Regulation of HIV-1 and Ebola virus replication by CpG dinucleotides, ZAP and TRIM25

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Human immunodeficiency virus type I (HIV-1) is a retrovirus whose worldwide spread has caused the acquired immune deficiency syndrome (AIDS) pandemic. In 2016, ~37 million people globally were living with HIV, ~1.8 million new people became infected and ~1 million people died from AIDS-related illnesses (http://www.unaids.org/en/resources/fact-sheet). Overall, ~76 million people have been infected with HIV since the epidemic started and ~35 million people have died from AIDS-related illnesses. HIV-1 primarily infects CD4 T cells and, when these cells die, the immune system is compromised allowing opportunistic infections and other diseases such as cancer to develop. Once a person is infected, the virus cannot be eliminated but its replication can be inhibited with anti-HIV drugs. Currently, there are approved anti-HIV drugs targeting four steps of the viral replication cycle and ~21 million people worldwide are currently accessing these drugs. These drugs can control the infection indefinitely, but do not cure a person. However, drug resistant strains of HIV are an increasing problem. Therefore, it is necessary to continue to develop new anti-HIV therapies.Ebola virus (EBOV) is a highly pathogenic virus that causes haemorrhagic fevers in humans with mortality rates up to 90%. The 2014-2016 West African epidemic caused a global emergency when it spread from rural Guinea to major population centres in that country and neighbouring Liberia and Sierra Leone. By the time the outbreak was declared over, EBOV had infected over 28,000 people and killed more than 11,000 (http://www.who.int/mediacentre/factsheets/fs103/en/). Although there are promising vaccines for EBOV, there is currently no effective therapy for an infected person. Therefore, studies of the virus-host interactions at the cellular level are essential for the development of novel EBOV therapeutics. The high mortality of EBOV necessitates its study in containment level 4 laboratories, which hampers progress in the understanding how the virus replicates. However, we have established a safe, non-infectious system to analyse Ebola virus biology.In this proposal, we will characterise how cellular proteins inhibit HIV-1 and Ebola virus replication when a specific pattern in the virus is sensed by a human cell. There are four nucleotide bases in all RNA sequences, including viral genomes: adenosine (A), cytosine (C), guanosine (G) and uracil (U). The abundance of a specific pattern of RNA sequence in a virus genome, C followed by a G, has been proposed to be recognised by the human cell and inhibits viral replication. However, it is unclear how this CG pattern inhibits the virus. In this grant, we will determine how the CG RNA sequence interacts with cellular proteins and how these proteins inhibit viral replication. In particular, we will characterise how the antiviral proteins ZAP and TRIM25 inhibit HIV-1 and Ebola virus in the context of the safe, non-infectious system.