{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T04:30:46Z","timestamp":1773289846538,"version":"3.50.1"},"reference-count":76,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,8]],"date-time":"2019-05-08T00:00:00Z","timestamp":1557273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BEACON Center for Evolution in Action","award":["NSF DBI0939454"],"award-info":[{"award-number":["NSF DBI0939454"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), was found in 1973. We reported earlier the highly disordered nature of proteins in outer shells of the HIV, HCV, and HSV. Such levels of disorder are completely absent among the classical viruses, such as smallpox, rabies, yellow fever, and polio viruses, for which efficient vaccines were discovered. This review analyzes the physiology and shell disorder of the various related and non-related viruses to argue that EIAV and the classical viruses need harder shells to survive during harsher conditions of non-sexual transmissions, thus making them vulnerable to antibody detection and neutralization. In contrast, the outer shell of the HIV-1 (with its preferential sexual transmission) is highly disordered, thereby allowing large scale motions of its surface glycoproteins and making it difficult for antibodies to bind to them. The theoretical underpinning of this concept is retrospectively traced to a classical 1920s experiment by the legendary scientist, Oswald Avery. This concept of viral shapeshifting has implications for improved treatment of cancer and infections via immune evasion.<\/jats:p>","DOI":"10.3390\/biom9050178","type":"journal-article","created":{"date-parts":[[2019,5,13]],"date-time":"2019-05-13T03:57:07Z","timestamp":1557719827000},"page":"178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["HIV Vaccine Mystery and Viral Shell Disorder"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3635-0806","authenticated-orcid":false,"given":"Gerard","family":"Goh","sequence":"first","affiliation":[{"name":"Goh\u2019s BioComputing, Singapore 548957, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0744-5243","authenticated-orcid":false,"given":"A.","family":"Dunker","sequence":"additional","affiliation":[{"name":"Center for Computational Biology, Indiana and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Foster","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA"},{"name":"Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID 83844, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4037-5857","authenticated-orcid":false,"given":"Vladimir","family":"Uversky","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"},{"name":"Institute for Biological Instrumentation, Russian Academy of Sciences, Moscow Region, Pushchino 142290, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3502","DOI":"10.1016\/j.vaccine.2013.05.018","article-title":"A brief history of the global effort to develop a preventive HIV vaccine","volume":"31","author":"Esparza","year":"2013","journal-title":"Vaccine"},{"key":"ref_2","unstructured":"Acheson, N.H. 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