Since the beginning of the epidemic researchers have been trying to find ways to cure HIV infection—which invades the very immune system needed to fight the virus—with safe and effective treatments. So far this goal has not been achieved. Great progress has been made, however, to develop treatments that, when taken daily, suppress the virus to levels that are currently undetectable using clinically approved laboratory methods.

Overview

If taken consistently over a lifetime these combination antiretroviral therapy (cART) drugs dramatically reduce HIV-related death and illness. cART does not eliminate HIV entirely from the body, nor does it restore immune function enough to allow discontinuation of treatment. The virus is able to persist in specific cell and tissue reservoirs where the drugs cannot affect it. HIV can hide in cells that are not visible to the immune system and may also replicate below the detectable levels. Once cART is discontinued, HIV that was previously hiding rebounds in a short period of time.

HIV cure research aims to overcome the problem of viral persistence. A global coordinated effort is underway to find a cure for HIV. The main scientific agenda for this research is guided by the International AIDS Society Towards an HIV Cure program. At the beginning of the movement, the CTN acted as a bridge between the IAS and CIHR to help bring Canadian research expertise to the international search for a cure. Canadian researchers—many operating within the CTN scope of activity—collaborate with and contribute to the work done internationally.

This resource provides a summary of HIV cure research that is supported by the CTN. It is not a complete roster of Canadian HIV cure research since much of the effort is in basic science or preclinical stages (research that is needed before clinical trials can take place) or is not supported by the CTN. The CTN works closely with Canadian researchers and is eager to help them move their intervention strategies into clinical testing.

Vaccines and Immunotherapies Research Core

Within the CTN, the Vaccines and Immunotherapies (VIT) Research Core, led by Drs. Jonathan Angel and Jean-Pierre Routy, focuses on research in targeted immunotherapies, prophylactic and therapeutic vaccines, and emerging areas of research in treatment and immune system support. The VIT Core oversees the CTN’s research studies related to finding a cure. Below are examples of a few strategies behind CTN studies involving HIV cure research.

 

Boosting immune function and decreasing the size of the reservoir

The CTN first became involved in HIV cure research in 1998 with CTN 033. This study aimed to show if injection of a vaccine (VaxSyn) would slow disease progression and strengthen participants’ immune systems as part of a functional cure but found no clinical benefit. Similarly, a set of three studies (CTN 229239, and 256) tested the safety and immunogenicity of a treatment made from participants’ own white blood cells (AGS-004) to increase immune function. Immunogenicity refers to the ability of a treatment to stimulate different immune system responses needed to fight a virus but does not necessarily mean clinical beneficial. More needs to be learned to understand which specific responses will be effective to control HIV. Although CTN 229 and 239 found that AGS-004 was safe and showed promise by stimulating the immune system, CTN 256 found that there was no antiviral effect compared to placebo.

A current pilot trial, CTNPT 020, is examining the safety and immunogenicity of a different vaccine (PENNVAX) delivered directly using a pulse of electricity. Another ongoing pilot trial, CTNPT 027, is testing the ability of metformin, a natural treatment for diabetes, to boost the immune system and reduce the size of the viral reservoir.

CTN 140, an early proof-of-concept study, tested if intensification of ART in combination with a therapeutic vaccine (Remune) would allow participants to control HIV without ART. A later pilot study, CTN 173, found that vaccination with Remune plus ALVAC – which was used in order to boost CD8 T cell responses – showed a slight trend in the delay of viral rebound during structured treatment interruption within the study populations but it was not significant. The size of the reservoir was not decreased in trial participants. The safety and tolerability of a different combination vaccine (Remune plus Amplivax) was confirmed by CTN 203.

Purging the reservoir

Valproic acid, a treatment for epilepsy, was tested in CTN 205 as a candidate to determine if it could reduce the size of the viral reservoir when combined with ART. Valproic acid is thought to stimulate hiding HIV, preventing it from staying dormant in immune cells. Although the trial was able to be done using a unique study design, valproic acid was not shown to reduce reservoir size in this study.

