Ever since antiretroviral treatments against HIV infection were introduced in 1996, scientists have eagerly been hunting for a cure for the disease.

Although drugs can allow people infected with HIV to live normal, healthy lives, people infected by HIV have to take antiretroviral treatments for as long as they live. Little bits of virus can lie dormant in immune cells for years, so that if patients stop taking the drugs, the dormant virus can come out of hiding and re-infect the patient.

And now, as the first people to start taking this treatment are entering middle or old age, doctors are seeing side effects from inflammation that are caused by having even tiny amounts of HIV in your blood. That’s yet another reason for developing a cure for the disease.

Now, researchers from the Norwegian University of Science and Technology’s (NTNU) Centre of Molecular Inflammation Research (CEMIR) have uncovered a previously unknown way in which the body’s immune system can detect and respond to HIV infection — which could help improve the chances of developing a cure.

Their results have been published in Nature Communications.

To understand exactly what the researchers did requires a refresher course in how HIV actually works inside the body and how the body responds.

When the virus gets into the body, it infects the very cells that the body would use to combat it — these are called CD4 T helper cells, or CD4 T cells.

Once the T cells are infected, they can’t do their part in helping protect the body from other diseases or infections. That’s why the illness that people get from HIV infection is called Acquired Immune Deficiency Syndrome, or AIDS.

Someone with full-blown AIDS would have almost no T cells, and they could die of any number of different infections or diseases that wouldn’t normally afflict someone with a healthy immune system.

“Today we have treatments that can stop HIV from replicating itself, and the T helper cells can come back,” said Hany Zakaria Meås, a postdoc at CEMIR and a co-first author of the article. “You can live a perfectly healthy life, but you have to take medicine your whole life, because the day you stop treating it, the virus will come back.”

The virus comes back if antiretroviral therapy is stopped because HIV hides its genetic material inside T cells that are dormant. That means there’s always the potential for more virus to appear and wreak havoc.

These reservoirs of virus have spurred a worldwide hunt for ways to shock, or kick the virus out of the cells where it lies dormant.

If the virus that lies dormant in cells could be smoked out into the open, the formally dormant virus could then be killed by the body’s immune system or drugs, and that would leave the patient HIV free, and cured, Meås said.

“We need to activate the virus so it can start replicating, and that will make the cell visible to the immune system,” he said. “That is the current idea for a cure. We just need to activate cells that are hiding away so we can kill them, while we give medicine that protects cells from infection, because there will be more virus produced.”

One such clinical trial in the UK, called the RIVER study, tried this approach but reported last year that the trial did not succeed, he said.

HIV comes in different varieties, and not all varieties are equally able to infect all T helper cells. To infect a cell, the virus has to have to have a specific ligand, which functions like a key, that has to match up on the target cell with the right kind of receptor, or keyhole.

When a T helper cell doesn’t have the receptor that matches the ligand on the HIV virus trying to infect the cell, that means the virus can’t actively infect that T cell. Instead, the virus can get trapped in a vesicle in the cell called an endosome.

The CEMIR researchers decided to look at what happened with uninfected T helper cells that had trapped HIV in endosomes. The uninfected cell responds to the HIV in the endosome by destroying the contents of the endosome, Meås said.

In the past, researchers have believed that this particular pathway — HIV being trapped in an endosome of a T helper cell, and the T helper cell destroying the contents of the endosome — was a kind of dead end for HIV infection. After all, the T helper cell hadn’t actually been infected, and the endosome destroyed the virus.

But now CEMIR researchers have found a previously undescribed immune response that results from HIV destruction in the endosome. This response may hold the key to allowing the shock-and-kill approach to work.

What the researchers found was when the endosome destroys the HIV, some of the genetic material is exposed to the T cell, which in turn activates a type of molecule called TLR8. This in turn results in the production of substances called cytokines, which cause inflammation in the body.

One reason this is surprising is that T cells are part of our immune system called the “adaptive” immune system, which responds to specific infectious substances over time.

