- Ambagala AP, Marsh AK, Chan JK, Mason R, Pilon R, Fournier J, Sandstrom P, Willer DO, MacDonald KS Establishment of an immortal cynomolgus macaque fibroblast cell line for propagation of CyCMV (In Press, Archives of Virology)
- Angie K. Marsh, David O. Willer, Olena Skokovets, Oluwadamilola H. Iwajomo, Jacqueline K. Chan, and Kelly S. MacDonald Evaluation of Cynomolgus Macaque Endogenous Retrovirus Expression following Simian Immunodeficiency Virus Infection PLoS One June 2012, Vol 7, (6) e40158
- Willer DO, Ambagala APN, Pilon R, Chan J, Fournier J, Brooks J, Sandstrom P, MacDonald KS. Experimental Infection of Cynomolgus Macaques (Macaca fascicularis) with human Varicella Zoster Virus (VZV) J. Virol. 2012 April; 86(7):3626-3634
- Marsh, A., Willer, D. O., Dzamba, M., Ambagala, A. P., Chan, J. K., Brudno, M., MacDonald, K. S. Genomic Sequencing and Characterization of a Novel Cynomolgus Macaque Cytomegalovirus. J.Virol. 2011 December; 85(24):12995-13009
- Ambagala AP, Marsh A, Chan J, Pilon R, Fournier J, Mazzulli T, Sandstrom P, Willer DO, MacDonald KS Isolation and Characterization of Cynomolgus Macaque (Macaca fascicularis) Cytomegalovirus (CyCMV) Virology 2011 March 30; 412 (1): 125-135
- Foster SB, Lu M, Thompson B, Rich KC, Matukas LM, Mason R, Winchester R, MacDonald KS, Shearer WT. Association between HLA inheritance and asthma in HIV-infected children. AIDS. 2010 Aug 24;24(13):2133-5
- Kaul R, MacDonald KS, Nagelkerke NJ, Kimani J, Fowke K, Ball TB, Luo M, Kariri A, Jaoko W, Moses S, Rowland-Jones S, Plummer FA. HIV viral set point and host immune control in individuals with HIV-specific CD8+ T cell responses to HIV acquisition. AIDS. 2010 Jun 19;24(10):1449-54
- Jones RB, Yue FY, Gu XX, Hunter DV, Mujib S, Gyenes G, Mason RD, Mohamed R, MacDonald KS, Kovacs C, Ostrowski MA. Human immunodeficiency virus type 1 escapes from interlukin-2 producing CD4+ T-cell responses without high-frequency fixation of mutations. J Virol. 2009 Sep;83(17):8722-32
- Christie NM, Willer DO, Lobritz MA, Chan JK, Arts EJ, Ostrowski MA, Cochrane A, Luscher MA, MacDonald KS. Viral Fitness Implications of Variation Within an Immunodominant CD8+ T-cell Epitope of HIV-1. Virology. 2009 May 25;388(1):137-46
- Levinson P, Kaul R, Kimani J, Ngugi E, Moses S, MacDonald KS, Broliden K, Hirbod T; Kibera HIV Study Group. Levels of innate immune factors in genital fluids: association of alpha defensins and LL-37 with genital infections and increased HIV acquisition. AIDS. 2009 Jan 28;23(3):309-17
- Sheung A, Rebbapragada A, Shin LY, Dobson-Belaire W, Kimani J, Ngugi E, MacDonald KS, Bwayo JJ, Moses S, Gray-Owen S, Kaul R; Kibera HIV Study Group. Mucosal Neisseria gonorrhoeae co-infection during HIV acquisition is associated with enhanced systemic HIV-specific CD8 T- cell responses. AIDS. 2008 Sep 12;22(14):1729-37
- Sheth PM, Sunderji S, Shin LY, Rebbapragada A, Huibner S, Kimani J, MacDonald KS, Ngugi E, Bwayo JJ, Moses S, Kovacs C, Loutfy M, Kaul R Co-infection by Herpes Simplex Virus Type 2 Is Associated with Reduced HIV-Specific T cell Responses and Systemic Immune Activation. J Infect Dis. 2008 May 15;197(10):1394-1401
- Hirbod T, Kaul R, Reichard C, Kimani J, Ngugi E, Bwayo JJ, Nagelkerke N, Hasselrot K, Li Bing, Moses S; Kibera HIV Study Group, Broliden K, MacDonald KS (Co Sr. Au.) HIV-neutralizing immunoglobulin A and HIV-specific proliferation are independently associated with reduced HIV acquisition in Kenyan sex workers. AIDS 2008 Mar 30; 22 (6): 727-35.
