HIV Vaccine Mystery and the Viral Shapeshifters

Created by: Gerard Goh

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.

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The biomedical community has been plagued with a mystery for over three decades when nearly a trillion dollars have been spent in search for an effective HIV vaccine with no success. Furthermore, the traditional textbook explanation of random mutations arising from the error-prone reverse transcription in retroviruses like HIV prevent any vaccine success,  actually raises more questions than answers. Given the fact that 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), the traditional paradigm is unable to explain the absence of vaccine for the sexually transmitted DNA and non-retroviral viruses respectively and the discovery of effectiveness vaccine of  the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV),  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.  EIAV and the classical viruses need harder shells to survive during harsher conditions of non-sexual transmissions and 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 difficult for antibodies to bind to them. The theoretical underpinning of this concept is retrospectively traced to a classical 1920s experiment by the great scientist, Oswald Avery. This concept of viral shapeshifting has implications for improved treatment of cancer and infections via immune evasion.  The main bioinformatics tool used is neural network, PONDR®-VLXT (www.pondr.com), that is trained to recognize disordered residues given a sequence of a protein. A database of over 300 viruses and strains that includes a wide range of viruses including SARS-CoV, MERS-CoV, Ebola, yellow fever, dengue polio, rabies and smallpox viruses reiterates that only very few viruses such as HIV, HCV and HSV have disordered outer shells. We may note the high disorder levels at the outer shells of HIV, HSV and  HCV, but also the complete absence in disorder for the rest of the viruses in Table 1. 

 

Table 1.  Percentage of disorder (PID) levels of shell proteins. 

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Except for HIV, HCV and HSV, effective vaccines have been found for all other viruses in Table 1. Figure 2 re-emphases the difference. The HIV-1 matrix is highly is highly disordered (in red) but EIAV matrix is not. It should further be noted the levels of outer shell disorder for most viruses with the exception of HSV and HCV  in Table 1 resemble that of EIAV, not HIV-1.

 

 

 

 

 

 

 

 

 

 

Figure 1. The matrix proteins of retroviral siblings with disorder represented in red. A) HIV-1 (1hiw.pdb)  2) EIAV (1hek.pdb)

 

A theoretical understanding of viral shapeshifter's immune evasion can be found in a famous 1920s experiment of the legendary scientist, Oswald Avery. Figure 2 illustrates the mechanism.  HIV-1 is the most glycosylated virus known and together with its surface glycoprotein, matrix disorder is able to help fend off the neutralizing antibodies.

 

  1.   Goh G.K. Viral shapeshifters: Strange behavoirs of hiv and other viruses. Singapore: Simplicity Research Institute: 20

  2. Goh GK, Dunker AK, Foster JA, Uversky UN. HIV vaccine mystery and viral shell disorder. Biomolecules. 2019;9:178.https://www.mdpi.com/2218-273X/9/5/178/htm 

Cite this article

Gerard, Goh. HIV Vaccine Mystery and the Viral Shapeshifters, Encyclopedia, 2019, v2, Available online: https://encyclopedia.pub/187