Replicative Homeostasis: A New Hypothesis to Explain How Viruses Such as HIV, HCV and HBV Persist and Escape Immune Controls

This article offers a new hypothesis concerning the persistence of certain viruses such as HIV, HCV and HBV and how they escape control by the immune system. In 40 days it has become the most downloaded article ever published by Virology Journal, an "Open Access" journal published by BioMed Central. This means that anyone can read, without charge, the articles appearing in it as soon as they are published.

The article explains why RNA viruses like Hepatitis C, HIV, West Nile / Yellow Fever / SARS / Ebola, etc persist, and demonstrates a mechanism of genotype/species maintenance, and of generating escape mutants in response to immune and other pressures. It explains why interferon may fail in some cases of hepatitis C and also explains the mechanism of antibody mediated disease enhancement. It also implies novel treatments for West Nile / HCV (and HIV, HBV, etc) might be possible, and describes what form they might take.

Hepatitis C (HCV), hepatitis B (HBV), the human immunodeficiency viruses (HIV), and other viruses that replicate via RNA intermediaries, cause an enormous burden of disease and premature death worldwide.

These viruses circulate within infected hosts as vast populations of closely related, but genetically diverse, molecules known as "quasispecies". The mechanism(s) by which this extreme genetic and antigenic diversity is stably maintained are unclear, but are fundamental to understanding viral persistence and pathobiology. The persistence of HCV, an RNA virus, is especially problematic and HCV stability, maintained despite rapid genomic mutation, is highly paradoxical.

This paper presents the hypothesis, and evidence, that viruses capable of persistent infection autoregulate replication and the likely mechanism mediating autoregulation--Replicative Homeostasis--is described.

Replicative homeostasis causes formation of stable, but highly reactive, equilibria that drive quasispecies expansion and generates escape mutation. Replicative homeostasis explains both viral kinetics and the enigma of RNA quasispecies stability and provides a rational, mechanistic basis for all observed viral behaviours and host responses.

More importantly, this paradigm has specific therapeutic implication and defines, precisely, new approaches to antiviral therapy. Replicative homeostasis may also modulate cellular gene expression.

Note: This article uses highly technical language that many readers will find difficult to follow at times. Although the language is challenging for non scientists, it is worth the effort to read through the entire article, which offers compelling insights into the possible mechanisms of how HIV, HCV and HBV, among other viruses, persist.

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reference
R Sallie. Replicative Homeostasis: A fundamental mechanism mediating selective viral replication and escape mutation. Virology Journal 2(1):10. February 11, 2005.