Correlating gene expression changes and innate immune responses with protective SIV vaccination in cynomolgus macaques

There are around 33 million people living with HIV/AIDS and around 25 million people have died. There is a desperate need for a protective vaccine but all the recent HIV vaccine trials have failed. This is essentially because we don t really understand how good vaccines work. In monkeys, the only vaccine strategy that works reliably is vaccination with live attenuated virus. This is not acceptable in humans because the attenuated virus could eventually make the vaccinated person ill and they may pass it on to others. This study aims to find out what it is that the vaccine virus does to the vaccinated animals, that makes them immune to a second infection. Based on earlier work at NIBSC we propose that vaccination stimulates innate immunity in the specific cells that the virus infects. This means that the cells infected with the vaccine virus are stimulated to make proteins that protect them and surrounding cells from further infection. We will identify the important genes and proteins by measuring change in their amounts after vaccination. In a parallel approach we will accurately measure amounts of specific proteins known to have anti retroviral properties, comparing vaccinated and unvaccinated animals. In this way we will seek a role for innate immunity in protective vaccination. Once we have identified proteins that appear after vaccination, we will test them for antiviral properties. An important aspect of this study is the close interaction between NIBSC and UCL sponsoring the transfer of technologies and expertise between centres with considerable experience in vaccination studies (NIBSC) and molecular virology and innate immunity (UCL).

Around 33 million people are living with HIV/AIDS and around 25 million people have died. There is a great need for a safe, effective human protective vaccine against HIV-1. Vaccination of cynomolgus macaques with live SIV, attenuated by nef mutation, effectively protects against homologous and heterologous challenge. We hypothesise that induction of innate immune antiviral pathways in specific tissues and cells underlies this protection. We propose to identify correlates of protection by measuring gene expression changes in vaccinated animals using DNA microarrays. We will also seek a role for innate immunity by measuring specific, characterised anti-retroviral restriction factors including TRIM5, APOBEC3G/F and tetherin. Once we have identified genes whose expression are stimulated by vaccination we will characterise their molecular mechanism of action, sensitivity to interferon and role in the protective phenotype. We will also seek a role for polymorphism in innate immune factors in outcome after vaccination, collaborating with those investigating a role for MHC polymorphism. A clear understanding of the importance of innate immunity in vaccination against primate lentiviral infection will be invaluable in the search for a protective HIV vaccine strategy in humans.