In November 2014 over 200 researchers, students, community members and service providers met in Toronto for Back to Basic, a conference focused on helping basic scientists and clinical researchers communicate their work to a wide range of audiences.
In addition to providing a forum for researchers to present their findings, Back to Basic placed an emphasis on interaction and clear communication – highlighting how data is generated, shaped, interpreted and used. The following report summarizes some of the key ideas shared at the conference.
Back to Basic was pleased to feature a keynote presentation by professor and researcher James Lavery, who specializes in public engagement and research ethics. A principal consultant on community and public engagement for the Bill & Melinda Gates Foundation's Global Health Program, Lavery's early experiences with HIV/AIDS activists helped shape his career in science communication.
Lavery began his presentation by reviewing the social and historical context for HIV/AIDS communication, and the changing models of communication that have been used. He explained that the field of science communication has stemmed from tough cases – the vaccine opposition movement, global warming, intelligence testing, and evolution are examples. Each of these topics are big-picture science issues that impact how we think about communication – all involve complex science and imperfect theory. Lavery noted that, even with our best theories, there can be disagreement about evidence and evidentiary standards. Some data sets can be fairly interpreted to arrive at differing conclusions. In these cases, differences in interpretation can lead to hardening of positions, which can stifle honest inquiry and undermine peer review.
Lavery argued that we must remember that there is a wide range of legitimate interest in complex phenomena. “Often,” he said, “if people don’t hold the same views as we do, we immediately then conclude that their positions are illegitimate. And that’s just not true – people can have interests that are fair and reasonable in a democratic society and completely disagree with our own.”
It’s this clash of Interests that takes science into a political space, where hardened positions must be defended with political tools. In Lavery’s view, this creates an us-vs-them mentality, and a gap where there isn’t any dialogue.
In discussing how communication has changed over time, Lavery emphasized that there has been a shift to more democratic, pluralistic models. Under these new models of communication, it’s not enough for scientists to explain themselves clearly to the public; there’s a dialogue that goes both ways.
Communication doesn’t really make any sense in the absence of relationships.
Citing a talk given by Alan Alda at the The American Association for the Advancement of Science, Lavery argued that the nature of our relationships determines what effective communication is, and that there are multiple perspectives on what's effective.
“It’s this notion of scientists and the community in a relationship,” he said, “that I think, for me, is the real foundation to build on in terms of improving science communication overall.”
Reviewing the history of HIV/AIDS communication, Lavery named the Morbidity and Mortality Weekly Report of Jul 3, 1981 as the most important document, because it brought the attention of the CDC, the USA and the world to HIV before it even had a name. He noted that, after this, the discussion of HIV quickly moved into a political space involving the marginalization of the so-called 4H Club – homosexuals, hemophiliacs, Haitians and heroin users – all of whom were vulnerable to HIV.
AIDS activists staged sit-in protests outside NIH, which Lavery said were surprising at the time, but designed to make the point that people were not being heard. Reading from Steven Epstein’s Impure Science, he discussed the NIH protests as credibility struggles, quoting, “by scientific credibility, I mean to refer to the believability of claims and claim makers. More specifically, credibility describes the capacity of claim makers to enrol supporters behind their argument, legitimate those arguments as authoritative knowledge and present themselves as the sort of people who can voice the truth.
Discussing protest signs at NIH that personally attacked NIAID Director Tony Fauci by saying “Dr. Fauci, you are killing us,” Lavery noted that this was both a highly effective political message and a highly confrontational one.Lavery expanded on this idea in an interview with Darien Taylor, and stressed that respectful confrontation has a place in healthy relationships. “We tend to be afraid of confrontation,” he said, “we don’t like upsetting people; we want everything to be nice and calm. But, when we have major power differences, and we have
really fundamental problems in justice, we can’t be silent. And I think, often, people don’t know how to not be silent.”
Reflecting on the lessons he learned from confrontations that took place during the AIDS crisis, he added, “HIV and AIDS has been really one of the paradigm cases of how this kind of interaction between the ‘public’ and the science establishment has played out.”
During his presentation, Lavery reflected that his time on the data safety management board for the RV144 HIV vaccine trials and the insight it gave him into what happens behind the scenes. The trials were proceeded by a heated exchange in Science Policy Forum, which led to controversy. Debate focused on the ethics of the vaccine trials and disagreement over the scientific rationale and social value of the project, but the real problem with RV144, Lavery explained, turned out to be that it’s hard to manufacture – so difficult that no one has received the vaccine yet. This was a fundamental rate limiter for the vaccine’s public health impact, but it wasn’t noticed during scientific debate.
Lavery also discussed the adherence challenges in the recent FEM-PrEP trial, which was stopped early for futility. Despite high self-reported adherence in the trial, more than 60% of participants did not take the medication according to instructions. Although this has led researchers to move toward incorporating biomedical measures of adherence into studies, Lavery reflected that, partly because there’s less funding for social science research, and partly due to poor communication, researchers still don’t understand adherence well enough. “It seems to me that we have this enormous drive on the science side and science funding,” he said, “but these fundamentally human issues are just kind of left out there.”
The social value of any science project is not determined by scientists alone.
Lavery also argued that researchers still don’t know how to listen effectively to understand the motivations and interests of trial participants. He stressed that successful studies depend on cooperation and understanding between researchers and participants, saying, “Scientists and participants don’t start with shared interests in the trials; those have to be discovered and nurtured.”
Respecting the role that community and communication have played in the AIDS movement, Back to Basic encouraged open discussion of communication gaps and strategies.
In response to Lavery’s presentation, immunologist Polly Matzinger expressed frustration with the mixed messages scientists receive about communicating with the public. “Scientists don’t get rewarded for communicating,” she said, “we don’t get grants for communicating, we don’t get paid for communicating, we don’t get promoted for communicating, in fact, we usually get slammed for communicating… If you want scientists to communicate, if you want to promote that, you need to find a way to reward them for it.”
Session moderator and HIV activist Darien Taylor reflected that, “Looking back to the bad old days of no drugs and activism to get drugs, it seems to me there was a lot of communication. … It wasn’t always friendly, it wasn’t always happy, but it forged relationships that I think still exist in very meaningful ways today. And I actually wonder, coming to this conference, if we’ve lost ground since those bad old days in our ability – or even in our sense that we need to communicate about issues of science and research anymore.”
