Construction of a Simian Immunodeficiency Virus Vaccine from Cynomolgus Macaque Cytomegalovirus

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.

Department dc:contributor.department

Immunology

Year dc:date.issued

2018

Author dc:creator

• Russell, Justen Norman Hoffman

Advisor dc:contributor.advisor

• MacDonald, Kelly S

• CMV
• Cynomolgus Macaque
• Cytomegalovirus
• HIV
• SIV
• Vaccine

Handle dc:identifier.uri

http://hdl.handle.net/1807/89861

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/89861