulting in aberrant signaling and/or inhibition of natural ligands from binding to chemokine receptors thereby blocking signaling pathways required for normal cellular functions.

Post-mortem analyses of AIDS cases with dementia have revealed neuronal apoptosis, loss, and damage to the synaptodendritic apparatus, which corresponds to significant decreases in the neuronal marker N-acetylaspartate (NAA) in brain magnetic resonance spectroscopy (MRS) studies in patients. Simian immunodeficiency virus (SIV)-infected rhesus macaques develop encephalitis histopathologically similar to HIV encephalitis and demonstrate neuronal apoptosis and synaptodendritic damage. Longitudinal studies with collaborators using MRS to examine acute and chronic SIV-infected rhesus macaques have revealed decreased neuronal N-acetylaspartate (NAA), which has a statistically significant linear correlation (p‹0.018) with reduced expression of the presynaptic protein synaptophysin. In further studies, animals experimentally depleted of CD8 T lymphocytes developed encephalitis at a higher percentage (75-100%) compared to the undepleted SIV-infected animals, underscoring the importance of CD8-mediated anti-viral control early in infection and the eventual development of SIVE. In addition, animals treated with antiretroviral therapy demonstrated a decrease in plasma viral loads, rapid removal of virus from the brain, and near complete reversal of NAA within 2 weeks post-treatment. The reversal of NAA suggests rapid and acute mechanisms of neuronal injury and repair play important roles in SIV neuropathogenesis.