The case of the “Mississippi child” has intrigued scientists since Deborah Persaud first announced the child’s lack of detectable virus at the Conference on Retroviruses and Opportunistic Infections in March 2013. The folks behind the CUREriculum, a group of advocacy organizations and the Martin Delany collaboratories, partnering with leading researchers, hosted a pilot webinar on December 3rd to an audience comprised of US based researchers and community members. Kaitlin Rainwater-Lovett, PhD, a translational immunovirologist (she knows how to use basic science to create practical solutions) research fellow in Deborah Persaud’s lab, led an interactive conversation that highlighted the struggles of finding a pediatric “cure” and the strategies the field is pursuing to tackle them. The CUREriculum is scheduled to launch in early 2015.

You can download a copy of the pilot webinar slides here. 

To find out more, contact Jessica Handibode at jessica@avac.org or Karine Dube at karine_dube@med.unc.edu.

Challenged by cure science? A new curriculum designed for non-scientists, advocates and cure-enthusiasts of all sorts could be just what you are looking for! This new curriculum is a collaborative project that brings together advocacy organizations (AVAC, Project Inform, TAG, NAPWHA, iBase and members of the Martin Delaney Collabratories (MDC) – such as CARE, DARE and defeatHIV, with leading researchers in the field. The effort emerged from the recognition that, while the science of HIV cure research has moved rapidly, literacy materials for lay audiences have not kept pace.

The first module in the curriculum was piloted on August 28th, 2014 with the global community advisory board (CAB) of the AIDS Clinical Trials Group (ACTG). “Everybody wants a cure for HIV and has wanted it for more than 30 years. It is important to translate the science to the community and to make sure there is accurate information about HIV cure research circulating to avoid false hopes,” said Jeff Taylor, co-chair of the Collaboratory of AIDS Researchers for Eradication (CARE) CAB and a steering committee member of the curriculum collaborative. The global CAB—which consists of community advisory boards from many countries—has been asking for materials to support local engagement with communities where ACTG-supported cure research is planned or ongoing. The ACTG is one of six clinical networks maintained by the National Institutes of Health and the only network focused on HIV-positive individuals exclusively. The global CAB of the ACTG works with network administration to discuss the research priorities and needs of the communities they represent. The members were excited and positive about the curriculum’s content.

The next pilot will be held on Saturday October 4, 2014 at 8:30am at the US Conference on AIDS being held in San Diego Oct 2-5. Anyone attending USCA is welcome to attend—details can be found in the program.

When completed, the curriculum will contain 17 modules—listed below. More pilots will be held in the months to come. The curriculum is scheduled for a soft launch in February 2015 at the Conference on Retroviruses and Opportunistic Infections taking place in Seattle, Washington. When completed, the curriculum will include participatory games, pre and post evaluations, recorded webinars, and PowerPoint slide decks.

Curriculum modules:

• HIV/AIDS and Cure Basics
• Role of Community in HIV Cure Research
• Informed Consent and HIV Cure Research
• Stem Cell Transplantation
• Gene Therapy
• Shock and Kill or Latency Reversing Agents
• Concepts in Basic Sciences and Translational Research – The Main Pathways
• Therapeutic Vaccines and Immune-Based Therapies
• Measuring the Latent HIV Reservoir
• HIV Treatment Interruption
• Participation in HIV Cure Trials
• Regulatory Issues in HIV Cure Research
• Early Antiretroviral Therapy

For more information, please contact:

• Jessica Handibode, Program Coordinator, AVAC – jessica@avac.org
• Karine Dubé, Program Manager, Collaboratory of AIDS Researchers for Eradication – karine_dube@med.unc.edu
• Jeff Taylor, CARE CAB Co-Chair – jefftaylorps@gmail.com

Welcome to the first installment of a periodic series of P-values posts by guest authors. We’ll be featuring scientists, advocates and implementers from around the world. If you’ve got a point of view you’d like to share or a topic you’re expert in and would like to explain, Let us know.

