OPTIMAL DELIVERY OF TWO SIGNALS TO ENHANCE ANTI-HIV CTL

Ohio State University, Columbus OH

Investigators

Abstract

DESCRIPTION: (Adapted from Applicant's Abstract) An important parameter for HIV vaccines is the strength of CTL responses it elicits. Optimal induction of CTL response requires at least two types of biological signals. Signal 1 is provided by antigenic peptide presented by MHC class I molecules. Costimulatory molecules, the prototypes of which are CD80 family members CD80 and CD86, deliver signal 2. While costimulatory activity can be conferred by expression of a single gene such as CD80, generation of antigenic signals for CTL requires co-ordinated expression of multiple genes, such as proteosome components LMP-2, LMP-7, transporter TAP-1, TAP-2, MHC class I heavy chain, and beta 2 microglobulin, in addition to the nominal antigen. This has made it difficult to design a vector that delivers both signals for T cell activation. The applicant has found that the proto-oncogene, PML, controls multiple genes devoted to MHC class I antigen-presentation. This finding makes possible the design of novel constructs that enable co-delivery of both signals to induce anti-HIV CTL responses. The central theme of the current pilot study is to design DNA vaccines that allow the MHC class I-low recipient cells to present both signal 1 and signal 2, and to test if these types of vaccines are superior to conventional DNA vaccines in inducing anti-HIV CTL responses. Specifically, the following questions will be addressed: 1. Can DNA vector and/or recombinant adenovirus-associated virus be produced that efficiently induce expression of HIV antigen, costimulatory molecules and multiple antigen presenting genes, such as LMP2/7 and TAP1/2? The applicant will co-express costimulatory molecule CD80, an HIV gp120 antigen epitope and the proto-oncogene PML that controls multiple genes devoted to antigen presentation. 2. Can both effector and memory T cells specific for an HIV gp120 CTL be induced? The effect of co-delivery of both antigenic and co-stimulatory signals in the induction of anti-HIV CTL responses will be tested. Should co-delivery of signals 1 and 2 induce better protection, then an expanded proposal will be submitted to evaluate the potential of this approach in the development of a vaccine for HIV/SIV infection in primates and humans.