Different viruses, different replication mechanisms

I often talk about HIV because that's my research field. However, HIV is not the only virus for which we currently don't have a vaccine. A recent news post on Scientific American warned that while HIV-related deaths are going down, chronic hepatitis C deaths are on the rise. According to the World Health Organization:

"It is estimated that 3-4 million people are infected with HCV each year. Some 130-170 million people are chronically infected with HCV and at risk of developing liver cirrhosis and/or liver cancer. More than 350,000 people die from HCV-related liver diseases each year."

HCV has many similarities with HIV: they are both highly variable with comparable mutation rates, leading to multiple subtypes, and they are both RNA viruses with similarly sized genomes (~9,500 bases). They also have similar clinical patterns, as the acute phase (first few months) is either asymptomatic or very mild in both infections, and is characterized by a rapid ramp-up in viral load (levels of viral RNA per blood unit). However, while the HIV viral load, after reaching a peak, comes back down, the HCV viral load reaches a plateau and remains constant for many weeks. Eventually, only 20-30% of individuals infected with hepatitis C will spontaneously clear the virus and resolve the infection, whereas 70-80% will progress to persistent infection.

The biology of the two viruses is also very different, and if, like me, you thought RNA viruses are all alike, think again.

A virus needs to use the host cell machinery in order to reproduce. Different viruses have developed different mechanisms in order to do this. The key step is to use the genetic information they carry in order to make new viral proteins and hence new viral progeny.

Retroviruses are RNA viruses that, in order to produce new progeny, they need the DNA intermediate step. HIV is one of such viruses: once inside the cell, its RNA is transcribed into DNA by an enzyme called reverse transcriptase (also packaged inside the virion). The viral genome is then transported to the cell nucleus by another enzyme and is integrated into the host genome. This is a fundamental step for HIV, because it allows it to utilize the cell machinery in order to reproduce itself.

HCV also uses the cell machinery, but in a different way. Instead of using reverse transcriptase to turn the RNA into DNA, it uses a different enzyme, called RNA polymerase, which produces messenger RNA from which viral proteins are made. Through this step, HCV makes new negative RNA strands that serve as templates for the new progeny. The negative RNA templates stay inside the cell and continue to produce positive RNAs, while the positive strands may either be used to produce a new negative strand template, or they may be packaged into new virions, or they may be translated into proteins. All of this happens in the cytoplasm, and, contrary to HIV, HCV never enters the cell nucleus. HCV replication and post-translational processing happen in a "membranous web" called "replication complex," and then new virions are matured in the Golgi apparatus before being released outside the cell through exocytosis.

So, you see, though all retroviruses are RNA viruses, the opposite is not true. I learned something new today. Thank goodness I learned it in time for my talk on Thursday!

Ashfaq, U., Javed, T., Rehman, S., Nawaz, Z., & Riazuddin, S. (2011). An overview of HCV molecular biology, replication and immune responses Virology Journal, 8 (1) DOI: 10.1186/1743-422X-8-161