THE ROLE OF NON-IMMUNE VACCINE RESPONSES IN PROTECTION CONFERRED BY LIVE ATTENUATED SIV

The World Health Organisation recognises HIV/AIDS as the number one infectious disease in the world. Doctors and scientists know that the best way to stop this disease would be to develop a vaccine to stop the 14,000 new infections with AIDS virus that occur each day worldwide.

The difficulty is that scientists do not know whether an AIDS vaccine needs to stimulate the production of antibodies, molecules in the blood that recognise the virus and stop it from infecting new cells, or killer T cells that eliminate virus infected cells before the infection can spread further. Alternatively the vaccine may need to do something different to be fully effective.

The team at NIBSC are studying an animal model of HIV and have found that animals vaccinated with a disabled form of the virus first are resistant to disease causing strains. This group think that events that occur within 3 weeks of vaccination are critical for the vaccine and that many of these occur in and around the gut. As a result, they will focus on unravelling these early events to enable a better AIDS vaccine to be designed and developed in the future.

In the quest for a safe, effective vaccine against HIV, many scientists believe that the potent protection conferred by live attenuated simian immunodeficiency virus (SIV) will provide pertinent insight into the responses that an AIDS vaccine will need to generate. Published work from the group at NIBSC, as well as the reports of others, have been unable to demonstrate unequivocal evidence that responses of adaptive immunity correlate with protection conferred by live attenuated SIV. Passive transfer of immune serum does not transfer protection to na?ve macaques and profound depletion of CD8+ve (cytotoxic) T cells throughout the course of vaccination does not abrogate protection. We propose to investigate whether responses apart from adaptive immunity are involved in this vaccine protection. We will characterise changes in lymphocyte subsets, activation status, and gene expression to determine, in detail, the pathogenesis of infection with a live attenuated virus SIVmacC8 in na?ve juvenile cynomolgus macaques and compare it with the pathogenesis of infection with a vigorous wild-type virus SIVmacL28 in na?ve juvenile macaques. Then we will characterise the pathogenesis of infection with SIVmacL28 in macaques that have been vaccinated with attenuated SIVmacC8 for three weeks at a time when we know that responses of adaptive immunity do not play a part in protection. For each part of the study, we will determine the kinetics of virus replication, establish the distribution of virus infected cells in 5 lymphoid tissues by in situ based techniques and determine the properties of purified infected and uninfected cells by immuno-staining and flow cytometric analysis of disaggregated tissues. The purpose of these studies will be to evaluate whether vaccination results in (i) the depletion of target cells (ii) the alteration of target cells so they are no longer capable of being infected (iii) the induction of anti-viral resistance mechanisms in infected or bystander cells not infected with the vaccine virus that prevent productive infection by wild-type virus (iv) the induction of anergy in potentially susceptible cells. As a result, we will establish the role of responses that exclude adaptive immunity in this potent vaccine protection and thus identify approaches to develop an AIDS vaccine that reproduces this protection in a safe and effective manner.