AbstractsBiology & Animal Science

Monocyte / Macrophage Traffic Plays an Essential Role in HIV and SIV Pathogenesis

by Jennifer Helen Campbell

Institution: Boston College
Year: 2014
Keywords: Brain; HIV / SIV; Macrophage; Monocyte; neuroAIDS; Small Intestine
Record ID: 2032181
Full text PDF: http://hdl.handle.net/2345/3823


Elucidating the mechanisms through which viral infection and persistence in CNS occurs is critical to understanding the development and progression of neurological disease. To date, no study has demonstrated that monocyte traffic in HIV and SIV infection directly results in neuronal injury. The central hypothesis in this thesis is that continuous trafficking of monocytes into tissues is essential for pathogenesis with viral infection. In the dissertation work presented here, two studies addressed this hypothesis. In Chapter 2, experiments examining the role of peripheral monocyte activation in the development of neuroAIDS using the tetracycline antibiotic minocycline will be described. We hypothesized that decreased monocyte activation with minocycline treatment would play a neuroprotective role in the context of rapid SIV infection with a high incidence of SIV encephalitis (SIVE). We observed a reversal of neuronal injury within days of minocycline treatment that correlated with loss of monocyte activation. From these findings we concluded that decreased activation of monocytes results in lower CNS traffic. However this effect may have occurred due to lower plasma virus, decreased SIV infection of monocytes, or the ability of minocycline to cross the BBB and modulate changes within the CNS directly. In Chapter 3 of this thesis, we hypothesized that continuous traffic of activated monocytes from the periphery into the CNS is required for neuronal injury with AIDS, and that by effectively stopping monocyte accumulation, CNS pathology can be blocked or reversed. We also hypothesized that monocyte trafficking is necessary for the seeding of brain and small intestine with cell-associated virus. In order to test these hypotheses, we utilized the anti-α4 blocking antibody natalizumab (Tysabri; Biogen Idec), which selectively binds to the α4 subunit of α4β1 (VLA-4) and α4β7 integrins, preventing the interaction between α4 and its various ligands. To address the first hypothesis, natalizumab was administered after four weeks of infection once significant neuronal damage had already occurred. We found that preventing cell traffic with natalizumab is sufficient to stabilize neuronal injury and loss, demonstrating conclusively that stopping monocyte traffic stabilizes CNS disease. To address the second hypothesis, rhesus macaques were treated with natalizumab on the day of SIV infection. Natalizumab treatment completely blocked SIV infection in the brain, and virus traffic to the small intestine was significantly suppressed. Overall, these studies demonstrate that continuous traffic of monocytes is required for neuronal injury and the formation of CNS lesions, and that early trafficking of leukocytes is critical for seeding of the CNS and contributes to seeding of the small intestine with virus.