Canadian HIV Vaccine Initiative - Projects Funded to Date

Canadian HIV Vaccine Initiative - Projects Funded to Date

(as of August 2010)

CIHR leads the CHVI Discovery and Social Research stream which aims to make a significant contribution to HIV vaccine research and capacity building. CHVI consultations were held in February 2008 at which time consensus was reached by Canadian and international researchers on relevant eligible research areas and appropriate funding mechanisms. The following funding mechanisms were recommended and have been launched since that time: Catalyst Grants, Operating Grants, Emerging Team and Team Grants. Outlined below are summaries of the research projects funded to date via this funding stream.

Catalyst Grants

Project Title: Heteroclitic Peptides to Increase Human Immunodeficiency Virus-specific CD8+ T cell Interleukin-2 Production
Principal Investigator: Michael D. Grant, Memorial University of Newfoundland

Therapeutic vaccines are vaccines that are administered to individuals already infected with a pathogen in order to boost the immune response to the infection. In chronic human immunodeficiency virus (HIV) infection, therapeutic vaccines stimulate pre-existing and new immunity against HIV. If the boosted immunity more effectively suppresses HIV replication, this could offer broader treatment options where antiretroviral drugs are not widely available and also reduce dependence on antiretroviral drugs elsewhere. While conserved portions of HIV or sequences known to be present in the infected individuals are usually targeted in therapeutic vaccines, Dr. Grant and his team plans to test sequence variants that arise rarely in nature. Their hypothesis is that these variants are rare because they provoke a stronger immune response in comparison to common sequences. The researchers plan to test this hypothesis, and thereby, identify HIV peptide sequence variants that could be used to make more effective therapeutic HIV vaccines for use in humans.

Project Title: Dissecting the mechanisms of protection by attenuated Nef-deleted HIV vaccine
Principal Investigator: Paul Jolicoeur, Institut de recherches cliniques de Montréal

The development of a vaccine against HIV-1 represents the best hope of controlling the worldwide AIDS epidemic, but to date no preventative HIV vaccine has been developed for clinical use. In monkeys, attenuated simian immunodeficiency virus (SIV) efficiently reduces SIV infection following challenge with the live virus, and currently represents the most potent vaccine against SIV. SIV belongs to the same family of viruses as HIV and causes a similar disease in monkeys. Although an attenuated SIV/HIV vaccine would be too dangerous for humans, knowing how it works would be very useful in designing an effective HIV vaccine. Protection is postulated to occur via the innate immune system, rather than by eliciting SIV-specific immune responses, such as antibodies. The aim of Dr. Jolicoeur's research is to further characterize the mechanisms of protection elicited by both attenuated SIV and HIV. The researchers will use mice for their studies because their innate immune system is very similar to that of monkeys and humans. As well, several genetic mouse variants are available allowing for the identification of genes involved in the protective effect. The research will aid in the identification of the innate immune components that could be stimulated to produce a non-dangerous and potent HIV vaccine for humans.

Project Title: Promoting innate immunity to HIV infection by vaccine delivery of third generation RNA analogs
Principal Investigator: Marc-Andre Langlois, Université Laval

Infection with the human immunodeficiency virus (HIV) can lead to a progressive deterioration of the body's immune system. AIDS (Acquired Immunodeficiency Syndrome) represents the stage when a HIV-infected individual's life is threatened by common pathogens that are normally destroyed by the immune system of healthy individuals. HIV is a retrovirus that has evolved to circumvent the human immune system in several ways, such that no cure or vaccine for HIV has successfully developed. For example, one of the virus' survival strategies is to infect and kill cells that are needed for effective responses to vaccines. Another strategy that the virus uses is to code for a protein called Vif. Vif degrades an endogenous cellular protein called APOBEC3G that has antiviral properties. Specifically, APOBEC3G binds and heavily mutates HIV DNA, ultimately leading to the inactivation and destruction of the virus, but this antiviral effect is greatly reduced in the presence of Vif. The overall aim the research being conducted by Dr. Langlois and his team is to validate a new Vif-inhibiting technology involving third-generation RNA analogs. The research could lead to the development of a vaccine that would inactivate infectious HIV particles in persons with HIV/AIDS and also promote the elimination of HIV infected cells by recruiting the intrinsic antiviral properties of the human immune system. 