Hyper attenuated HIV/SIV vaccine Candidates:
My work in this area focuses on the development of robust cellular immunity based at the genital mucosa where natural infection with HIV and SIV occur. In this respect, I have investigated a number of highly attenuated SIV constructs that provide protection from disease transmission. See Willer et al. Multi Low-Dose Mucosal SIV mac239 Challenge of Cynomolgus macaques Immunized with “Hyper-Attenuated” SIV Constructs J Virol. 2010 Mar; 84(5):2304-17
Herpes Family Viruses as long term reactivating HIV vaccine vectors: Immunogenicity and Protective Efficacy:
Herpes viruses have co-evolved with humans and nonhuman primates throughout evolution. They are ideally adapted to their host and have found mechanisms to persist and provide lifelong infection. They are able to intermittently self-activate and boost antibody and cellular immunity.
A live attenuated vaccine strain, VZVoka has been developed from Varicella Zoster Virus, the cause of chicken pox, and in reactivation the cause of herpes zoster. This vaccine, in use in North America for about a decade, has the benefit of almost 3 decades of use in Japan where it has been shown to virtually eradicate the occurence of chicken pox, but also to reduce the incidence of shingles if given to adults to boost their cellular immunity. Thus it has a remarkable ability to provide long-lived humoral and cellular mucosal and systemic immunity.
Despite its relative species specificy, human VZVoka is able to infect cynomolgous macaques and produce cellular and humoral immune responses as our infectivity trials have shown. ref. J. Virol. April 2012 ; 86:3626-3634 An ongoing large non-human primate immunogenicity and challenge study of a VZVoka -SIV construct shows excellent immune responses including the SIV gene inserts with minimal mucosal immune perturbation. A multi-low dose mucosal SIV challenge is ongoing with monitoring for disease progression over a minimum of 52 weeks. A human study to examine the mucosal immune activation produced by this vaccine backbone has been funded by a new CIHR sponsored Kenyan-Canadian HIV Vaccine Team grant.
Species restriction of human and rhesus CMV necessitated the identification and genomic sequencing of Cynomolgus macaque CMV. We have for the first time identified, characterized and sequenced CyCMV as part of this effort and are generating a Bacterial artificial chromosome derivative. This will be the basis for future SIV vaccine candidates based on CyCMV as the delivery vector. refs. Ambagala, et al Isolation and Characterization of Cynomolgus Macaque Cytomegalovirus (CyCMV) Virology 412, 125–135, 2011. Marsh, A., et al. Genomic Sequencing and Characterization of a Novel Cynomolgus Macaque Cytomegalovirus. J.Virol. 85(24):12995, 2011. A recent HIV vaccine CIHR team grant focused around the development of the CMV vector based vaccine has recently been funded. The goals of this project will be to explore the synergistic benefit of using both CMV and VZV as vectors and the differences in the generation and maintenance of effector memory T-cell responses of these two herpesviruses in the non-human primate model.
Understanding Cellular Immunity Against HIV:
Characterizing Differentially Protective class I HLA Restricted Immune Responses against Conserved HIV Epitopes
We have shown that certain clusters of functionally related HLA molecules called supertypes are associated with a reduced risk of HIV-1 infection in highly exposed sex workers and in the setting of perinatal HIV-1 transmission. We have compelling evidence to suggest that supertypes are a key functional element for evolutionary selection against intracellular pathogens such as HIV-1. We have also demonstrated immunodominant epitopes which appear to persist with remarkable stability throughout HIV infection while others mutate in the face of immune selective pressure. We sought to determine if the conventional assumption that viral fitness requirements explained the lack of mutation in these apparently protective persisting epitopes such as HLA A2 restricted SLYNTVATL. We have demonstrated through both immunological and virological means that fitness constraints do not explain the lack of mutations which occur in this epitope and thus allow us to question whether effective immune responses are elicited by it. These results have informed vaccine design and now there is increasing evidence that inclusion of certain immunodominant HIV epitopes does not result in the development of protective CTL but might have a deleterious effect by preventing subdominant epitopes from being recognized. See. Christie et al Viral Fitness Implications of Variation Within an Immunodominant CD8+ T-cell Epitope of HIV-1 Virology 388, 1, 137-146, 2009, Iversen et al. Nat Immunol. 2006 Feb; 7(2):179-89.