Targeting the gut

Research in early HIV infection has pointed investigators towards the gut as a site of initial damage, inflammation, and microbial translocation. Microbial translocation is when bacteria in the gut pass into the general blood stream, contributing to harmful immune activation and inflammation. This makes the gut a potential target for interventional strategies. CTN 257 looks to assess the impact of HIV infection and ART on mucosal (gut) and circulating immune cells in the early stages of HIV infection.

CTNPT 022b is determining whether a probiotic supplement in combination with ART can help reduce inflammation and harmful immune activation, a potential component of a functional cure. Reducing inflammation may reduce the number of immune cells targeted by HIV for infection and return the gut to a condition of relative health, therefore preserving immune function.

Cohorts to better understand factors in cure research

Individual differences in immune responses to ART and to HIV infection itself are important to researchers as the basis upon which treatments can be developed. The CANOC collaboration (CTN 242), a national retrospective observational cohort study of over 10,000 participants pulled from databases in Quebec, Ontario and BC, allows researchers to decipher which factors are most important for treatment and cure strategies. The CTN’s contribution to the CANOC collaboration is through the Clinical Management Sciences (CMS) Research Core.

A five-year study (CTN 247) is following a cohort of slow progressors – people who show some natural control of HIV progression – to understand the factors that contribute to improved immune function and disease outcomes. EPIC4 (CTN 281), another promising cohort, is comprised of a group of children and infants who acquired HIV via vertical transmission – during childbirth, in utero, or during breastfeeding. After being started on ART shortly after birth, children in the EPIC4 cohort have achieved viral suppression. This cohort gives researchers a chance to study the effects of early ART as a functional cure but is also a long-term source of information about the immune system, treatments, and HIV characteristics. The EPIC4 cohort study is conducted through the CTN’s Prevention and Vulnerable Populations (PVP) Research Core. So far, none of these children have been taken off ART but four are being closely followed to determine if the virus would rebound if treatment was stopped.

Cure research outside the CTN: where do we fit?

 

Canadian HIV Cure Enterprise (CanCURE)

Before research gets to the clinical phase, studies are needed to understand the fundamental characteristics of the immune system and HIV, often using animal models. The Canadian HIV Cure Enterprise (CanCURE) national team is a CTN research partner and is a collaboration between CIHR, CANFAR, and IAS. CanCURE is committed to finding a cure for HIV from basic research through to clinical trials. Several CTN researchers are CanCURE investigators: Drs. Jean-Pierre Routy, Jonathan Angel, Mario Ostrowski, and Eric Cohen are principal investigators, and Drs. Rupert Kaul and Mark Wainberg are co-investigators.

CanCURE focuses its research plan on HIV in myeloid lineage cells, including macrophages. Myeloid cells are a group of immune cells in the blood that are different from lymphoid cells (the cell type that CD4 T cells belong to). The team will study these cells, often lodged in deep tissue reservoirs such as the brain, to understand the relevant mechanisms of viral persistence and relationship to persistence in CD4 cells, and to develop treatments that might deplete or control HIV in these cells.

HIV Cure Research in the Canadian Context

Studies that are not directly focused on curing HIV or shrinking the viral reservoir as a principal objective can indirectly contribute significantly to the field of HIV cure research. For example, a recent finding from CTN 247 – the slow progressors cohort, led by Dr. Cécile Tremblay – has identified a biomarker in the blood (interleukin-32, or IL-32) that may help predict when people who could previously naturally control their HIV levels begin to lose control. Not only does this finding represent a potential monitoring tool for HIV control, it could also be used as a target for drug therapy to reduce harmful inflammation and immune dysfunction. Dr. Tremblay and her team have secured federal funding to research Il-32 in this context over the next 5 years.

Aside from CanCURE, CTN Researchers are involved in a number of studies across Canada that aren’t directly supported by the CTN. For example, CTN Investigators Drs. Colin Kovacs and Mario Ostrowski recently completed a clinical trial looking at the impact of early, intensive cART (including raltegravir and maraviroc) on reducing the size of the viral reservoir. This year, CTN Investigators Drs. Nicole Bernard and Cécile Tremblay received a 5-year project grant from CIHR to investigate how antibody dependent functions may affect HIV control and lead to design and delivery of new effective therapeutic antibodies. This research, which is funded for the next 5 years, hopes to contribute to the design of therapeutic antibodies to control HIV infection. Previously Dr. Routy and others investigated the effect of IL-7 on HIV persistence. Unfortunately, that trial showed that IL-7 was of no benefit.