Taylor also interviewed Matzinger, who is, herself, a powerful public speaker, about her presentation strategy and her views on education. Matzinger explained that her presentation style is based around creating opportunities to monitor audience response so that she can adjust her talk accordingly. This is why she never presents with slides and instead draws diagrams in real time as she’s speaking.
Matzinger also expressed admiration for Sugata Mitra’s philosophy that the job of a great teacher is to ask great questions and let students find the answers. “I think one of the things that’s really important,” she said, “is to remember that there was a time when you didn’t know.” She stressed that good teachers know how to hone information down to its essentials and to tailor their message for the audience receiving it.
Back to Basic’s plenary on community engagement included a mix of researchers, service providers and people living with HIV. Moderator Colin Kovacs set a reflective tone by invoking Jürgen Habermas, who said that, “In a process of enlightenment, there can only be participants.”
Order of Canada recipient Ron Rosenes also took the stage to discuss the importance of collaboration between researchers and community. He argued that including people with lived experience in research gives voice to disenfranchised and marginalized groups, and helps bring the totality of lived experience to the table.
It isn't just about us, and it isn't just about them. It's about the ways in which we meet researchers half way.
He noted that, while it’s more challenging to participate in basic as opposed to social science research, researchers have the opportunity to meet the community half way. He added that, in particular, people living with HIV can add value in discussions of informed consent and bioethics.
Lena Serghides and Connie Kim both spoke about the impact that community engagement had had on them as researchers.
Serghides noted that basic scientists often have better access to the community when they collaborate with clinicians, and that she began to engage with the community through attending community advisory board meetings. After that, her research process and questions were influenced by what the community was interested in, and she shifted her work to find answers to community members’ questions.
Serghides explained that the HIV field has moved so fast in large part because of the willingness of the community to participate and be engaged. “My research,” she said, “has really been motivated by the enthusiasm I see from the participants and from the community… and key questions have actually come from the community.”
Kim explained that, as a PhD student, she would collect and analyze blood samples without interacting with study participants. While she appreciated the need for participants to be anonymous, it was also important to her to remember the human connection and impact of the work she was doing.
When she began to work with community scholars, she found that they asked different, big picture questions about the impact research would have on the community. “As a student who spent 16 hours a day in the lab,” she said, “it was very nice to see community members really interested and engaging and trying to understand more and asking very important questions.” The experience changed her career path to one that involved more community engagement.
Wangari Tharao offered a service provider’s perspective on research collaborations she had been involved in through Women’s Health in Women’s Hands, which primarily serves the African, Caribbean and Black (ACB) community. In particular, she mentioned projects the organization has recently been involved in with Charu Kaushic and Rupert Kaul, as the product of relationships that began in 2006.
The co-infection project Women’s Health completed with Kaul involved collecting samples and swabs from participants, as well as asking invasive personal questions. Shortly after the project began, rumors started to circulate that the researchers were doing genetic testing, which has negative associations in the ACB community and discouraged people from participating. In considering how to overcome historical mistrust of institutions, the group changed to a community recruitment model and trained 25 peer researchers. The peers were then able to recruit 500 men for the study in only eight months.
In an interview with Darien Taylor, Tharao explained that, as a service provider, “there is the responsibility of safeguarding communities so that they’re not exploited, but at the same time, there’s also the need to be able to get the information that you actually need. It’s a really fine balance.” The involvement of Women’s Health encourages people to participate in research, because they know the organization will protect their interests – that also means that Women’s Health has more responsibility. “You have the role of being a custodian,” she said, “to ensure that things don’t go wrong.”
Reflecting on lessons learned from this and similar research projects, Tharao explained that the reason collaborations with Kaushic and Kaul have been successful is that these researchers are invested in Women’s Health beyond their immediate needs and are willing to help with projects initiated by the organization.
She noted that “researchers have to recognize that community-based organizations don’t have the infrastructure for research,” and include building that infrastructure in their plans. They also need to consider what they’re giving back to the community, which is where the transferable skills of peer researchers can come into play.
Tharao noted that community members who participated in the co-infection project said they also wanted to have more contact with the core researchers who were analyzing their samples and data.
Back to Basic invited eleven researchers to give lightning presentations on their projects, modelled after the Three-Minute Thesis (3MT) format. These presenters took on the challenge of explaining their research clearly and succinctly in three minutes or less before an audience of researchers, service providers and people living with HIV.
Back to Basic was pleased to welcome Science correspondent Jon Cohen as a keynote speaker. Over the course of his career, Cohen has covered HIV research and the HIV/AIDS epidemic in dozens of countries and published a well researched book, Shots in the Dark: The Wayward Search for an AIDS Vaccine.
In an interview with Darien Taylor, Cohen explained that he was originally studying medicine when he discovered his passion for journalism. After changing his major to Science Writing, he made contact with researcher Jonas Salk and formed a relationship that later led to his interest in HIV. “The beauty of journalism, unlike medicine,” he said, “is that there is no path that leads you to Rome. Everyone finds their own path.”
During his presentation, Cohen shared photos and stories documenting HIV/AIDS care internationally from the 1980s to the present day.
Cohen reviewed major milestones in HIV treatment, from the time HIV surfaced (1981) and was identified (1983) to the 1996 Newsweek cover that asked whether we had reached the end of AIDS. He noted that the activism movement emerged and grew out of frustration – mostly directed at government and the pharmaceutical industry. This frustration reached a boiling point at the 2000 AIDS meeting in Durban, South Africa, which resulted in a spike in AIDS funding and greater access to antiretroviral medication.
While Cohen credited the generic drug industry in Brazil and Thailand for making the bold move to produce ARVs more cheaply, he acknowledged that the process still moves slowly. He argued that, while there is still great optimism today about ending AIDS, one of the greatest failures is that people aren’t communicating well about what works and doesn’t work.
He explained that, even after the funding spike in 2000, people are still dying of AIDS. “This is still happening all over the world, even in the face of there being very potent and safe drugs.”
