This is a competing renewal grant application requesting continuing support of the project DA017618 """"""""Mouse model of HIV-1 infection and drug addiction"""""""". In the first funding cycle we accomplished our overall objective to develop a model of HIV-1 infection in conventional mice and applied it for studies on HIV-1 neuropathogenesis. Infection of mice induces lasting cognitive deficits that develop despite effective protective anti-HIV-1 immunity and in the absence of overt neuropathology or viral encephalitis. We believe these results establish an animal model of milder forms of HIV-1 Associated Neurocognitive Disorder (HAND). We hypothesize that the etiology of HAND is different from etiology of HIV induced immunodeficiency as indicated in HAND observed early in viral infection in the presence of an intact immune system. We propose that early HAND (E-HAND) is driven by responses of macrophages to HIV-1 infection but its extent is limited by effective antiviral responses. The damage to the nervous system resulting from initial HIV-1 infection in the brain may set the conditions for rapid progression of HAND after the immune system weakens and may represent early brain injury that is poorly responsive to antiretroviral treatments later in infection.
Four Specific Aims are proposed to test these hypotheses:
In Aim 1, we will define will define overall parameters of cognitive/behavioral deficits (E-HAND) in EcoHIV infected immunocompetent mice in relation to the progress of infection.
In Aim 2, we will define the period of HIV-1 infection when the brain is most vulnerable to the induction of E-HAND;these studies will test the hypothesis that adaptive antiviral responses to systemic EcoHIV infection limit EcoHIV replication in the brain but not E-HAND.
In Aim 3, we will test the hypothesis that infiltration of macrophages from the periphery, rather that expansion of virus in the brain, is responsible for the induction of E-HAND under intact immune system.
In Aim 4, we will determine whether induction of immunodeficiency or overt neuropathology in infected animals with E-HAND promotes transition to more severe forms of HAND and whether E-HAND and severe HAND can be reversed by antiviral treatment. These studies will evaluate the possibility that some neurological damage caused by early HIV infection in the brain might be irreversible. We believe that the proposed studies are important in light of the increasingly wide use of antiretrovirals which prevent progression to AIDS but fail to prevent certain forms of HIV-1 neurocognitive disease. Our long-range goal is to employ our model to determine the biological interactions between the behavioral defects experienced during early HIV-1 infection and the injuries inflicted by illicit drug abuse to devise interventions that will preserve cognitive and motor function.

Public Health Relevance

This program proposes will use an animal model system where HIV-1 has been redesigned to infect mice instead of people;when infected by this virus, EcoHIV, mice experience memory problems like those shown in HIV-1 infected people. This program will study in depth the extent of central nervous system disease by relying heavily on tests of behavior, together with tests of EcoHIV presence and activity in the brain as well as tests of the antiviral responses in mice that control EcoHIV and stop its further impairment of brain function. It will identify how HIV-1 injures the brain and test the best approach to spare the brain from further injury.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA017618-06
Application #
8037324
Study Section
Special Emphasis Panel (ZRG1-AARR-K (02))
Program Officer
Pollock, Jonathan D
Project Start
2003-12-01
Project End
2016-02-29
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
6
Fiscal Year
2011
Total Cost
$599,908
Indirect Cost
Name
St. Luke's-Roosevelt Institute for Health Sciences
Department
Type
DUNS #
623216371
City
New York
State
NY
Country
United States
Zip Code
10019
Olson, Katherine E; Bade, Aditya N; Namminga, Krista L et al. (2018) Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. J Neurovirol 24:398-410
Nitkiewicz, Jadwiga; Borjabad, Alejandra; Morgello, Susan et al. (2017) HIV induces expression of complement component C3 in astrocytes by NF-?B-dependent activation of interleukin-6 synthesis. J Neuroinflammation 14:23
Geraghty, Patrick; Hadas, Eran; Kim, Boe-Hyun et al. (2017) HIV infection model of chronic obstructive pulmonary disease in mice. Am J Physiol Lung Cell Mol Physiol 312:L500-L509
Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48
Moidunny, Shamsudheen; Matos, Marco; Wesseling, Evelyn et al. (2016) Oncostatin M promotes excitotoxicity by inhibiting glutamate uptake in astrocytes: implications in HIV-associated neurotoxicity. J Neuroinflammation 13:144
Rappaport, Jay; Volsky, David J (2015) Role of the macrophage in HIV-associated neurocognitive disorders and other comorbidities in patients on effective antiretroviral treatment. J Neurovirol 21:235-41
Sindberg, Gregory M; Sharma, Umakant; Banerjee, Santanu et al. (2015) An infectious murine model for studying the systemic effects of opioids on early HIV pathogenesis in the gut. J Neuroimmune Pharmacol 10:74-87
He, Hongxia; Sharer, Leroy R; Chao, Wei et al. (2014) Enhanced human immunodeficiency virus Type 1 expression and neuropathogenesis in knockout mice lacking Type I interferon responses. J Neuropathol Exp Neurol 73:59-71
Saini, Manisha; Potash, Mary Jane (2014) Chronic, highly productive HIV infection in monocytes during supportive culture. Curr HIV Res 12:317-24
Potash, Mary Jane; Hadas, Eran; Volsky, David J (2014) Response to 'Remarks on the article of Hadas et al.: Transmission of chimeric HIV by mating in conventional mice: prevention by pre-exposure antiretroviral therapy and reduced susceptibility during estrus'. Dis Model Mech 7:178-9

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