Fig. 1.
a Translation of HIV Gag and Pol genes produces two large polyproteins, Pr55Gag and Pr160Gag-Pol, which are cleaved at 12 protease cleavage sites (PCS) to produce 13 proteins in a mature HIV virion. Cleavage of Pr55Gag polyprotein by HIV protease at PCS1 produces matrix p17 (MA), at PCS2-capsid p24 (CA), PCS3-p2, PCS4-nucleocapsid/p1 (NC), PCS5-p1 and PCS6-p6gag. The cleavage of the Pr160 Gag-Pol polyprotein that is derived from ribosomal frame shifting results in the production of viral enzymes. Cleavage at PCS7 produces the transframe protein (TFP), at PCS8 produces p6Pol, PCS9-protease (PR), PCS10-reverse transcriptase (RT-p15), PCS11-RT-RNase H (RTp66)-integrase (IN) and PCS12-Nef [25–27]. b HIV envelope proteins gp120 and gp41 expression on the plasma membrane (PM) of infected cells occurs through secretory pathway involving the endoplasmic reticulum (ER), Golgi apparatus (GA) and membrane-bound vesicles. Transcription of HIV mRNA produces a precursor Gag polyprotein (Pr55Gag) containing HIV MA, CA, NC and p6 proteins. A precursor GagPol polyprotein (Pr160Gag-Pol) is synthesized by a frameshifting during transcription of Gag-encoding viral RNA and contains MA, CA, NC, PR, RT and IN domains. Viral assembly occurs on the inner surface of the PM, beginning with the binding of Gag on Pr55Gag and Pr160Gag-Pol to lipid rafts, and in the process Env (gp120 and gp41) is incorporated to the assembling complex [28]. The complex guides the budding leading to the formation of an immature virion, which eventually matures into an infectious virion after protease cleavage of Pr55Gag and Pr160Gag-Pol polyproteins incorporated in the virion. The PCS vaccine under evaluation uses 12 different recombinant vesicular stomatitis viruses (rVSV), each expressing a 20-amino acid peptide overlapping one of the 12 PCS. Vaccination with a combination of the 12 rVSVs in macaques elicits anti-PCS antibodies targeting different PCSs. The potential mechanism of the rVSV PCS vaccine may involve disrupting one or multiple stages of viral maturation and mediating cytotoxic killing of infected cells through antibody dependent cytotoxic cellular activity or cytotoxic T lymphocyte reactions