Project Title: Functional correlate of mucosal antibody response to HIV infection in blood
Principal Investigator: Denis P Snider, McMaster University

Worldwide, most HIV infections are sexually transmitted, and women are the most frequently infected. In order to protect against HIV infection, vaccines must be effective at blocking entry of the virus. In sexual transmission, HIV enters through the mucosal surfaces of the body. These surfaces can respond with a specific type of antibody, the IgA type. Studies have shown that women who are able to resist HIV infection have IgA antibodies against HIV, while those that become infected have little or no IgA. Thus, when developing new HIV vaccines, it is useful to be able to measure the amount and quality of mucosal IgA antibody against HIV. Unfortunately, testing for IgA antibodies using fluid samples from mucosal surfaces is invasive and results can be highly variable. A blood test would be a much more simple, reliable, and useful approach. Dr. Snider and his team plan to determine whether it is possible to use the circulating immune cells in blood that are responsible for IgA antibody production, as a reliable way to measure the amount and quality of mucosal IgA antibody against HIV. They will determine whether they can detect whether IgA antibody has been produced, its quantity, and whether the antibody can inhibit the virus. They will also compare HIV-resistant and HIV-infected individuals to see if any differences exist in the mucosal IgA antibodies. These studies could ultimately lead to a novel approach for measuring mucosal IgA responses, which would be very useful for the development of preventative HIV vaccines. 

Project Title: A new human cell experimental system for evaluating prototype HIV-1 vaccines
Principal Investigator: Michel J Tremblay, Université Laval

The development of an effective vaccine against human immunodeficiency virus type-1 (HIV-1) remains an enormous scientific challenge, partly due to the lack of a suitable experimental cell culture system in which to investigate protective immune responses to HIV-1. For example, researchers usually examine cellular responses to HIV using cultures of dispersed peripheral blood lymphocytes. These cultures lack the full cellular repertoire within lymphoid tissue, where effective immune responses are generated. In addition, because the cells are in suspension, the intimate association normally found between cells is lost. Given the role played by lymphoid tissue in generating immune responses, and the fact that secondary lymphoid organs are the preferred sites for HIV-1 replication and propagation, Dr. Tremblay and his group will determine whether human lymphoid tissue cultured ex vivo could represent an appropriate experimental cell system to critically evaluate candidate HIV-1 vaccines. The research results could lead to a novel cellular system to determine which vaccine candidates generate the most robust and appropriate immune responses to HIV-1 and even other viruses that are vaccine targets.

Project Title: Discovery of new B cell immunogens for HIV vaccines
Principal Investigator: Mario A Ostrowski, University of Toronto 

Over 33 million individuals worldwide are infected with the Human Immunodeficiency Virus Type-1 (HIV-1), and yet there is no effective vaccine to prevent HIV-1 infection. One of the greatest challenges in HIV-1 vaccine development has been the difficulty in eliciting neutralizing antibodies. Neutralizing antibodies are desirable because most of the vaccines against other types of viruses elicit this type of immune response. In addition, it would be useful to have a vaccine that targeted the large variety of HIV-1 viruses circulating in the population, but none has been developed to date. There are a number of molecules that are produced by human immune cells, such as CD40L, BAFF and APRIL that enhance antibody production. Dr. Ostrowski and his team are determining whether these molecules can be combined with the HIV-1 envelope protein to generate stronger neutralizing antibody responses and a more effective HIV vaccine. If the approach is successful, the studies will lay the groundwork for developing a better vaccine against HIV-1. 

Project Title: A combined early and late HIV-1 protein-specific exosome-targeted T cell vaccine capable of stimulating HIV-1 specific CD8+ CTL responses in absence of CD4+ T cells and counteracting immune suppression
Principal Investigator: Jim (Jianhua), Xiang, University of Saskatchewan
 
Cytotoxic T cells (CD8+ T cells) are immune cells that recognize and kill virally infected cells. These cells are therefore critical in controlling HIV-1 proliferation. In most cases, another type of immune cell, called a helper (or CD4+) T cell is required for the generation and maintenance of cytotoxic T cells. Helper T cells, however, are one of the major types of cells in the body that become infected with the HIV virus, and as a result the number of helper T cells decreases over time, eventually resulting in acquired immunodeficiency syndrome (AIDS). Thus, stimulating efficient cytotoxic T lymphocyte responses in people with AIDS is one of the major challenges in AIDS therapy. Dr. Xiang and his team have recently developed a new vaccine strategy (aTexo) that uses small vesicles, or exosomes, that are released from dendritic cells, which contain all the necessary machinery for eliciting cytotoxic immune responses. In fact, the exosomes can activate cytotoxic T cells even in the absence of helper T cells. Dr. Liang is using this strategy to develop a novel vaccine that combines several HIV proteins including tat, gp120 and gag. The research could lead to the development of a novel way to stimulate cytotoxic T cell responses in persons with AIDS who have reduced numbers of helper T cells.