The CTN supports a wide range of HIV cure-related studies and our researchers are involved in many projects that contribute knowledge to this area. Beyond the CTN there are many important cure studies and clinical trials going on in Canada. CANFAR is currently funding research by Dr. Sadhna Joshi (University of Toronto) to further develop strategies to prevent HIV from entering the immune cells. Drs. Lisa Barrett, Sharon Oldford, Nate Stepner, and Marina Turner at Dalhousie University are part of the EpiStem collaborative project. This group seeks to guide and investigate the potential for HIV cure in HIV-infected patients who need stem cells transplantations. Dr. Zabrina Brumme (Simon Fraser University) is the principal investigator of a CIHR-funded international collaboration to synthesize knowledge about HIV, genetics, and viral behaviour with the ultimate goal of developing an HIV vaccine. These are just a few of examples showing the breadth of HIV cure-related research happening in Canada. As the dedicated group of scientists, community members, and policy makers progress towards tackling the unsolved areas of HIV, the CTN strives to continue its significant contribution and collaborative effort in clinical research, both in Canada and around the world.

CTN StudyShort NamePrincipal Investigator(s)Long NameStudy Description
CTN 033rgp160 vaccine (VaxSyn)Dr. Chris TsoukasActive Immunization of Patients with HIV Infection: The Study of the Effect of VaxSyn on Progression of Immunodeficiency (gp160)This study determined whether injections of an artificial vaccine (VaxSyn) would strengthen the body’s immune reaction against HIV in those living with HIV. See here for study results.
CTN 140Stopping AntiretroviralsDr. Emil TomaStopping Antiretrovirals After Therapy Intensification, Macrophage Stimulation and Immune Activation in HIV-Infected Adults on HAART and with HIV Viral Load Below Detection LimitAn early proof-of-concept study, CTN 140 tested if intensification of ART in combination with a therapeutic vaccine (Remune) would allow participants to control HIV without ART.
CTN 173Vaccination before treatment interruptionDr. Jonathan AngelA Pilot Study to Determine the Impact of Therapeutic HIV Vaccination Followed by a Scheduled Interruption of Antiretroviral Therapy on HIV-Specific Immune Function and Virologic Rebound in Patients With Prolonged Viral SuppressionThe purpose of this study was to determine if vaccination before a structured treatment interruption (STI) is associated with an improvement in immune function, resulting in a delayed and reduced rebound in the amount of virus in the blood. See here for study results.
CTN 203Phase I/II study of Remune plus AmplivaxDr. Bill CameronA Phase I/II safety and immunogencity study of a combination of whole-killed HIV-1 antigen and Amplivax, administered with or without IFA, in HIV-1 infected ParticipantsThe purpose of this study was to determine the optimal dose and formulation of Remune, an experimental therapeutic HIV vaccine, in individuals on ART. See here for study results.
CTN 205Valproic acid and HIVDr. Jean-Pierre RoutyUse of valproic acid to purge HIV from resting CD4+ memory cellsThe purpose of this study was to attempt to reduce the size of HIV reservoirs in infected CD4 cells by administration of ART and valproic acid. See here for study results.
CTN 229Effect of AGS-004 immunotherapeutic agent in HIV-positive people on HAARTDr. Jean-Pierre RoutyA pilot study (Phase I/II) testing the immunologic activity and safety of AGS-004, an autologous HIV immunotherapeutic, in HIV-infected adults on HAARTThis study assessed the safety and immunogenicity of AGS-004, an HIV immunotherapy created from a person's own white blood cells, in HIV-infected adults who are on ART. See here for study results.
CTN 239Phase II study of AGS-004 an immunotherapeutic agent combination with ART followed by ART interruptionDr. Jean-Pierre RoutyA phase II study testing the activity and safety of AGS-004 as an immunotherapeutic in successfully ART-treated subjects infected with HIV-1 in combination with ART followed by ART interruptionAs a follow up to CTN 229, this study aimed to assess the immunogenicity and safety of AGS-004 during a 12-week ART structured treatment interruption. See here for study results.