Taking an international view, Cohen noted that there continue to be long wait lines for HIV treatment in Haiti, and that he visited a Guatemalan tuberculosis clinic where people aren't routinely tested for TB after they test positive for HIV. In 2013, he interviewed a man in Tijuana, Mexico who waited two months to begin ART because his blood was sent to Mexico City for testing, even though he had a previous diagnosis of HIV and had previously received ARVs.
Cohen noted that access to harm reduction services is limited in many countries, despite the benefit these services provide. "We shouldn't be arguing about needle exchange any longer," he said. "That [arguing] should end."
"Many people who are high risk have many risks."
During his travels, he encountered many instances where harm reduction services were actually or effectively outlawed, and others where services were delivered in an uncaring way. In one example, he visited an Indian heroin rehabilitation unit where patients were shackled to their beds with chains. "That is not rehabilitation," Cohen said, "That's inhumane, it shouldn't be happening, and we should all be telling people 'you can't do this.'"
Turning his attention to Canada and the USA, Cohen argued that, although the treatment cascade in these countries is improving, there’s still more work to be done. The key affected populations are usually marginalized. “In the South,” he said, “to be a young black gay man is to be marginalized by definition.” He noted that it was likely even harder to be transgender.
Based on the evidence he’d seen, Cohen was doubtful about the prospect of a fully-effective HIV vaccine on the horizon. He expressed concern that a partially-effective vaccine would do more harm than good, saying, “I just don’t think we can live with a 30% effective anything.”
Throughout his presentation, Cohen emphasized the need for more and better communication about strategies to improve the lives of people with HIV. Noting that too few places actively seek and embrace criticism, he praised Washington DC for responding to feedback from grass-roots organizations that put out an annual report grading the city on its performance.
Cohen also cited research into broadly neutralizing antibodies, SIV vaccine trials, and the study of HIV transmission networks – including the work being done in San Diego, California – as being key. He noted that the O52 study on serodiscordant couples has shown the value of treatment as prevention – specifically, that treatment was up to 96% effective in preventing HIV transmission when HIV-positive partners were adherent to ART.
He also mentioned the medical and social benefits of PrEP, recalling how, in 2010, PrEP trials in Peru had the surprising effect of giving men the confidence to start playing volleyball – viewed as a gay sport – in public.
Cohen emphasized the need for simpler, less expensive treatment. He cited an example in which, until 2005, the only biomedical prevention for mother-to-child transmission could not be used in most of the world because it required an intravenous drip. This changed when a clinic in Uganda found that a single dose of nevirapine could work as effective prevention. “It was a cheap, simple way to help people,” Cohen said, “and it worked.”
He noted that long-lasting injectables are being developed, and that simplifying treatment in this way will make it much easier for people to reach an undetectable viral load.
Noting that there is a window between the point of HIV infection and the time a standard HIV test will return accurate results, Cohen praised a mobile van program in San Diego for providing PCR tests that can detect HIV sooner. He also praised Birmingham, Alabama for offering opt-out HIV testing in its emergency rooms, Washington DC for offering testing at the department of motor vehicles, and mobile testing programs in St. Petersburg, Russia. He noted that in KwaZulu-Natal, South Africa, there is also a door-to-door program that tests thousands of people voluntarily.
Cohen explained that New York City – in which an estimated 200,000 people use injection drugs – has reduced new infections to below 1% with harm reduction programs that offer clean syringes, counselling, opiate substitutes and social services.
Peer outreach workers remain critical to HIV interventions, and Cohen discussed venue-based interventions in Baltimore, Botswana and Honduras that provide information and condoms to club-goers and sex workers. He also praised a program in Mexico City where outreach workers build trust with sex workers, monitor their safety with clients and arrange visits to local STI clinics.
Cohen concluded by emphasizing that peer outreach workers who have overcome challenges and gone on to help others have given him a sense of what can happen when aspirations match reality.
As part of an overview panel, Alan Cochrane used analogy to explain how HIV replicates in the body: The virus lays siege to a cell in the same way that medieval armies laid siege to a castle. Like a castle, the cell has natural defenses against siege and, like an army, the goal of the virus is not to destroy the cell or castle, but to occupy it indefinitely. Treatment for HIV is therefore designed to interfere with the siege at one or several of its stages.
In step one of the siege, the virus or invading army tries to attach itself to the outer wall of the cell or castle. The protein GP120 allows HIV to stick to a cell, and GP41 is the battering ram it uses to break through. Drugs like Maraviroc and T20 have been developed to interfere with each of these steps.
In step two of the siege, the virus reaches the inside of the cell and disguises itself by changing its genome from RNA to DNA so that it can move freely. The cell has natural defenses against replication, in the form of ApoBEC3G/3F, TRIM5alpha, SamHD1, tetherin/BST-2, MX2/MXB, and TRIM22, and drugs like 3TC, nevarapine, delaviridine, and efavirenz can help as well.
In step three of the siege, the virus attacks the nucleus of the cell, as an army would attack the castle keep – in both cases, this is the space the invader ultimately wants to occupy. HIV uses VPR protein to cross the barrier into the nucleus and then inserts its DNA into the genome for a seamless transition. HIV-infected cells are then indistinguishable from other cells until they activate. A drug called raltegravir interferes with HIV’s progression through this stage.
Once HIV has successfully taken over a cell, it can either activate right away – and start waging war on the cells around it – or it can enter a period of latency in which it goes to sleep and wakes up later. Cochrane likened this stage to dealing with a sleeping dragon. He noted that latency is established within three days of a new HIV infection, and that latently-infected cells can live for 60 years and activate at any time. Unfortunately, researchers cannot yet determine which cells have latent virus and where they are in the body. Nevertheless, Cochrane outlined several strategies that can be used against latent or sleeping HIV infection:
In step four, once the virus has activated, its task is to replicate itself. Cochrane explained that, to do this, the virus needs many different parts and then needs to assemble them in the right way. His lab studies treatment that interferes with the balance in parts and how they come together. Drugs such as indinavir, nelfinavir and aprenavir can also block the virus from reaching the final stage of maturation, in which it can produce new copies of itself.