Project Title: Attacking HIV protease cleavage sites with immunization - Explore the rapid mutation rate of HIV-1
Ma Luo, University of Manitoba 

Even though it has been more than twenty-five years since the discovery the human immunodeficiency virus (HIV), an effective preventative vaccine remains elusive. The difficulty in developing an effective HIV vaccine using traditional approaches highlights the need for novel strategies. One novel strategy that Dr. Luo and his research team are investigating is developing a vaccine that targets HIV-1 protease. HIV-1 protease is a viral protein that cleaves a large precursor viral protein into smaller functional proteins. The cleavage is specific, temporally regulated and essential for the production of infectious viral particles. The regions on the precursor protein that are recognized and cleaved by the HIV protease are highly conserved amongst the major subtypes of HIV-1. Directing immune responses against these cleavage sites could stimulate the immune system to destroy the virus before it would establish itself in the host. Also, it would force the accumulation of mutations at the protease cleavage sites, thus eliminating the ability of the protease to create infective viral particles. The team is developing vaccines that will stimulate immune responses to peptides corresponding to 12 different protease cleavage sites. Once produced, the effectiveness of the vaccines will be tested by determining whether immunization of macaques with the vaccines will reduce or prevention transmission of SIV, a HIV-like virus that infects monkeys. The research could form the basis for the development of a novel HIV vaccine in humans.

Operating Grants

Project Title: The functional profile of NK cells in HIV exposed uninfected subjects: Association with carriage of NK receptor-HLA ligand genotypes
Principle Investigator: Nicole Bernard, McGill University

Natural killer (NK) cells are key players in the innate immune response to viruses such as HIV. NK cells can recognize and kill virally infected cells very early after infection. They do so through cell surface receptors that recognize a cell surface molecule called HLA present on most cells in the body, including those that HIV enters in a new infection. The NK receptors and HLA molecules have many variants that differ from one person to another, which can influence the potency of NK cell activation when these cells see a virally infected target. Previous work in Dr. Bernard's laboratory identified variants of NK receptors and HLA that are present more frequently in people who remain uninfected despite exposure to HIV than in HIV susceptible individuals. The protective variant of NK receptor might increase the activation the NK cells leading to increased killing of HIV- infected cells. Dr. Bernard and her team will study the anti-viral functions of NK cells from individuals carrying NK receptor-HLA combinations associated with protection from HIV infection compared to those from subjects with other combination. Understanding how HIV exposed, but uninfected, individuals are protected from infection may provide clues on how to specifically manipulate the immune system in the context of vaccines to reduce the risk of HIV infection.

Project Title: The potential of APOBEC3G in the development of a novel anti-HIV-1 therapeutic
Shan Cen, Montreal Jewish General Hospital

The main targets for HIV in the body are T lymphocytes and macrophages. In these cells, copies of the HIVvirus are made providing the viral protein Vif is expressed. Vif is known to bind to an antiviral host-cell factor called APOBEC3G and modify it so that it is degraded by the cell. It is is not well understood, however, how the antiviral factor APOBEC3G acts to inhibit viral replication. Because APOBEC3G is a cytidine deaminase, it has been postulated that APOBEC3G mutates the genetic code of the virus, which results, for example, in the production of nonfunctional viral proteins. Dr. Cen, however, has shown that APOBEC3G can act independently of its cytidine deaminase activity, suggesting that APOBEC3G has other functions. Therefore, the goal of Dr. Cen's current research is to more fully understand the function of APOBEC3G and how Vif abolishes the anti-HIV activity of APOBEC3G. Greater understanding of these functions might lead to novel HIV treatments that would either enhance the activity of APOBEC3G or inactivate Vif.

