This project proposes to extend studies on efficacy of an attenuated SHIV vaccine to protect macaques against SHIV/KU-induced AIDS following inoculation of this highly virulent virus on mucosal surfaces. The model is relevant to biological properties of patient isolates of HIV-1. Following a traumatic intravaginal deposition of SHIV/KU into non- immunized sexually mature macaques, the virus caused infection in large cells in the mucosa and within two days, infected cells were present in the pelvic and mesenteric lymph nodes. This was followed by explosive replication in the lymphoid system, resulting in severe global loss of CD4+ T cells within 1 month and AIDS within 8 months in 6/6 macaques. In collaboration with Dr. Harold McClure at Yerkes, we initiated vaccine experiments using attenuated gene-deleted SHIV's in hopes of protecting macaques against SHIV/KU-induced STD. These studies showed that 5/6 macaques injected subcutaneously with deltavpu deltanefSHIV-4 and 6/6 immunized orally with deltavpuSHIV-PPc resisted productive systemic infection and AIDS caused by intravaginally-inoculated SHIV/KU, given 6 months later. In this application, the PI and Dr. McClure plan to further utilize the resources of Yerkes Regional Primate Center to pursue new studies on the vaccine efficacy against SHIV/KU disease using orally inoculated deltavpuSHIV-PPc vaccine. We will collaborate with Dr. J. Sastry at the University of Texas, Bastrop, to study CMI correlates of protection. In five Specific Aims, we will determine 1) whether vaccine protection will last as long as two years; 2) whether vaccination is effective against challenge virus SHIV/KU given orally and rectally in addition to vaginally; 3) whether immunized animals will resist heterologous pathogenic viruses that are not neutralized by antibodies induced by the vaccine virus; 4) whether fetuses become infected during vaccination or challenge of pregnant animals and, 5) whether new born animals exposed to vaccine virus at birth will resist heterologous pathogenic virus later. We will use animals in Aims 1, 2 and 3 to explore immunological correlates of vaccine-induced protection. 70 animals will be used in the five-year period and they will be house at Yerkes.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Project (R01)
Project #
5R01RR013152-03
Application #
6188594
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Robinson, Jerry
Project Start
1998-07-15
Project End
2002-07-14
Budget Start
2000-07-15
Budget End
2002-07-14
Support Year
3
Fiscal Year
2000
Total Cost
$546,770
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
Buch, Shilpa; Sui, Yongjun; Potula, Raghava et al. (2004) Role of interleukin-4 and monocyte chemoattractant protein-1 in the neuropathogenesis of X4 simian human immunodeficiency virus infection in macaques. J Neurovirol 10 Suppl 1:118-24
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
Buch, Shilpa J; Villinger, Francois; Pinson, David et al. (2002) Innate differences between simian-human immunodeficiency virus (SHIV)(KU-2)-infected rhesus and pig-tailed macaques in development of neurological disease. Virology 295:54-62
Hicks, Andrey; Potula, Raghava; Sui, Yong Jun et al. (2002) Neuropathogenesis of lentiviral infection in macaques: roles of CXCR4 and CCR5 viruses and interleukin-4 in enhancing monocyte chemoattractant protein-1 production in macrophages. Am J Pathol 161:813-22
Buch, S; Pinson, D; King, C L et al. (2001) Inhibitory and enhancing effects of IFN-gamma and IL-4 on SHIV(KU) replication in rhesus macaque macrophages: correlation between Th2 cytokines and productive infection in tissue macrophages during late-stage infection. Cytokine 13:295-304
Kumar, A; Narayan, O (2001) Immunization for long-term protection against AIDS using the macaque model. Virology 285:1-5
Kumar, A; Lifson, J D; Li, Z et al. (2001) Sequential immunization of macaques with two differentially attenuated vaccines induced long-term virus-specific immune responses and conferred protection against AIDS caused by heterologous simian human immunodeficiency Virus (SHIV(89.6)P). Virology 279:241-56
Kumar, A; Buch, S; Foresman, L et al. (2001) Development of virus-specific immune responses in SHIV(KU)-infected macaques treated with PMPA. Virology 279:97-108
Stipp, H L; Kumar, A; Narayan, O (2000) Characterization of immune escape viruses from a macaque immunized with live-virus vaccine and challenged with pathogenic SHIVKU-1. AIDS Res Hum Retroviruses 16:1573-80
Silverstein, P S; Mackay, G A; Mukherjee, S et al. (2000) Pathogenic simian/human immunodeficiency virus SHIV(KU) inoculated into immunized macaques caused infection, but virus burdens progressively declined with time. J Virol 74:10489-97

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