Towards a functional Cure for HIV: Combining reservoir purging agent (HDACi) with therapeutic vaccination (Vacc-4x)- The REDUC Study.

Human immunodeficiency virus (HIV)-1 infection remains a threat to global health. In 2015 there were 36.7 million people living with HIV-1 worldwide. HIV treatment is a combination of antiretroviral therapies (ART) that can reduce the level of virus in blood to undetectable levels. Although ART can control infection, it is not a cure since virus returns if ART is stopped. ART must therefore be taken for life. Only one person has been declared free of HIV infection several years after bone marrow transplantation. This has led to an intense focus on being able to cure HIV. A functional cure is where HIV is reduced to a level that is so low that ART can be safely stopped, but not all traces of the virus are eradicated. Untreated HIV infection kills cells of the immune system. As part of its life cycle, HIV’s genetic material (HIV RNA) is converted to an HIV DNA form that integrates into host chromosomes. Some of these infected cells (immune memory cells) remain dormant for years without expressing viral proteins and therefore remain invisible to the immune system. To remove these hidden reservoirs, the virus needs to be reactivated to express viral proteins making the virus visible to the immune system. This project, led by Bionor Immuno (now Bionor Pharma AS) represents the first clinical study to be completed worldwide testing the concept of HIV virus reactivation followed by immune-mediated removal of the reservoirs (‘shock and kill’). Virus was reactivated using romidepsin (provided by Celgene), and Bionor’s immunotherapy, Vacc-4x, was used to improve the potential for immune-based removal of infected cells. The clinical study was carried out at Aarhus University Hospital in Denmark and involved collaboration with the University of Lausanne, Switzerland and the University of Pennsylvania, USA. Part A of the study showed that romidepsin could reactivate HIV virus production during ART but there was no reduction in viral reservoir measurements. This was published in the international journal PLOSPathogens in 2015. Part B involved first immunizing study participants with Vacc-4x before reactivating the virus. A statistically significant reduction in HIV reservoirs was observed. The results of this study show that addition of an immunotherapy improved the potential to reduce HIV reservoirs, which is important for achieving a future functional HIV cure. This work was published in the journal Lancet HIV in 2016. Immune responses in relation to virus levels in Part B is currently being prepared for publication.

Infection with human immunodeficiency virus (HIV)-1 can be controlled using combination antiretroviral therapy (ART) where available. Although daily ART maintains the virus below detection levels, it is not a cure. Lifelong ART places a significant financ ial burden on healthcare services, particularly in low-middle income countries. There are 35.3 million people living with HIV of which the vast majority reside in low-middle income countries. There is now a growing interest in achieving a functional cure of HIV infection. HIV infects CD4 T-cells that are pivotal in orchestrating immune responses and defining immune competence. Virus is produced from activated CD4 T-cells (engaged in immune activity) whereas it remains latent (dormant) in resting and long- lived memory CD4 T-cells. HIV persists in these latent reservoirs as integrated provirus in the host chromosomal DNA where lack of viral gene expression renders these cells invisible to the immune system. Latent reservoirs therefore represent the greatest challenge to an HIV cure. Histone deacetylase inhibitors (HDACi) represent a new approach to reactivate latent reservoirs by relaxing tightly bundled chromosomes and permitting HIV gene expression. However, an immune-based component will also be required . This study will test the therapeutic vaccine candidate Vacc-4x in combination with the HDACi Romidepsin in the presence of ART in a clinical study. Pre-immunization with Vacc-4x will allow for more effective immune-based removal of infected cells follow ing latency reversal. The clinical study will take place at Aarhus University Hospital and involve collaborators also in Switzerland and the United States. This project represents one of the first clinical studies worldwide to pioneer this approach toward s a functional HIV cure.