This post is the first of what will be a series of posts from scientists working on cure research. Dr. David Margolis and Karine Dubé of The Martin Delaney Collaboratory of AIDS Researchers for Eradication explain one strategy being pursued by scientists as a possible way to cure HIV. After reading this, if you want to learn more check out this video on related research.

Highly active antiretroviral therapy (HAART) is a true miracle of modern science and has contributed to saving millions of lives worldwide. HAART can successfully reduce plasma HIV-1 levels in adherent HIV-positive patients to below the detection limit of clinical assays. As wonderful as HAART is, it does not clear HIV from the human body, but can only suppress it. HIV remains dormant or latent in around 1 out of every million white blood cells in suppressed patients in the form of HIV provirus that becomes integrated within the human genome (also called the reservoir).

There are several approaches to eradicating latent HIV infection that have been proposed by the Martin Delaney Collaboratories, including, but not limited to: intensification of HIV treatment in the acute phase of infection, gene therapy and stem cell transplantation research as well as latency reserving agents. Latency reversing agents are small pharmacological molecules that would help uncover where HIV is hiding in the cells of HIV-infected patients whose viral load has been suppressed.

The Collaboratory of AIDS Researchers for Eradication – CARE – endorses the approach of small pharmacological molecules to finding a cure for HIV infection. We believe that this method represents the safest, most scalable, and accessible strategy to eradicating HIV in the future. By using established drug discovery tools, we hope to launch a pipeline of small pharmacological molecules to be used in human studies. These small molecules would induce the expression of the replication-competent latent HIV proviral genomes within resting CD4+ T cells and make them susceptible to the immune clearance and the effect of HAART. In the literature, this is also called the “shock and kill” strategy or “induction and clearance.” This method relies on reactivating the rare remaining reservoirs while patients take their HAART.

Our priority is to discover new molecules that are safe and can act alone or in synergy with other drugs to reactivate HIV virus transcription. We screened over 10,000 new pharmacological molecules and we are examining their mechanisms of action. As these new compounds have various levels of potency and toxicity, it is important to evaluate them carefully using cell models and animal models before advancing them into clinical testing. Experiments are being conducted in vitro (in artificial laboratory cell models), ex vivo (in patient’s cells studied in the laboratory) and in vivo (in animal models or real human patients) using various cell lines and animal models, included humanized mice and non-human primates.

The small pharmacological molecules being proposed would act as inducing agents to disrupt the state of proviral latency. Examples of small molecules that have been studied include inhibitors of histone deacetylase (HDAC) that play a role in maintaining HIV in a transcriptionally silent state. For example, Dr. Archin and colleagues demonstrated in a proof-of-concept study that a single dose of the drug vorinostat, an HDAC inhibitor, can disrupt HIV latency in HIV-positive patients on HAART. HDAC inhibitors have several advantages compared to other latency reversing agents. Because they have also been studied extensively as part of anticancer trials, we know more about their toxicological and pharmacological effects at this time.

Studying small pharmacological molecules also means that we need to carefully examine the regulatory pathways for these drugs. For example, the positive transcription elongation factor b (P-TEFb) plays an important role in regulating HIV transcription. When P-TEFb is active, this means that HIV viral transcription is stimulated. Another protein required for HIV expression is NF-κB, which is an activating regulatory protein needed for the transcription of many genes.

We are also studying molecules that induce signaling using the protein kinase C (PKC) pathway. Some of the PCK agonists under investigation include prostatin (which can induce transcription of latent HIV-1 in J-Lat cells and peripheral blood mononuclear cells (PBMCs) from HIV-positive patients on HAART). Two other PKC agonists under study include bryostatin and ingenol; however less is more about these compounds’ ability to safely induce HIV expression in vivo.

At this time, we cannot predict which compounds or combination of compounds may be effective at inducing expression of proviral DNA. We hope to investigate synergy both mechanistically and mathematically. Ideally, the chosen pharmacological molecules will reactivate latent HIV provirus without inducing a global activation of T cells. We also hope to get around the problem of toxicity by using low concentrations of the most effective inducing agents.