In her keynote address, immunologist Polly Matzinger explained an alternative model of immune response that she and colleague Ephraim Fuchs have advanced since the 1990s.
"If you want to make a model that describes what the immune system does, you have to describe what it does. Not just what you think it evolved to do, but what it does."
After recapping the history of immunological theory as it developed in the twentieth century, Matzinger outlined differences between the dominant model of immunology (self/nonself) and the model she proposes (danger). In short, the self/nonself model proposes that the immune system acts like a police force – it’s constantly on patrol for likely suspects, where “suspect” is defined as anything it doesn’t recognize. In the danger model, the immune system is like a firehouse: it only responds when summoned by an alarm, and it doesn’t matter if the alarm is caused by something it recognizes or not.
Matzinger noted that the self/nonself model of immunology doesn’t seem to explain why tumors aren’t rejected by the immune system, why peptide or protein vaccines need an adjuvant to be effective, and why cells that produce lactation after women give birth are not attacked as foreign proteins. “When my generation grew up and started lactating, our breasts didn’t fall off,” she said. “Somehow, the immune system knows how to deal with a changing self.”
Matzinger explained that, while she’d always had misgivings about the self/nonself model, she accepted the explanations of senior scientists and ignored her instincts until meeting Fuchs at the National Institutes of Health. “If something doesn’t fit into your model, you ignore it,” she said – that’s why it’s taken so long to question self/nonself.
After two years of arguing over immunology, Matzinger and Fuchs came up with the idea that the immune system, rather than fighting things that are foreign, fights things that are dangerous. Matzinger advanced the theory farther with the insight that the immune system defines something as “dangerous” if it does damage – that the alarm signals released by damaged cells are what spurs the immune system into action.
For Matzinger, this model better explains why the immune system doesn’t reject changes at puberty, why lactation, fetuses and tumors are not rejected but transplants are, why graft vs host disease exists and why there are parasites that don’t produce an immune response. Specifically, she noted that:
These and other examples have convinced her that the danger model is a simpler and more comprehensive way of understanding the immune system.
Mario Ostrowski followed Pollly Matzinger’s presentation by explaining how the danger model can apply to HIV. He noted that one of the challenges in designing a vaccine for HIV is that “HIV actually likes it when the immune system is turned on by danger,” since it can bind with danger signals like Interluken-1 and replicate.
Ostrowski, whose current research explores the question of how to make a vaccine that minimizes danger, discussed examples of human and primate research studies in which a decreased immune response seemed to prevent HIV infection. This includes a cohort of sex workers in Nairobi who seem naturally resistant to HIV, as well as studies done by Jean-Marie Andrieu, in which monkeys failed to contract SIV after ingesting probiotics. He argued that the danger model fits perfectly with HIV and is a promising area for cure research.
Cytokines are signaling molecules that direct the immune system to produce and mobilize specific cells. Scientists have observed that people with active HIV infection have increased levels of sCD127, a little-studied cytokine. This research begins to document what causes increases of sCD127 in immune cells, in order to better understand how HIV damages the immune system.
HIV infection damages immune cells in the gut, allowing bacteria to leak into the blood stream. This may account for many HIV co-morbidities. These researchers suspected that HIV damages gut immune cells by interfering with the actions of the signaling molecule (cytokine), interleukin-7. Their research shows that immune cells in the gut do respond to IL-7, an important step towards designing a treatment.
To reproduce, the HIV virus highjacks human cells, entering the cell and using the cell's machinery to make copies of itself. HIV treatment drugs work by interrupting this process, but more classes of drugs are needed as drug resistance becomes more common. This research team may have found a step in the copying process, called mRNA splicing, where the virus is vulnerable.
This research team is looking for ways to prevent HIV from using human cells to copy itself and spread throughout the body. The team has identified a compound (#191) that may interfere with the copying process. Even if this compound does not prove to be a practical treatment drug, this research demonstrates another possible way to target the virus.
Interferon helps fight viral infections and is produced by immune system cells. The longer a person has HIV, the fewer interferon-producing cells they have. This research team has shown that when a cell has produced a lot of interferon, it signals its exhaustion by producing Tim-3 on its surface, and the body destroys it. By blocking Tim-3, the researchers kept cells working and improved interferon production.
Charu Kaushic delivered an overview of gender differences related to HIV that began by defining what we mean by “gender.” For immunologists, “gender” is usually a categorical distinction based on biological sex – the physiological characteristics a person has. For the general public, “gender” often refers to a range or spectrum of self-identity, involving socially-constructed roles and other non-biological traits.
Kaushic noted that social, economic and sexual inequalities, sexual violence, access to care, education, cultural practices like genital mutilation, stigma, discrimination and homophobia are all mediated by gender and should affect how we approach a cure for HIV.
When researchers report statistics about gender, which are used to help scientists develop new treatments for HIV, the statistics often focus only on differences between men and women, although some studies include information on participants’ sexual orientations. Kaushic emphasized that it’s much more difficult to find reliable data on transgender people, but that the data that exists suggests higher rates of HIV in trans populations.
In summarizing the effect of biological differences between men and women in HIV/AIDS, Kaushic included the following points:
Statistics presented by Rupert Kaul estimate the HIV transmission risk for receptive anal sex at 1/72 and for insertive anal sex at 1/909; risk for oral sex is much lower, and in the range of 1/10,000. These risk factors are driven by the blood and genital viral load of an HIV-positive partner, breaks in the mucosa of an HIV-negative partner, and any other factor that increases the number of CD4 cells, including sexually transmitted diseases (STDs) or irritants. Kaul noted that co-infections can increase semen viral load up to 10 fold.
In terms of reducing transmission risk, Kaul provided the following examples:
Kaul noted that, for ART to act as prevention, people who have HIV need to know that they are infected and be willing to take antiretrovirals carefully – at present, only an estimated 19% of HIV-positive people in the USA are on treatment and undetectable. He also noted that HHS guidelines on the use of ARVs recommend ART for all HIV-infected individuals, both for treatment and prevention of transmission.
Kaul concluded by explaining that, while condom use and wise choices are still important, ARVs currently “trump everything” in terms of prevention. He also noted that a cure for HIV would be an effective form of prevention.
