About
This PhD thesis describes the construction of prototype vaccines against SIV, a primate model for HIV.
Herpesviruses, like CMV VZV (Chickenpox), are never actually cured. After an initial infection, the virus hangs around for life. This does not typically cause any symptoms, but the viruses are active and the immune response against them is quite robust.
We attempted to use some of this immune response to protect against HIV as well BY genetically modifying the viruses to express SIV proteins a vaccine was generated that could be tested in the lab.
Scientific Abstract
| The current HIV pandemic has killed more than 35 million people since 1985, and infects a further 30 million globally. Vaccines based on herpesvirus vectors, in particular cytomegalovirus, generate unique, robust immune responses that may overcome many of the typical obstacles to an effective preventative HIV vaccine. Recent studies using a cytomegalovirus based vaccine in the rhesus macaque monkey model have protected close to half of all vaccinated monkeys from SIV, but questions remain as to the mechanism of protection and whether similar results will be seen in humans against HIV. These questions may be answerable through the use of the cynomolgus macaque monkey model, and a minimally passaged cytomegalovirus vector that more closely resembles human cytomegalovirus. To this end a novel cytomegalovirus was isolated from a Mauritian cynomolgus macaque monkey. This virus was sequenced in full and phylogenetically characterized alongside other primate cytomegaloviruses and their hosts. To generate a vaccine construct the newly isolated and minimally passaged cynomolgus macaque cytomegalovirus was first cloned as a bacterial artificial chromosome (BAC) to facilitate the preservation of the virus without further accumulation of attenuations from in vitro passaging. After sequencing the BAC, and comparison of the growth kinetics of the viruses derived from the BAC to determine if there was an observed in vitro loss of fitness, the BAC was used to construct a vaccine against SIV. This new cynomolgus macaque cytomegalovirus based SIV vaccine for use in cynomolgus macaques retains wildtype growth kinetics in vitro. It is the first cytomegalovirus based SIV vaccine for use in the cynomolgus macaque model and the first cytomegalovirus used in vaccine studies that purposely has been generated with a focus on retention of viral fitness. This is a valuable molecular tool that will permit the further understanding of herpesviruses as vaccine vectors and their potential application in humans. |