Our immune system also has an “innate” part, which we are born with, and which provides more general immune protection by recognizing and responding to bits of viruses or bacteria that are common across many different viruses or bacteria.

TLR8 is a part of the body’s innate immune system. T cells are part of the adaptive immune system. Generally, it has been thought that these two systems were separate, independent branches.

“In this study we show that a receptor associated with the innate system actually exists and functions in the adaptive immune system,” Meås said.

The inflammation caused by the cytokines helps to wake up T cells that had formally been dormant and that contain HIV genetic material, said Markus Haug, a staff scientist at CEMIR and co-first author of the study.

“The T cell detects the virus and produces cytokines, and these cytokines act on cells that are properly infected with HIV and makes them produce more virus. The dormant T helper cells produce virus, and the T cells that were actively producing virus will produce more of it,” Haug said.

In other words, the TLR8 signal and cytokine-induced inflammation shock the HIV out of the dormant cells — where it can be destroyed.

The destruction of HIV by endosomes and the associated inflammation may also be one reason why patients who have been on antiretroviral treatments for decades are now beginning to develop inflammatory diseases more commonly associated with people decades older.

These include dementia, cardiovascular diseases, metabolic syndrome and cancers that aren’t related to HIV.

Meås said that the mechanism where endosomes destroy HIV might release enough genetic material to trigger the T cell’s innate immune receptors to cause inflammation.

Beyond that, however, the findings do offer hope, said Jan Kristian Damås, a chief attending physician at the Department of Infectious Diseases, St. Olav’s Hospital, Trondheim University Hospital and an NTNU professor associated with CEMIR. Damås works with HIV patients and recruited the nine patients whose cells were used as part of the research. He is also an author on the paper.

“Today we have very efficient drugs for suppressing HIV. However, we are not able to eradicate the virus and just weeks after patients stop medication the virus will reappear from virus reservoirs. Researchers and scientists believe that we can find a cure for HIV if we are able to eradicate these reservoirs,” Damås said.

“The breakthrough paper by Meås and Haug brings novel insight in mechanisms for reversal of HIV latency, and their findings of TLR8 as an important receptor for HIV in T cells, clearly represent a potential novel therapeutic target for treating HIV. Moreover, their findings may also represent major step forward in vaccine development as TLR8 ligands could be used as vaccine adjuvants that shape the type of T cell responses that is induced by the vaccine.”

The United States National Institutes of Health has announced that its HVTN 702 clinical trial of an HIV vaccine has been stopped. While no safety concerns were found during the trial, the independent data and safety monitoring board found that the vaccine was ineffective in preventing HIV transmission.

The trial, conducted at 14 sites across South Africa, followed more than 5400 HIV-negative 18–35-year-olds over 18 months. The participants received six injections during the six-month period, either the vaccine or a placebo. An analysis undertaken after at least 60% of the participants had been in the study for more than 18 months showed that there were 129 HIV infections among the people who had the vaccine, while 123 people who had the placebo became infected.

“While we are obviously disappointed with the results, important science has been learned that can be carried forward to future trials. I thank the study team for this important vaccine trial,” said Winnie Byanyima, UNAIDS Executive Director.

Other major vaccines are currently being tested at scale—the Mosaico trial, which is testing a vaccine among transgender people and gay men and other men who have sex with men in the Americas and in Europe, and the Imbokodo trial, which is testing a vaccine among women in sub-Saharan Africa. An effective HIV vaccine may well prove to be key for sustaining progress against HIV in the future.

Despite considerable investment in prevention during the trial, there was still an HIV incidence of around 4% per year among the women in the trial. This is simply too high. HIV transmission can be prevented. This requires the right combination of interventions, including HIV testing; antiretroviral therapy for people living with HIV; pre-exposure prophylaxis, condoms and other prevention options; sexual and reproductive health services, including comprehensive sexuality education; keeping girls in school; and the lifting of social, legal and economic barriers for women and girls.

