Hundreds of billions of dollars have been spent for over three decades in the search for an\neffective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two\nother sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV)\nand the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of\nretroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible\nviruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas eective\nvaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV),\nwas found in 1973. We reported earlier the highly disordered nature of proteins in outer shells of\nthe HIV, HCV, and HSV. Such levels of disorder are completely absent among the classical viruses,\nsuch as smallpox, rabies, yellow fever, and polio viruses, for which efficient vaccines were discovered.\nThis review analyzes the physiology and shell disorder of the various related and non-related viruses\nto argue that EIAV and the classical viruses need harder shells to survive during harsher conditions\nof non-sexual transmissions, thus making them vulnerable to antibody detection and neutralization.\nIn contrast, the outer shell of the HIV-1 (with its preferential sexual transmission) is highly disordered,\nthereby allowing large scale motions of its surface glycoproteins and making it difficult for antibodies\nto bind to them. The theoretical underpinning of this concept is retrospectively traced to a classical\n1920s experiment by the legendary scientist, Oswald Avery. This concept of viral shapeshifting has\nimplications for improved treatment of cancer and infections via immune evasion.
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