Studies have shown that women who use the contraceptive Depo-Provera are more vulnerable to HIV infection. This research looks for an explanation, measuring how hormonal contraceptives affect cells in the female genital tract, and how some hormones increase the absorption of HIV into cells. This work will help physicians make better recommendations about birth control and HIV risk.
Recently, genetically modified mice with human immune systems have been developed to study HIV. These mice are also an opportunity to study hormones and HIV, since female mice have two clear reproductive phases: one dominated by estrogen, one by progesterone. Findings show that mice only become infected when progesterone is high, which may help scientists better understand a woman's risk of infection.
HIV infection spreads throughout the body including into a man's testes and the testes may be an area where HIV hides from treatment drugs. However, this research shows that the body does have pathways to carry antiretroviral drugs into the testes, though the process is complex and some drugs may not penetrate well.
During pregnancy, blood vessels develop in the placenta to support the fetus. This research team is using pregnant mice to study whether antiretroviral drugs limit blood vessel growth. This work suggests that proteinase inhibitor drugs can interfere with blood vessel growth, a finding which may guide doctors to choose safer treatments for pregnant women that will have fewer risks for their babies.
As part of an overview plenary, Rupert Kaul outlined some of the major comorbidities or co-occurring health conditions affecting people living with HIV, including opportunistic infections and cancers, virulent infections, imbalances in normal bacteria (known as the microbiome) and increased severe non-AIDS illnesses. He emphasized that, while HIV can cause damage directly, damage is more often caused by comorbidities, and that comorbidities are therefore an important driver of the increased risk of death for people living with HIV.
Kaul noted that inflammation, which is seen as a link between several different comorbidities, can be driven by such things as changes in the microbiome. “You actually have more bacteria in your system than you have cells in your system,” he said, “so you’re more bacteria than you are human.”
He also acknowledged that the intersection between HIV and aging is a relatively new field and that there are still many studies to be done on that topic.
"As we all age, we have less reserve in our brains, we have less reserve in our hearts, and so it may be that we would see people develop symptoms … within a shorter time."
In a separate presentation, Sharon Walmsley noted that many chronic conditions – including CVD, non-AIDS cancers, osteoporosis, diabetes mellitus, frailty, cognitive disorders, chronic liver disease, COPD and chronic renal disease – have been demonstrated to occur at higher rates in people living with HIV who are on ART.
In a concurrent session, Angela Crawley discussed the impact of HIV/HCV coinfection, specifically.
Crawley noted that in some countries, including Egypt, HCV prevalence exceeds 20% and that, in the USA, one in five baby boomers are HCV-positive. In Canada, 30% of HIV-positive people are HCV-positive, and, according to statistics from CATIE, 250,000 Canadians are living with HCV and 13,000 Canadians are co-infected. Data from the CDC suggests that injection drug use still accounts for 60% of new HCV infections.
Crawley explained that 60-80% of people with HCV develop a chronic infection, and that 1-5% of people infected with HCV go on to die from long-term liver infection or liver cancer. HIV/HCV coinfection also leads to higher HCV viral loads, faster progression of fibrosis and chirrhosis and faster progression to AIDS-associated disease and comorbidities. End-stage liver disease is the leading cause of death when HCV is left untreated. She noted that, while there is no vaccine against HCV, new direct-acting antivirals (DAA) can lead to an 85-95% cure.
Currently, Crawley's own research is focused on CD8 T-cells (killer T-cells) and Mucosal-associated Innate T-cells (MAIT cells), which make up 5% of the total T-cell population and can slow or speed up liver fibrosis. She emphasized that, despite new treatments for HCV, there is still a need to help people who don't respond to existing treatments, to study the long-term effects of treatment, and to develop new immunotherapies to complement treatment.
Cytokines are signaling molecules that direct the immune system to produce and mobilize specific cells. HIV damages the immune system by disrupting these signals. This research reveals that hepatitis C also disrupts cytokines, mostly in the liver. For people with HIV and hepatitis C, the damage is cumulative and particularly harmful to killer T-cells, the immune cells tasked with destroying virus-infected cells.
People with Hepatitis C are more likely to have changes in their cells that lead to Type 2 Diabetes. This research looked at published studies about the use of metformin and other diabetes therapies in people with Hepatitis C. These studies suggest that the drugs may improve outcomes for some people with Hepatitis C, but more research is needed to understand their best use.
Inflammation helps the body control infection. However, when an infection is chronic, such as HIV, and inflammation goes on for a long time, it has adverse consequences. HIV-associated inflammation contributes to co-morbidities affecting the heart, liver, kidneys and brain. This research looks at the role of blood cells called monocytes in inflammation, and suggests that measures of monocyte activation may be useful indicators of comorbidity risk.
Many immune cells decrease in chronic HIV infection, including MAIT (mucosal-associated invariant T) cells, which secrete factors that help control liver fibrosis. This team found that people with HIV and Hepatitis C have fewer MAIT cells and more damaged MAIT cells than healthy people. This may explain why people who have HIV in addition to Hepatitis C have a greater risk of liver damage.
People co-infected with HIV and hepatitis C have a greater risk of liver damage. This research collected blood samples from people with both conditions to understand how the infections interact and to document their combined effects on the immune system. It showed changes in some of the cytokines (IL-17a and IL-21) that direct the immune system. Understanding these interactions may help improve treatment.
Ken Rosenthal was unable to join Back to Basic in person, and instead delivered a pre-recorded presentation on the possibilities for an HIV vaccine.
Rosenthal explained that, under normal circumstances, vaccines operate by introducing an inactive virus to the body and allowing the immune system to produce neutralizing antibodies. The result is the creation of memory B and T-cells that retain the ability to fight the virus. HIV presents a different challenge because the virus is highly variable, replicates to very high levels, has a high maturation rate and rapidly evolves to escape immune responses. HIV also differs from typical viruses in that it integrates its own genetic material into the host genome, establishing a latent infection. If even a small percentage of cells are latently-infected, the virus can re-emerge, allowing HIV to evade antibodies and T-cell-mediated immunity.
Presently, researchers don’t know which immune response is important to control and protect against HIV. Non-human models also don’t predict the results of human efficacy trials, which means that costly and challenging clinical efficacy studies still have to be performed.
