Abstract
Paradigm shifts throughout the history of microbiology have typically been ignored, or met with skepticism and resistance, by the scientific community. This has been especially true in the field of virology, where the discovery of a “contagium vivum fluidum”, or infectious fluid remaining after excluding bacteria by filtration, was initially ignored because it did not coincide with the established view of microorganisms. Subsequent studies on such infectious agents, eventually termed “viruses”, were met with skepticism. However, after an abundance of proof accumulated, viruses were eventually acknowledged as defined microbiological entities. Next, the proposed role of viruses in oncogenesis in animals was disputed, as was the unique mechanism of genome replication by reverse transcription of RNA by the retroviruses. This same pattern of skepticism holds true for the prediction of the existence of retroviral “antisense” transcripts and genes. From the time of their discovery, it was thought that retroviruses encoded proteins on only one strand of proviral DNA. However, in 1988, it was predicted that human immunodeficiency virus type 1 (HIV-1), and other retroviruses, express an antisense protein encoded on the DNA strand opposite that encoding the known viral proteins. Confirmation came quickly with the characterization of the antisense protein, HBZ, of the human T-cell leukemia virus type 1 (HTLV-1), and the finding that both the protein and its antisense mRNA transcript play key roles in viral replication and pathogenesis. However, acceptance of the existence, and potential importance, of a corresponding antisense transcript and protein (ASP) in HIV-1 infection and pathogenesis has lagged, despite gradually accumulating theoretical and experimental evidence. The most striking theoretical evidence is the finding that asp is highly conserved in group M viruses and correlates exclusively with subtypes, or clades, responsible for the AIDS pandemic. This review outlines the history of the major shifts in thought pertaining to the nature and characteristics of viruses, and in particular retroviruses, and details the development of the hypothesis that retroviral antisense transcripts and genes exist. We conclude that there is a need to accelerate studies on ASP, and its transcript(s), with the view that both may be important, and overlooked, targets in anti-HIV therapeutic and vaccine strategies.
Highlights
Virology is a very recent scientific discipline, with the concept of viruses dating back barely more than a century
In 1988, it was predicted that human immunodeficiency virus type 1 (HIV-1), and other retroviruses, express an antisense protein encoded on the DNA strand opposite that encoding the known viral proteins
HIV-1 investigators may not be aware of the work demonstrating the crucial importance of the antisense protein HBZ in human T-cell leukemia virus type 1 (HTLV-1) pathogenesis
Summary
Virology is a very recent scientific discipline, with the concept of viruses dating back barely more than a century. This explains, at least in part, why these biological agents have remained virtually absent from the philosophy of biology until recently, as pointed out by Thomas Pradeu and colleagues [1]. Other reasons can explain this gap, most notably the unparalleled diversity and complexity of viruses, which make them difficult biological entities to define and categorize. The unique nature of viruses raised major conceptual questions (e.g., the origin of life, definition of living organisms, etc.) and the accelerated pace of discoveries provoked numerous paradigm shifts, which contributed to this delay. We focus on retroviral antisense genes that question, and modify, scientific preconceptions on genetics
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