The major effect of HIV-1 infection is elimination of the CD4+T cell population, the event that correlates with the profound immunosuppression caused by the virus. Antiretroviral therapy of the infection causes dramatic curtailment of virus replication, evidenced by virtual elimination of virus particles from plasma and recovery of CD4+T cell numbers. However, the virus persists in lymphoid tissues, and upon withdrawal of therapy (for whatever reason), virus replication begins again in most of these individuals, with renewed attack on the CD4+T cell population. The question arises whether a vaccine given during the period of drug therapy could induce protective immune responses that would prevent viral resurgence when the therapy is withdrawn. Problems with this concept are that immunological correlates of protection against HIV are not known, and a prophylactic vaccine, on which a therapeutic vaccine should be based, has not been developed yet. Even if an effective prophylactic vaccine were on hand, proof of concept for therapeutic immunization would still be required. In this application, we will use the SHIVKU/macaque model of HIV infection-disease to examine the feasibility of therapeutic immunization. SHIV has the env of HIV-1 on a background of SIV and is the closest genetically related agent to HIV-1 that will replicate productively in macaques. We adapted SHIV to macaques and derived a highly virulent strain, SHIVKU, which causes a very rapid type of HIV-like disease, with sub-total elimination of CD4+T cells and AIDS in 6 months. Using genetic engineering, we also recently developed a live virus vaccine that replicated transiently in macaques and induced immune responses that prevented replication of SHIVKU, given as challenge, for 2.5 years. Having established its efficacy prophylactically, we will now examine the potential of this vaccine for therapeutic efficacy. Macaques will be inoculated with SHIVKU then placed on temporary antiretroviral therapy, which will suppress replication of this virus. A portion of the animals will then be inoculated with drug-resistant vaccine virus. Following withdrawal of therapy, we will determine whether vaccine -induced immune responses inhibited resurgence of SHIVKU from reservoirs of latently infected cells in lymphoid tissues. In anticipation of success, we will then determine whether a more conservative therapeutic immunogen, inactivated virus particles, could also function therapeutically. These studies will establish proof-of- concept for the feasibility of performing this type of immunization to effectively prevent HIV resurgence in drug- treated infected individuals who come off therapy. This vaccine approach would provide a clear alternative to the dreary prospect of permanent post infection drug therapy.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Project (R01)
Project #
5R01RR006753-13
Application #
6637368
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
O'Neill, Raymond R
Project Start
1993-02-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2005-07-31
Support Year
13
Fiscal Year
2003
Total Cost
$690,390
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
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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
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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
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
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

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