The advent of highly active anti-retroviral therapy (HAART) has reduced the incidence of HIV-1 associated dementia (HIV-D);however, the prevalence has risen, as HIV-1-infected individuals are now living longer with AIDS. The initiation of HAART therapy in patients exhibiting neurocognitive abnormalities has often demonstrated dramatic benefits, despite poor penetrance of anti-retroviral drugs across the blood brain barrier (BBB). Our major hypothesis put forth in this application is that alterations in monocyte/macrophage (MF) homeostasis, which leads to the expansion of a more invasive monocyte subset that is able to enter the CNS compartment in HIV-D, is responsive to HAART. CD163, a hemoglobin/haptoglobin scavenger receptor, has been reported by several groups as an identifying marker of the immunosuppressive macrophage type 2 (MF- 2). We observed significant accumulation of CD163+/CD16+ MFs in the CNS of patients with HIV encephalopathy (HIVE), the neuropathology of HIV-D, located perivascularly, within nodular lesions and in the brain parenchyma. These cells are the major reservoir of productive HIV-1 infection in the CNS. In a separate study, we found an increase in the percent frequency of circulating CD163+/CD16+ monocytes in HIV-1 infected individuals with detectable viral loads when compared with HIV-1 infected persons under successful pharmacological intervention and seronegative individuals. Moreover, expansion of this monocyte subset correlates strongly with viral load and CD4+ T cell loss This subset, which is CD163+/CD16+, may be more permissive to HIV-1 infection and contribute to the development of cognitive dysfunction by bringing virus into the CNS as well as through secreted factors and by-products associated with their activation status. We further hypothesize that the reduction in the incidence of HIV-D in the HAART era is, at least in part, reflective of the ability of HAART to restore monocyte/ MF homeostasis. The studies proposed in this application have three Specific Aims.
Specific Aim 1 will test the hypothesis that monocyte/MF homeostasis is dysregulated in HIV-1 infected individuals, which is attenuated or reversed by successful HAART therapy.
Specific Aim 2 Specific will test the hypothesis that the CD163+/CD16+ perivascular and parenchymal MFs that accumulate in the CNS in HIV-1 infected individuals with encephalopathy exhibit immune polarization, consistent with altered monocyte/MF homeostasis. Finally, Specific Aim 3 will test the hypothesis that monocyte subset homeostasis is altered by HIV-1 infection in vivo and in vitro. The studies proposed in this application should provide novel insights regarding the role of altered monocyte/ MF homeostasis in HIV induced neurocognitive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063605-05
Application #
8241097
Study Section
Special Emphasis Panel (ZMH1-ERB-S (02))
Program Officer
Wong, May
Project Start
2008-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$367,500
Indirect Cost
$122,500
Name
Temple University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Fischer, Tracy; Wyatt, Christina M; D'Agati, Vivette D et al. (2014) Mononuclear phagocyte accumulation in visceral tissue in HIV encephalitis: evidence for increased monocyte/macrophage trafficking and altered differentiation. Curr HIV Res 12:201-12
Tavazzi, Eleonora; Morrison, David; Sullivan, Peter et al. (2014) Brain inflammation is a common feature of HIV-infected patients without HIV encephalitis or productive brain infection. Curr HIV Res 12:97-110
Levine, Seymour; Saltzman, Arthur; Ginsberg, Stephen D (2011) Vacuolar pathology in the median eminence of the hypothalamus after hyponatremia. J Neuropathol Exp Neurol 70:151-6