Once the HIV provirus is being expressed, the immune system needs to kill the infected cells. It will thus be important to re-invigorate the immune system of HIV-infected patients to ensure an effective immune response, so latency reversing agents can be used with immune-based therapies. For example, some of the immune cells could be expanded ex vivo and then be re-infused into HIV-infected patients.

Scientists within the Collaboratory are also working on ways to improve measures of the HIV reservoir. As of now, the quantitative viral outgrowth assay is the gold standard in terms of measuring replication-competent proviruses from resting CD4+ T cells. We are also using digital droplet PCR testing to quantify HIV DNA.

We are excited about the prospect of studying new latency reversing agents – as well as combinations of agents – that would be capable of aborting the state of HIV proviral quiescence. This strategy offers a diversity of options for the advancement of new compounds into clinical trials. It is also the safest way forward. We believe that small molecules represent the big picture for curing HIV infection.

CARE Website:
www.delaneycare.org

If you have any questions, please send them to:

• Dr. David Margolis (david_margolis@med.unc.edu), Principal Investigator, The Collaboratory of AIDS Researchers for Eradication (CARE)
• Karine Dubé (karine_dube@med.unc.edu) Program Manager, The Collaboratory of AIDS Researchers for Eradication (CARE)

Getting into a taxi in any country and ask the driver about the AIDS epidemic is a great way to learn about local views and priorities—and to gauge what news has grabbed the popular imagination. From a decidedly unscientific survey, we’ve found that the notion of a cure for AIDS has dominated taxi discourse—and conversations in many other places—for much of the past year. One of the stories that seized attention of drivers, advocates and scientists was that of the “Mississippi baby”—an infant who was treated after birth with highly active antiretroviral therapy and was then lost to follow up. When she returned to medical care, she had no detectable virus in her blood—and it was thought that she might be cured of HIV.

Recently, there’s been disappointing news of a reversal in this case. Doctors have now detected HIV in the child’s blood for the first time in the two years that she spent without taking antiretrovirals. The fact that the child spent that much time off treatment with no detectable virus is intriguing, since it suggests that she was effectively controlling the virus via immune responses. The fact that the virus returned underscores how far we may have to travel to get to a cure. Treatment Action Group’s Richard Jefferys has an excellent blog post summarizing knowns and unknowns around these developments.

For a look beyond the headlines at the agenda, funding needs and challenges related to cure and therapeutic vaccine research, check out a recent article by AVAC, the Treatment Action Group, and the Global HIV Vaccine Enterprise. This piece builds on the discussions at a workshop on therapeutic vaccines that the groups held together in September 2013 and which included over 100 researchers, funders and advocates to discuss current issues in therapeutic HIV vaccine research and development.

Therapeutic vaccines are tools that aim to help people with HIV control the virus through enhanced HIV-specific immune responses. No such vaccine exists but in theory it could improve treatment efficacy or perhaps, some day, eliminate the need for ART.

Therapeutic vaccines have become a hot topic in cure conversations, too. It’s clear that HIV lurks in dormant, non-replicating cells and that these reservoirs need to be eliminated for an effective cure. Cure research is exploring a variety of one-two punch combinations that would flush out these reservoirs and then neutralize the remaining virus. A therapeutic vaccine could be an ideal tool for the second step in this process.

As the recent paper describes, research and investment into therapeutic vaccines has languished in the past few years. The paper suggests that there is a way to revamp and refocus the current pipeline of candidates to target immune responses not found in natural infection or targeted in previous studies. The paper notes that strategies to enhance vaccine responses in the therapeutic context should develop separately from work on preventive vaccines—but that the two fields should be in close communication to maximize synergies.

Unfortunately, when there’s a setback like the viral rebound in the Mississippi baby case, this too makes headlines and can turn “taxi talk” to despairing statements about how we won’t ever vanquish the virus. The truth is that we don’t yet know whether therapeutic vaccines can be developed to effectively control ART—and we don’t know whether a cure will be possible. But it’s important to move forward with sustained and energized research. There are clues to follow and uncertainty is unavoidable. At a moment like this one, when the headlines are reporting disappointing news, it’s especially important for advocates to help convey the necessity of moving forward.