Rosenthal noted that, after 30 years of trying to develop an HIV vaccine, there are only four HIV vaccine concepts that have advanced to clinical efficacy testing – three of them showed no protection against HIV, and one, the RV144 study, showed 31% protection at 42 months.
Rosenthal also outlined other advances in the field since 2012, including:
Each of these advances has contributed to our knowledge of HIV, which will help researchers to develop possible vaccines.
Rosenthal explained that the holy grail of HIV vaccine research is broadly neutralizing antibodies – so far 30 have been identified, and all require extraordinary levels of somatic hypermutation, meaning that B-cells take a long time to produce them. The study of broadly neutralizing antibodies can provide useful information to researchers, even though the antibodies themselves may have limited utility, since they attack host molecules and, in the long term, people who generate broadly neutralizing antibodies become immune to their protection.
Rosenthal noted several specific drug trials that are currently underway, including the Poxvirus-Protein Public Private Partnership (P5), which builds on the results of RV144, and recombinant adenovirus trials, in which a cold virus is injected with HIV or SIV, and then boosted with either gp140 trimers or mosaic immunogens.
There are also several new vaccine concepts, including the effector memory T-cell concept, in which cytomegalovirus (CMV) vectors containing SIV/HIV antigens are used as a vaccine. In primate trials, these vaccines protected 50% of monkeys from contracting SIV. Rosenthal noted that CMV vectors appear to persist indefinitely in the monkeys, creating memory T-cells that stay in mucosal membranes and can almost immediately activate and control SIV at the site of infection.
Another approach is to design a vaccine that shuts off or reduces immune response to prevent HIV-infection. Rosenthal explained that, as HIV needs to activate cells in order to infect and replicate in them, this vaccine concept would induce tolerance to prevent HIV from gaining a foothold. Primate studies of this model have shown that mucosal immunization with a vaccine consisting of SIV and a living bacterial adjuvant, combined with suppressed T-cell activation, prevented SIV infection.
Rosenthal emphasized that the acceleration of clinical efficacy trials is critical to developing a vaccine, and that this will require increased industry cooperation, the mobilization of resources, the expansion of the current vaccine pipeline and robust preclinical studies.
In a concurrent session, Rupert Kaul delivered an overview of prevention options, noting that, while the best way to reduce HIV exposure is for HIV-positive partners to take ARVs, the most usual outcome of HIV exposure is to not get infected. His talk focused on why some exposures to HIV do not result in infection and how prevention strategies can take advantage of this fact.
Kaul explained that all sexual transmission of HIV occurs across mucosal membranes. Because of this, prevention strategies involve reducing HIV exposure through condom use and ARVs as well as protecting the integrity of the membrane by avoiding inflammation or irritation caused by STDs and hyperosmolar lubricants. Irritation and inflammation cause breaks in the mucosal barrier and bring more HIV-susceptible cells to the mucosa. Kaul also noted that drug interventions like PrEP may prove easier to use than topical creams and microbicides.
Speaking in the same concurrent session, Darrell Tan reviewed the basics of biomedical HIV prevention tools, including PEP and PrEP. Post-exposure prophylaxis (PEP) refers to the use of ARVs for 28 days immediately after a potential exposure to HIV, whereas pre-exposure prophylaxis (PrEP) refers to the use of either oral or topical ARVs before exposure.
Tan discussed a recent study into one topical form of PrEP - tenofovir gel - for HIV prevention in women. The study showed a 39% reduction in transmission when the gel was applied 12 hours before and after sexual exposure.
Oral PrEP trials have shown efficacy in men who have sex with men, heterosexual men and women, and people who use injection drugs. Tan emphasized that results show PrEP works when taken, and explained that researchers can correlate drug levels with adherence patterns. People who take 4-7 tablets each week had up to a 100% risk reduction; those who took fewer saw a reduction of 44%-84%.
Tan noted that questions remain about PrEP dosage levels, the relationship between adherence and HIV protection for vaginal and injection drug-related exposures to HIV and what level of adherence would be necessary for PrEP to protect against genital herpes.
In a session focused on breast milk transmission, Lena Serghides provided an overview of risk, policy and questions for researchers to consider.
Serghides presented statistics showing that, despite scale-up of ARV-based prevention, 250,000 infants become infected with HIV each year and 40% of these infections happen during breastfeeding. While ARVs have reduced the chance of infection by 60%, they have not prevented all infections.
When safe alternatives are not available, WHO recommends exclusive breastfeeding to infants born to HIV-positive mothers until six months of age and continued breastfeeding until 12 months, with mothers taking cART and infants receiving Nevirapine.
Serghides noted that the benefits of breast milk include enhancement to the infant's immune system, guarding the integrity of the infant's gut and promoting psychological development – all reasons why mothers may wish to breastfeed safely rather than finding an alternative.
Breast milk contains innate protective factors, including antibodies, anti-microbial factors, immune modulators and immune cells. These antibodies prevent bacteria and viruses from attaching to mucosal surfaces, and protect these surfaces through mucosal painting (covering the surface with a thin layer of antibodies). Antibodies in breast milk are also protected from digestion in the gut.
In mature milk, there are between 10,000 and 50,000 immune cells/ml. These are different from blood immune cells in that a higher proportion are activated memory cells.
CD4 T-cells: Breast milk has almost exclusively activated memory T-cells. Activated cells are high-risk for HIV infection, and, during feeding, infants are exposed to one million CD4 T-cells each day.
B-cells: Breast milk has almost exclusively memory B-cells, which are primed and ready to secrete antibodies.
CD8 T-cells: Most CD8 T-cells in breast milk are activated. HIV-specific CD8 T-cells are more frequent in breast milk than in blood, but may help limit HIV production by infected CD4 T-cells.
Macrophages: Macrophages are cells formed in response to an infection that serve as a more effective defense against pathogens and secrete innate immune factors. Unfortunately, they also express DC-SIGN protein, which HIV uses to transport between tissues.
