HIV Vaccine Mystery and Viral Shell Disorder

Abstract

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.

Keywords: HIV; glycoconjugate; hepatitis; herpes; immune escape; intrinsic disorder; polio; rabies; smallpox; unstructured; yellow fever.

Figure 1

The shells of various viruses. (a) Virion of human immunodeficiency virus (HIV). (b) Rabies virus. (c) Variola (Smallpox) virus. (Figures reproduced with the permission of Gerard KM Goh, 2017).

Figure 1

The shells of various viruses. (a) Virion of human immunodeficiency virus (HIV). (b) Rabies virus. (c) Variola (Smallpox) virus. (Figures reproduced with the permission of Gerard KM Goh, 2017).

Figure 2

Comparison of PID of shell proteins of related. (a) Retroviruses: HIV vs. EIAV (b) HIV-1 vs. polio, smallpox and rabies viruses. (c) YFV vs. HCV, HSV and HIV-1. (*) denotes viruses for which effective vaccines are available. For illustrative purposes, only the tegument proteins with the highest and lowest PIDs are shown. Figure 2a shows the mean PID, whereas, in (b,c), each PID represents maximal PID found for the specific protein. The reason for the use of both mean and maximal values is that the mean PID alone can be quite misleading for the readers, and sometimes maximal number paints a more accurate picture. “ALL” refers to the mean shell PIDs of viruses in general as seen in the current database of over 300 viruses and strains. YFV M (Matrix) and C (Capsid) PIDs are displayed.

Figure 3

Crystal Structures with Disorder Annotated in Red. (a) A highly disordered HIV matrix (1hiw.pdb). (b) A highly ordered EIAV matrix (1hek.pdb). (c) Complex of poliovirus capsid proteins (1p02.pdb). The varying non-red colors in each sample denote different chains. The Protein Data Bank (PDB) structures without disorder annotations are available at: http://www.ncbi.nlm.nih.gov/structure/. A JAVA program was written to generate codes that could be read by Jmol. The JAVA program reads the disorder information from the MYSQL shell disorder database.

Figure 4

Mechanism of Immune Escape. Figure reproduced with the permission of Gerard KM Goh, 2017.