Project Title: The effect of the CD4 pathogenicity island on HIV susceptibility and disease progression
Keith Fowke, University of Manitoba

Humans share the the same set of genes, but we all possess slightly different versions of those genes, which makes us unique. These genetic differences, called polymorphisms, are associated with differing susceptibility to diseases, such as HIV. Previous work from Dr. Fowke's laboratory demonstrated a link between increased susceptibility to HIV infection and a particular version of the gene encoding the main host protein that HIV uses to enter into a cell, called CD4. In addition, the group has shown that the genes found on the chromosome close to the CD4 gene might also be linked to altered HIV susceptibility. They have coined this chromosomal region the "CD4 pathogenicity island". For the current project, the researchers will explore the genetic linkages between the genes in the CD4 pathogenecity island, and will also determine how the gene products function at the molecular level to increase or decrease susceptibility to HIV infection. These studies will lead to a better understanding of the molecular pathways or genetic variants that alter HIV transmission and disease progression, thereby identifying potential new targets for further anti-HIV drug development. 

Project Title: Studying the antiviral activity of bone marrow stromal cell antigen 2 and the countering mechanism from HIV-1 Vpu
Chen Liang, Montreal Jewish General Hospital

Current antiretroviral drugs dramatically lower the viral load in persons with HIV, and can thus extend their lives for more than 25 years on average. The appearance of multi-drug resistance HIV-1 strains, however, eventually will exhaust the drugs' effectiveness. Therefore, it is essential to continually develop new antiretroviral drugs. One way to discover new drug targets is to more fully understand viral-host cell interactions. Dr. Liang is studying a recently discovered host factor named bone marrow stromal cell antigen 2 (BST2) that potently blocks HIV-1 production when cells are infected with an HIV virus that does not code for a functional viral protein called Vpu. In contrast when functional Vpu is expressed, new viral particles are produced. Understanding how BST2 restricts HIV-1 production and how Vpu counteracts BST2 is the objective of his research. The research results will create new knowledge of the pathways that are involved in both BST2 and Vpu function. With this knowledge, it might be possible to develop new HIV drugs that either enhance BST2 activity or inhibit the activity of Vpu.

Project Title: A comparative immunogenicity study of HIV-1 Pr160Gag-Pol virus-like particles bearing gp120, CD40L and/or TLR5 agonist flagellin
Michel Tremblay, Université Laval

Despite some recent promising results from a preventative HIV vaccine trial in humans in Thailand, the development of a safe and effective HIV-1 vaccine is still an immense challenge. One of the difficulties is eliciting potent and appropriate immune responses to HIV antigens. It has been previously demonstrated that virus-like particles (VLPs) are superior to conventional protein immunogens in activating immune responses. Unfortunately, VLPs for HIV-1 are reported to display a low immunogenicity when used one their own. Therefore, the goal of the research that is being conducted by Dr. Tremblay and his group is to improve the immunogenicity of HIV-1-based VLPs by incorporating constituents that can stimulate immune cells. Once these immune regulators are identified, they could be incorporated into the design and development of future HIV vaccines.

Emerging Team Grants

CHVI Team in the soci-cultural aspects of implementing HIV vaccine programs among MSM and FSWs in Asia and Africa
Principle Investigator: Robert Lorway, University of Manitoba

Promising vaccine trials and recent advances in basic scientific understanding of HIV immunology suggest that a highly efficacious HIV preventive vaccine will appear in the near future. However, it cannot be assumed that the availability of an efficacious vaccine will ensure a population's uptake, given the array of potential psychosocial, cultural and political barriers. Research that examines these barriers has tended to be conducted in North America. Moreover, communities of men having sex with men (MSM) and female sex workers (FSW) who encountered numerous barriers to health services are noticeably absent from this body of research. For this reason, the proposed research program will examine the acceptability of a future HIV vaccine among highly stigmatized MSM and FSWs, as well as members of civil society organizations engaged in HIV prevention work within these communities. This program will be conducted at 3 culturally contrasting sites in Asia and Africa. 

CHVI Team in HIV Vaccine Design Based on Novel Strategies to Induce Protective Mucosal Cellular and Humoral Immunity
Principle Investigator: Kelly MacDonald, University of Toronto

This project involves basic science HIV vaccine research. The team will develop and test two vaccine candidates. Both vaccine projects will involve molecular biological techniques to construct the vaccines and test them for expression. The first project involves the construction of a Cytomegalovirus-based vaccine vector expressing green fluorescent protein and SIV gene inserts. The second project involves the development of a complex DNA vaccine based on a fusion protein of two trimerized proteins: one of gp140 and the other of a TNF superfamily molecule. Other innate immune molecules will also be tested for potential incorporation into the model. Small animal models and in vivo methods will be used to examine immunogenicity. Further testing involving immunological methods as well as molecular and retrovirology will be done in rabbits and nonhuman primates.