SHIVKU containing the envelope of HIV-1 is a recently derived virus that causes AIDS and neurological disease in Rh macaques after severe depletion of CD4+ T cells. In previous studies, we used this virus to characterize the histological nature of the neuropathological changes and the nature of the altered systemic infection during and after withdrawal of anti-retroviral therapy. We also established that it causes a low-grade systemic infection after given as a challenge to vaccinated animals. In this application, in Aim 1, we will use the model to obtain more detailed information on the chronology of development of CNS disease in order to better understand the nature of virus-host responses associated with this complication. This information will be used as a backdrop for intervention strategies focused on the nature of the infection in the CNS of animals placed on drug therapy and in vaccinated animals. Questions that cannot be answered in humans can now be approached.
In Aim 2 we will determine the effects of anti-retroviral therapy on the progress of infection in the CNS and on neuropathological processes already in progress.
In Aim 3 we will determine whether live vaccine virus causes infection in the CNS. Although vaccination prevented AIDS, SHIVKU given as challenge still caused systemic infection, a result that can be expected in immunized humans exposed to HIV-1. As part of Aim 3 we will determine also whether this low-grade infection by SHIVKU also becomes established in the CNS. Do these viruses which cause persistent CNS infection mutate along divergent pathways from virus in lymph nodes? In Aim 4 we will extend in vitro findings that anti-IL-4 strategies causes reduction of virus replication in macaque macrophages. We will use gene therapy with antisense IL-4 DNA to treat SHIV encephalitis in Rh macaques in attempts to cause reduction in virus replication in brain macrophages and thus cure the encephalitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040238-04
Application #
6529476
Study Section
Special Emphasis Panel (ZMH1-BRB-T (01))
Program Officer
Nunn, Michael
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$571,692
Indirect Cost
Name
University of Kansas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Kumar, Anil; Liu, Zhenqian; Sheffer, Darlene et al. (2008) Protection of macaques against AIDS with a live attenuated SHIV vaccine is of finite duration. Virology 371:238-45
Liu, ZhenQian; Singh, Dinesh K; Sheffer, Darlene et al. (2006) Immunoprophylaxis against AIDS in macaques with a lentiviral DNA vaccine. Virology 351:444-54
Hegde, Ramakrishna; Liu, ZhenQian; Mackay, Glenn et al. (2005) Antigen expression kinetics and immune responses of mice immunized with noninfectious simian-human immunodeficiency virus DNA. J Virol 79:14688-97
Smith, Marilyn S; Niu, Yafen; Buch, Shilpa et al. (2005) Active simian immunodeficiency virus (strain smmPGm) infection in macaque central nervous system correlates with neurologic disease. J Acquir Immune Defic Syndr 38:518-30
Singh, Dinesh K; Liu, Zhenqian; Sheffer, Darlene et al. (2005) A noninfectious simian/human immunodeficiency virus DNA vaccine that protects macaques against AIDS. J Virol 79:3419-28
Mackay, Glenn A; Liu, Zhenqian; Singh, Dinesh K et al. (2004) Protection against late-onset AIDS in macaques prophylactically immunized with a live simian HIV vaccine was dependent on persistence of the vaccine virus. J Immunol 173:4100-7
Kumar, Anil; Mukherjee, Sampa; Shen, Jing et al. (2002) Immunization of macaques with live simian human immunodeficiency virus (SHIV) vaccines conferred protection against AIDS induced by homologous and heterologous SHIVs and simian immunodeficiency virus. Virology 301:189-205
Smith, Marilyn S; Niu, Yafen; Li, Zhuang et al. (2002) Systemic infection and limited replication of SHIV vaccine virus in brains of macaques inoculated intracerebrally with infectious viral DNA. Virology 301:130-5
Mackay, Glenn A; Niu, Yafen; Liu, Zhen Qian et al. (2002) Presence of Intact vpu and nef genes in nonpathogenic SHIV is essential for acquisition of pathogenicity of this virus by serial passage in macaques. Virology 295:133-46
Kumar, A; Narayan, O (2001) Immunization for long-term protection against AIDS using the macaque model. Virology 285:1-5