This project is a therapeutic immunization trial in HIV -1 infected patients, successfully treated with highly active antiretroviral therapy, using the Venezuelan equine encephalitis virus (VEE) vaccine vectors expressing modified HIV gag and pol genes and full length gp160 env construct developed in Project 4. This vector, in the form of VEE replicon particles (VRP), has been used safely and successfully for immunization and protection against a variety of infectious agents, including attenuation of simian immunodeficiency virus replication in rhesus macaques. The rationale for this proposed therapeutic immunization trial is that a small minority of HIV infected subjects are able to successfully control HIV replication in the absence of antiretroviral therapy, and that this control is based on preserved HIV -specific immune responses. In addition, Rosenberg et al., demonstrated that in persons treated during acute infection HIV-specific immune responses could be augmented by serial interruption of antiretroviral therapy resulting in at least transient control of HIV replication in a substantially higher proportion of patients than would be expected from natural history studies. This evidence strongly suggests that HIV specific immune responses can be responsible for significant control of HIV replication in the absence of therapy. We hypothesize that a strongly immunogenic HIV vaccine based on the VEE vectors will be safe in individuals successfully treated during acute and chronic infection and will stimulate and/or augment broad HIV specific humoral and cellular immune responses. If such responses suppressed HIV replication in the absence of HAART, HIV disease progression could be delayed or prevented with sparing of antiretroviral therapy with its attendant cost, toxicity and risk of resistance development. Alternatively, augmentation of HIV specific immunity might enhance the durability of antiviral regimens, conferring significant clinical benefit.
The specific aims of the proposed clinical trial are to I) Evaluate the safety and immunogenicity of three doses of the VEE replicon particle (VRP) vaccine vector containing modified HIV gag and pol genes and full length gp160 env gene in individuals with chronic HIV -1 infection on successful highly active antiretroviral therapy. 2) Evaluate the safety and immunogenicity of the VRP HIV vaccine in individuals who received antiretroviral therapy during acute HIV-1 infection. 3) Evaluate control of HIV-1 replication following supervised treatment interruption (STI) in subjects who received antiretroviral therapy during acute HIV -1 infection.
| Fluet, M E; Whitmore, A C; Moshkoff, D A et al. (2008) Effects of rapid antigen degradation and VEE glycoprotein specificity on immune responses induced by a VEE replicon vaccine. Virology 370:22-32 |
| Ljungberg, Karl; Whitmore, Alan C; Fluet, Meagan E et al. (2007) Increased immunogenicity of a DNA-launched Venezuelan equine encephalitis virus-based replicon DNA vaccine. J Virol 81:13412-23 |