Risk of transmission through breast milk is increased by viral load, length of breast feeding and inflammation of the mammary gland (as through mastitis, breast abscess and engorgement). The more HIV-infected cells there are in breast milk, the higher the transmission risk. Serghides identified five types of cells that can contribute to HIV transmission:
Mammary epithelial cells: These cells are a major component of breast milk and are susceptible to HIV infection, but also express protective factors against HIV. HIV may use these cells for transport, but is unlikely to use them as a reservoir.
Latently-infected CD4 T-cells: These comparatively rare cells harbor HIV DNA and, once activated, can produce HIV ten times more efficiently than blood cells.
Activated CD4 cells: These cells are productively infected with HIV and are the source of almost all HIV RNA. They can support HIV replication even in people treated with ARVs. Although ART can successfully decrease HIV RNA levels in breast milk, HIV antigen-producing T-cells have been identified in samples with no detectable HIV RNA.
Macrophages: Between 0.1-1% of macrophages in breast milk are HIV-infected and can produce viral particles. Macrophages also live longer than T-cells and express DC-SIGN which may increase cell to cell infection.
Cell-free HIV Particles: These particles are detectable in breast milk from 80% of untreated HIV-positive women and, occasionally, in breast milk of HIV-positive women on ART. Viral load is often different between the two breasts.
Serghides noted that, in two studies, 15% of HIV-positive mothers who transmitted the virus through breastfeeding had undetectable levels of HIV RNA and that, in HIV-positive women who initiated triple ARV therapy while breastfeeding, ARVs reduced transmission by only 50-60%.
While HIV transmission risk is fully controlled in only 5-12% of HIV-positive women in low-income settings, researchers do not yet have similar data for women in high-income settings. Studies have also found higher levels of proteins such as b2-microglobulin and galectin-3 in women who transmitted to their infants, which may prove useful in later research.
According to Serghides, promising avenues for future research include: inducing production of protective antibodies in breast milk; inducing protective antibodies in the infant’s gut; and investigating the protective factors in breast milk. She also noted that we don’t yet know how exposure to ARVs during breastfeeding affects infants in the long term.
Serghides concluded by highlighting interventions already being tested, including flash heat treatments for breast milk in South Africa, Bangladesh and Tanzania as well as kangaroo care to promote the psychological development of infants without breastfeeding.
Logan Kennedy responded to Lena Serghides’ presentation by discussing the ways that basic science research translates in terms of community experience and policy in Ontario. Kennedy explained that infant feeding policy around the globe is informed by three types of science: basic science, epidemiological data on infant morbidity and mortality, and clinical trial data, within a population and regional context (such as access to drinking water and formula).
Within this framework:
In Canada, the recommendation is to avoid breastfeeding all together because the risk of HIV transmission outweighs the risks associated with replacement feeding. This recommendation is partly based on the premise that Canada meets the WHO definition of a high-income country. However, as Kennedy noted, in Ontario we assume that all mothers have access to clean water and formula storage, which may not be the case.
Kennedy referenced a statement from the Canadian Pediatric Society and Canadian Pediatric AIDS Research Group, saying that HIV-positive women found to be breastfeeding should be referred to a pediatric HIV expert and that “an automatic referral to child protection services is not warranted, but may be considered in some instances after consultation with a pediatric HIV specialist.” She pointed out that stigma and fear of disclosure are barriers that may prevent HIV-positive mothers from seeking help.
Kennedy concluded by arguing that clinicians, policy makers and community members cannot place undue confidence in adherence to guidelines. Open discussion about what informs guidelines and how families can manage the implications of these guidelines are paramount for optimized care.
Killer T-cells destroy virus-infected cells within the body. Unfortunately, in the case of HIV, they are unable to destroy all infected cells. Eventually they become exhausted and produce Tim-3 on the surface of the cell, a signal that the cell should be destroyed. This research team is working to understand how Tim-3 works and how it might be blocked, keeping killer T-cells active.
Herpes viruses cause diseases that flare up and then stay dormant. A vaccine which uses a weakened non-disease-causing version of the virus acts similarly, stimulating the immune system and then going quiet in repeated cycles. HIV proteins could be added to this vaccine. Early stage animal research shows that the vaccine cannot prevent infection, but it might allow the body to control the virus without drugs.
A person's immune system produces antibodies to the HIV virus but these antibodies are not able to attack the virus due to unique molecules on the surface of the virus that change its shape and appearance. This research group has engineered similar molecules and is using them to understand the virus and to create new, more effective vaccines.
This research team focused on a molecule on the surface of HIV. Other scientists had reported that the molecule was the point at which T-cells bind to HIV, allowing the virus to infect them. Binding molecules are important targets for vaccines. However this team showed that binding did not occur as expected. It is vital for scientists to report negative results to prevent further unproductive research.
As part of an overview plenary, Eric Arts outlined the reasons that so few new treatments for HIV are under development. He explained that one challenge with HIV treatment is that, “because everything the virus has is stolen from the host, it’s very easy to get a lot of side effects” and, for that reason, antiviral discovery is one of the hardest forms of drug discovery.
In an interview with Darien Taylor, he explained that existing HIV drugs fall into four classes and that failure of one regimen within a given class almost always eliminates the rest of that class as an option. People who’ve already developed resistance to existing treatments benefit most from new drugs. “The difficulty now,” he said, is that “there’s no market pressure anymore to develop those new drugs. When you can treat 90-95% of patients out there effectively then, unfortunately, those five percent, even though it’s a large population, don’t get the attention they deserve.” In his view, it would take a major failure in one of the existing drug classes to spur the development of new drugs.
"If we learn anything from our mistakes it's that we can repeat those mistakes perfectly the next time."
In his presentation, Arts explained that resistance occurs mostly because people are non-adherent to their medication, but also because of spontaneous mutations or bad luck. Each day, every person living with HIV has multiple strains of the virus in their systems with different potential drug resistances. A person treated with only one drug typically develops ARV resistance in 2-3 days. Treating with triple combination therapy protects against drug resistance, since the virus is destroyed by one of the drugs in the combination before it can become resistant to all.
Arts concluded by noting that Western University, where he works, has recently announced the creation of an Imaging Pathogens for Knowledge Translation (ImPaKT) Facility, where more drug resistance testing will be done.
