Virus particles (known as virions) consist of two or three parts: the genetic material made from either DNA or RNA, molecules that carry genetic information; a protein coat that protects these genes; and in some cases, an envelope of lipids that surrounds the protein coat when they are outside a cell. The shapes of viruses range from simple helical and icosahedral forms to more complex structures. Virions may also include other accessory proteins of viral or host origin.
Viral infections in animals provoke an immune response that usually eliminates the infecting virus. Immune responses can also be produced by vaccines, which confer an artificially acquired immunity to the specific viral infection. However, some viruses including those causing AIDS and viral hepatitis evade these immune responses or persist in spite of them and result in chronic infections. Antibiotics have no effect on viruses, but several antiviral drugs have been developed.
Antiviral drugs are often nucleoside analogues (mimics of DNA building-blocks), which viral RNA or DNA polymerases mistakenly incorporate into their genomes during replication. The life-cycle of the virus is then halted because the newly synthesized DNA is inactive. This is because these analogues lack the hydroxyl groups, which, along with phosphorus atoms, link together to form the strong “backbone” of the DNA molecule. This is called DNA chain termination. Examples of nucleoside analogues are ACICLOVIR® for Herpes simplex virus, one of the oldest and most frequently prescribed antiviral drugs. Other nucleoside analogs such as LAMIVUDINE® target a different polymerase, reverse transcriptase, of HIV and Hepatitis B virus. Other antiviral drugs target different stages of the viral life cycle. For example, HIV is dependent on a proteolytic enzyme called the HIV-1 protease for it to become fully infectious. There is a large class of drugs called protease inhibitors that inactivate this enzyme. All of these drugs affect enzymes, biochemical catalysts, that are mechanistically similar to human enzymes, resulting in cross-reactivity.
Chronic hepatitis B virus infection poses great health risks to a large population. Approximately 360 million people suffer from chronic HBV. Chronic HBV contributes to about 600,000 deaths each year, about one third from hepatocellular carcinoma. More than 100 million chronically infected people live in the People's Republic of China, more than 1 million live in the United States. In a chronically infected individual, up to 95% of hepatocytes are infected. Few people recover from chronic infections. Chronic HBV is often treated with nucleoside analogs such as LAMIVUDINE®, ENTACAVIR®, or TENOFOVIR®.
Despite the palliative therapeutics available so far, there is no reliable cure for chronic viral infections. Once initiated, treatment of HBV with nucleoside analogs may be lifelong to prevent viral rebound, which can be life threatening. However, long term treatment is expensive and raises its own issues. Repeated administration of antiviral drugs may cause side effects and may lead to the emergence of drug resistant HBV mutants. Because of extensive gene overlap in HBV, some mutants are insensitive to the modern recombinant HBV vaccine. The vaccine, which has been in use for approximately two decades, is protective but not therapeutic for existing infections.
Therefore, there remains the need to develop an effective anti-viral strategy to cope with the challenges that chronic viruses such as HBV and also HIV pose to existing therapeutics.