Picker: An Attenuated CMV Vector
HIV may be unique among human pathogens for its ability to evade or defeat vaccine-induced immunity. Current information indicates that the window of opportunity to prevent HIV infection is very short; perhaps limited to a time when the virus is localized at mucosal sites and has not replicated enough to generate diversity sufficient for immune escape. Moreover, HIV infects CD4+T-cells, and the very act of recall of vaccine-induced memory responses upon infection may bring more activated CD4+ target cells to the virus.
One vaccine approach would be to position virus-specific CD8+ T-cells at sites of infection to halt infection immediately. CD8+ T-cells act by killing virus-infected CD4+ T-cells, recognizing them by the viral peptide fragments that infected cells present on MHC Class-1 molecules. To win the battle, CD8+ T-cells that are ready to act may need to surround and outnumber the first infected CD4+ T-cells. Continuous surveillance by CD8+ T-cells may be needed to put out any "brushfires" subsequent to initial containment of the virus.
To date, HIV/AIDS vaccines designed to harness CD8+ T-cells to control HIV infection have been largely unsuccessful. Dr. Louis Picker and his laboratory team at Oregon Health and Sciences University propose that conventional CD8+ T-cell vaccines are losing the race to contain HIV due to the type of memory that they induce. Unless there are sufficient fully differentiated effector memory CD8+T-cells at the mucosal sites of infection, the vaccine-induced memory will take too long to "wake up", and HIV will have already have moved out of the best window of opportunity to contain it.
Using the Rhesus macaque /SIV model of AIDS, Louis Picker and his team have demonstrated that persistent vectors based on the ubiquitous β-herpesvirus cytomegalovirus (CMV) elicit and indefinitely maintain high frequency, tissue-resident effector memory T cell (TEM) responses. These cells can intercept and stringently control a highly pathogenic, AIDS-causing SIV very early in infection, and maintain this control (and perhaps even clear infection) over the long term.
The tangible products of this project will be both an optimized HCMV/HIV vector appropriate for GMP manufacture and phase 1 clinical testing, and non-human primate data that provide a strong rationale for the clinical translation of this vector design and support its regulatory approval. The studies outlined in this proposal will be performed at the Vaccine and Gene Therapy Institute (VGTI), at the Oregon Health & Science University (OHSU), and Oregon National Primate Research Center (ONPRC) by a highly integrated and experienced team of immunologists, virologists, and veterinarians that have been working collaboratively on this project under the overall direction of Dr. Picker since 2001.
1. Determine the ability of prototype Δpp71 RhCMV/SIV vectors encoding homologous vs. heterologous SIV inserts to protect against highly pathogenic mucosal SIVmac239 challenge and determine immune correlates of this protection.
2. Design, construct and validate advanced Δpp71 RhCMV/SIV vector designs with the ultimate goal to place 2-4 SIV antigens into a single vector by replacement of pp71 and/or conserved, dispensable CMV genes.
3. Construct and assess HCMV/HIV vectors based on the RhCMV/SIV vector designs tested in vivo in Objective 2.