During a concurrent session, Sharon Walmsley reviewed new and existing approaches to HIV treatment, noting that, as of 2014, there were 28 approved ART drugs and up to 10 recommended first-line regimens. She emphasized that the considerations of any successful treatment include antiretroviral activity, safety and tolerability, convenience, access and cost.
Between 1995 and 2010, the number of patients with undetectable viral loads has risen from 43% to 78%, and the proportion with a treatment response (defined as a viral load of less than 50 copies/ml) has increased as well.Newer treatment approaches include ARVs that are active against drug-resistant strains of the virus. Doravirine (an NNRTI) is currently
being studied, as are CD4 attachment inhibitors such as fostemsavir (BMS-66308), maturation inhibitors and anti-inflammatory/anti-immune activation drugs.
Between 1995 and 2010, levels of treatment cessation have dropped – within the first 48 weeks of treatment only 1-3.2% of people stop integrase inhibitors due to side effects, and Walmsley noted that zidovudine and nevirapine are no longer recommended for initial therapy.
Newer approaches involve using lower doses of existing drugs and using newer drug classes. Many combinations are now “nuc-sparing regimens,” treatment combinations that avoid the side-effects caused by NRTIs (Nucleoside Reverse Transcriptase Inhibitors).
The number of pills required for ART has already been reduced. Newer approaches involve developing new co-formulations and injectable drugs.
Reasons for non-adherence to treatment include: forgetting, travel, stressful life events, general health status, HIV stigma, frequency and severity of symptoms, patients’ beliefs about HAART and concerns about side effects, and complexity of the regimen. Developing more convenient treatments should reduce non-adherence and lead to better health outcomes.
HIV infection damages immune cells in the gut, allowing bacteria to leak into the blood. This causes inflammation and may account for many HIV co-morbidities. This research tested the idea of treating newly infected men living with HIV aggressively using five-drug combination antiretroviral therapy to see if gut damage was prevented or reversed. Intensive therapy proved no better than standard therapies.
This research team is exploring the causes of HIV-Associated Neurocognitive Disorder (HAND). They have shown that HIV proteins injected directly into the brains of rats rapidly produce signs of inflammation and abnormalities in immune system signals. This is a rapid way of studying the changes associated with HIV infection and may also be a useful tool for studying HAND treatments.
In a project related to the studies by Wong and colleagues, this research team is looking for ways to prevent HIV from using human cells to copy itself and spread throughout the body. The team has identified several compounds that interfere with the copying process. Further work with the compounds will help researchers to understand this vulnerability, and may lead to new drug possibilities.
Today there are many potential combinations of antiretroviral treatments for HIV. Why do people switch from one set of drugs to another? This study shows that people taking two or more pills a day are more likely to switch, as are people taking particular types of drugs. This information can help physicians guide people living with HIV to choose sustainable treatment regimens.
This research explored whether a group of cancer drugs could also be used to treat HIV. These drugs stop rapidly growing cancer cells from building new proteins. HIV uses the same mechanisms within the cell to reproduce. This research team showed that these drugs, which are already approved for cancer treatment, could slow down the virus' reproduction, and have potential as HIV treatments.
As part of an overview plenary, Bard Jones outlined the two kinds of cure research on the horizon – a sterilizing cure, which would purge latent reservoirs of the virus, and a functional cure, which would teach the immune system how to control HIV without the use of ART. From a scientist's perspective, the functional cure appears an easier goal to attain, but community feedback still carries weight in deciding which type of cure has more value.
He outlined strategies for developing a cure as the following:
During his presentation, Jones discussed examples of sterilizing and functional cure attempts that have been made, including the landmark case of Timothy Brown, who had a total bone marrow replacement with HIV-resistant cells and was cured of HIV. He noted that, unfortunately, another group of patients – known as the Boston Patients – underwent a similar procedure, not involving HIV-resistant cells, but only experienced a brief remission before the virus came back. By contrast, the Visconti Cohort represents a possible functional cure, as 15% of participants have been able to control their HIV after stopping ART.
"There's a lot of talk about how we keep new investigators engaged in HIV research, and, in my opinion, that talk switches much too quickly to things like funding and grants. … I think how you keep investigators engaged is by… showing them they're part of a community that's actually interested in their research."
Jones concluded by posing several questions that will be important to cure research in the future:
His research team is working to genetically modify immune cells to resist HIV infection. The team has shown that they can give immune stem cells the ability to block HIV infection, and that these modified cells can develop into more mature immune cells. If ultimately proven safe and successful, this approach would permanently modify the immune system to control HIV, eliminating the need for antiviral drugs.
Cytokines are signaling molecules that direct the immune system to produce and mobilize specific cells. IL-7 is an important cytokine that mobilizes T killer cells and is decreased in HIV infection. Although T killer cells are not directly damaged by HIV, they become less effective. This research charts the specific immune effects of IL-7 on killer T-cells in order to identify ways to improve immune function.
HIV hides inside immune cells, preventing antiretroviral drugs from curing the infection. This research group is using immune-based treatments to drive HIV out of hiding. They use a combination of killer T-cells and a cytokine called interleukin-15 (IL-15). This strategy was very effective using cells from one patient, but not using cells from another. Scientists need to better understand these variations.
This research group is exploring another strategy to drive HIV out of hiding. Early in HIV infection, a person's immune system reacts aggressively, but is not able to clear the virus. This team uses that early immune response to develop a vaccine. Once the person is stable on antiretroviral therapy, the vaccine is used to turn the immune system back on, releasing hidden virus to be destroyed by drug treatments.
Engineering viruses to selectively kill cancer cells is a new experimental treatment. The maraba virus has been engineered to destroy immune cells that have changes associated with leukemia. When immune cells are infected with HIV, including latent infections where HIV is hiding in the cell, similar changes occur. This team's research suggests that this engineered virus may have potential as an HIV treatment.
HIV produces a protein called Nef, which interferes with the signals infected cells send to the immune system. This helps HIV hide and stops killer T-cells from recognizing and destroying HIV-infected cells. This team is testing a way to block the actions of Nef, making infected cells visible to the immune system, as well as ways of stimulating killer T-cells to better recognize infected cells.
The Back to Basic Conference is an Ontario HIV Treatment Network event.
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