CTN 242CANOC – The Canadian Observational CohortDr. Robert HoggAn observational study and is designed to examine and link HIV/AIDS information drawn from databases across CanadaThis large, national cohort study is designed to link HIV databases across Canada and allow researchers to gather observational data for substudies, some of which focus on the viral reservoir and biomarkers. See here for a full study description.
CTN 247Canadian cohort of HIV-positive slow progressorsDr. Cécile TremblayA study of host and viral factors associated with disease progression in long term HIV infected subjectsThe objective of this cohort is to gain a better understanding of individuals who maintain a slower than usual loss of CD4 cells (slow progressors), their virus type, factors determining their rate of HIV progression, and how their immune systems work. See here for a full study description.
CTN 256Phase IIB study of efficacy and safety of AGS-004Dr. Jean-Pierre RoutyA randomized, double blind, phase IIB study testing the efficacy and safety of AGS-004 on host control of HIV replication during analytical treatment interruptionThis large-scale study followed the smaller CTN 239 and tested the safety of multiple doses of AGS-004 and its ability to stimulate the immune system and control HIV during ART interuption. See here for a full study description.
CTN 257Impact of HIV on mucosaDr. Jean-Pierre RoutyImpact of HIV infection and antiretroviral therapy on mucosal and systemic memory CD4 T cellsThis study is assessing the impact of HIV on cells of the gut during early HIV infection, and how this contributes to HIV disease progression and the viral reservoir. See here for a full study description.
CTN 281EPIC4: Early pediatric initiation Canadian child cure cohortDr. Hugo SoudeynsEffectiveness of early treatment with anti-retroviral therapy in children with HIVThis cohort study aims to determine whether early use of cART in vertically transmitted cases (HIV passed on from mother to child) results in a state of HIV suppression that can be controlled without further drug use. See here for a full study description.
CTN 294The LAGHDA StudyDr. Mark WainbergLongitudinal Analysis of HIV Genetic Diversification under Antiretroviral therapy (LAHGDA) This study will compare the genetic evolution of HIV DNA between people taking different ART drugs.
CTNPT 004Effects of HLA allele frequencies on HIV disease progressionDrs. Ken Kasper, Marissa Becker, and Yoav KeynanEffects of HLA allele frequencies on HIV disease progression and viral load among newly diagnosed HIV infected individuals in ManitobaThis pilot trial looked at if variation in the human leucocyte antigen (HLA) gene can influence the rate of CD4 decline. See here for a full study description.
CTNPT 020Therapeutic HIV vaccine with early HAART treatment initiationDrs. Mario Ostrowski and Colin KovacsA pilot randomized, open label study to evaluate the effect of a therapeutic HIV vaccine consisting of PENNVAX®-GP (gag, pol, env) and INO-9012 DNA vaccine delivered via electroporation on reducing HIV viral reservoirs in infected individuals, who initiated therapy during the acute/early phase of infection.This pilot trial will see if increasing the immune response against HIV using a vaccine delivered via electroporation (or a pulse of electricity) can reduce the viral reservoir. See here for a full study description.
CTNPT 022BPROOV IT IIDr. Rupert KaulProbiotic Visbiome for Inflammation and Translocation in HIV IIThe purpose of this pilot study is to determine if taking a probiotic with ART can help reduce inflammation and harmful immune activation in those who don’t respond completely to ART. See here for a full study description.
CTNPT 027The Lilac StudyDr. Jean-Pierre RoutyThe effect of metformin on HIV reservoir size in non-diabetic ART-treated patientsThis study will evaluate the ability of metformin, a drug used to treat type 2 diabetes, to improve immune function and reduce the size of the HIV viral reservoir. See here for a full study description.

For more information

Online information about HIV cure research from some other organizations:

This document was co-authored with:

Robert J. Reinhard

Community Liaison for CanCURE

Public/Global health consultant
Toronto, ON, Canada
rjreinhard@gmail.com

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