Development of therapeutic vaccination strategies for the treatment of HIV-1 infection

The only effective treatment for infection with the human immunodeficiency virus (HIV), the cause of AIDS, is a combination of three anti-HIV drugs taken for life. Less than one in six people living with HIV and in immediate need of treatment are actually receiving it. We are exploring the possibility of using vaccines to boost the body?s immune defences against HIV: the aim is to see whether the immune system can keep the virus at low levels in the bloodstream without continuous drug treatment. We have already seen excellent immune boosting effects with a new HIV vaccine (a modified smallpox vaccine carrying a fragment of HIV, called ?MVA.HIVA?) when it is given to HIV-positive people who are taking anti-HIV drugs. We now need to find out how well vaccinated patients control their virus when their treatment is stopped temporarily. In order to do this we will carry out detailed tests measuring patients? immune responses before, during and after vaccination and then measure HIV levels in the bloodstream while they are off treatment. We will also investigate whether there is greater benefit from using MVA.HIVA together with another vaccine, ?MVA.RENTA?, which carries additional fragments of HIV. If these small studies are successful, we will design a larger study which will aim to test whether vaccination combined with intermittent drug treatment is a realistic alternative to continuous drug treatment. This could have significant benefits for people with HIV as the overall cost and harmful effects of treatment would be reduced.

Lifelong treatment with antiretroviral drugs (highly active antiretroviral therapy or HAART) is currently the only means to halt or prevent progression to AIDS but has several limitations, including cost and complexity of treatment regimens, drug toxicity and potential for drug resistance. Exhaustive exploration of drug-sparing treatment strategies which can limit HIV-1 replication is warranted. Enhancement of host cellular immunity by therapeutic vaccination during HAART may potentiate HIV-1 control after drug withdrawal. We have observed significant boosting of virus-specific CD8+ and CD4+ T cell responses in HIV-1-infected patients given a recombinant modified vaccinia virus Ankara (MVA) / HIV-1 gag vaccine (MVA.HIVA) during HAART. Peak responses after vaccination were ten- to 100-fold greater than in HIV-uninfected individuals given the same vaccine. We propose to extend our preliminary findings by conducting a series of experimental studies investigating the potential of MVA.HIVA and another new vaccine, MVA.RENTA (expressing HIV-1 reverse transcriptase, nef, tat and gp41) to stimulate a broad T cell response with the capacity to suppress viral rebound in HIV-1-infected patients undergoing a supervised HAART interruption. These studies will aim to investigate the relationship between breadth, quality and evolution of the immune response, the timing of the treatment interruption and subsequent viral rebound kinetics. These questions have not been adequately addressed by other therapeutic vaccination studies to date, yet are crucial to the design of phase I randomised trials. They may also yield insights into immune correlates of viral containment which could advance prophylactic vaccine development.