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 #
5R01DA017618-08
Application #
8451906
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
2013-03-01
Budget End
2014-02-28
Support Year
8
Fiscal Year
2013
Total Cost
$634,314
Indirect Cost
$212,069
Name
St. Luke's-Roosevelt Institute for Health Sciences
Department
Type
DUNS #
623216371
City
New York
State
NY
Country
United States
Zip Code
10019
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
Hadas, Eran; Chao, Wei; He, Hongxia et al. (2013) Transmission of chimeric HIV by mating in conventional mice: prevention by pre-exposure antiretroviral therapy and reduced susceptibility during estrus. Dis Model Mech 6:1292-8
Kelschenbach, Jennifer L; Saini, Manisha; Hadas, Eran et al. (2012) Mice chronically infected with chimeric HIV resist peripheral and brain superinfection: a model of protective immunity to HIV. J Neuroimmune Pharmacol 7:380-7
Im, Eung-Jun; Hong, Jessie P; Roshorm, Yaowaluck et al. (2011) Protective efficacy of serially up-ranked subdominant CD8+ T cell epitopes against virus challenges. PLoS Pathog 7:e1002041
Borjabad, Alejandra; Morgello, Susan; Chao, Wei et al. (2011) Significant effects of antiretroviral therapy on global gene expression in brain tissues of patients with HIV-1-associated neurocognitive disorders. PLoS Pathog 7:e1002213
Hayouka, Zvi; Levin, Aviad; Maes, Michal et al. (2010) Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370. Biochem Biophys Res Commun 394:260-5
Borjabad, Alejandra; Brooks, Andrew I; Volsky, David J (2010) Gene expression profiles of HIV-1-infected glia and brain: toward better understanding of the role of astrocytes in HIV-1-associated neurocognitive disorders. J Neuroimmune Pharmacol 5:44-62
Levin, Aviad; Hayouka, Zvi; Brack-Werner, Ruth et al. (2009) Novel regulation of HIV-1 replication and pathogenicity: Rev inhibition of integration. Protein Eng Des Sel 22:753-63
Roshorm, Yaowaluck; Hong, Jessie P; Kobayashi, Naoki et al. (2009) Novel HIV-1 clade B candidate vaccines designed for HLA-B*5101(+) patients protected mice against chimaeric ecotropic HIV-1 challenge. Eur J Immunol 39:1831-40
Wang, Tong; Gong, Nan; Liu, Jianuo et al. (2008) HIV-1-infected astrocytes and the microglial proteome. J Neuroimmune Pharmacol 3:173-86

Showing the most recent 10 out of 17 publications