Areas of high HIV prevalence, known as ‘hotspots’, do not necessarily fuel the epidemic in the wider population, say researchers.

Hotspots are often targeted for intense HIV control interventions, including treatment and prevention, to maximise their effect and reach the people in greatest need first.

These strategies often assume that hotspots are also sources of disease transmission to other areas, and that targeting hotspots will have the added indirect benefit of reducing new HIV infections in the wider population.

However, a new study by an international team of researchers, led by scientists at Imperial College London and the Rakai Health Sciences Program in Uganda, suggests this is not necessarily the case. Instead, the research shows that some hotspots seed very few infections to neighbouring communities and actually receive more infections from outside.

The study was carried out with ‘hotspot’ fishing communities on the shores of Lake Victoria in Uganda, where approximately 40 percent of the population are infected with HIV, amongst the highest HIV prevalence levels in the world. The team mapped how disease was transmitted between these communities and larger inland communities with much lower HIV prevalence.

Contrary to expectation, they found that more HIV infections were driven by the inland communities with lower HIV prevalence than by the HIV hotspots. The results are published today in Lancet HIV.

Lead researcher Dr Oliver Ratmann, from the Department of Mathematics at Imperial, said: “Our finding shows that HIV disease dynamics are not as obvious as they may seem, and advises caution against equating and stigmatizing hotspots as population groups that drive HIV spread in Africa.”

Co-author of the study Dr Kate Grabowski, from the Johns Hopkins Bloomberg School of Public Health, added: “We were really surprised by the findings. Lake Victoria fishing communities have long been assumed to be drivers of transmission in neighbouring East African communities; however, our results show that is likely not the case.”

The team used recent advances in molecular biology and advanced statistics to map the transmission of HIV between people – the chain of infection events that lead to someone getting the disease.

This is possible because the virus changes subtly as it is passed around. Previously, scientists using this information had been able to say if the disease had likely passed between two people, but not which direction was more probable.

The new study was conducted as part of the PANGEA-HIV consortium, an international partnership to use viral sequence analysis to assess the transmission of HIV in Africa funded by the Bill and Melinda Gates Foundation.

The team deep-sequenced the genome of the virus from more than 2,500 HIV-positive people in Lake Victoria hotspots and surrounding inland communities between 2010-2015. They integrated this information with surveys about migration in the region, to accurately track disease spread in a highly mobile population.

They found that only 5.4 percent of infections in the region occurred between the hotspots and inland communities. Of these, nearly three times as many new infections occurred from inland communities into hotspot communities, rather than out from hotspot communities.

Dr Ratmann said: “It has long been assumed that the hotspot communities around Lake Victoria were a ‘source’ of HIV infections, but it seems the opposite is true, and they are a ‘sink’, with more infections originating outside the hotspot.”

The researchers suggest this surprising result might be because the fishing communities are relatively small compared to the larger inland population, and because of migration dynamics related to local economies and social context.

Despite their much lower proportions of HIV-positive individuals, inland communities have higher overall numbers of infected people, who are also more likely to move to the fishing communities than vice versa.

However, they also caution this is one case study and similar studies in other regions may reveal different patterns. They are currently repeating the research further north on the shore of Lake Victoria to test the robustness of their findings.

Starting HIV antiretroviral therapy (ART) within hours of birth has been hypothesized to have positive effects raising the possibility of remission in some children with HIV. To test the hypothesis, researchers at Columbia Mailman School of Public Health and Columbia University Irving Medical Center designed a trial in a group of newborns with HIV who started ART within 14 days of birth.

The results showed that about 75 percent of infants attained viral suppression on ART; but only 52 percent attained and sustained viral suppression on ART. The success of attaining and sustaining viral suppression was similar in the 46 infants starting ART less than two days old (51 percent) and the 27 infants starting therapy between 2 and 14 days after birth (54 percent). The findings are published online in E-Clinical Medicine.

“The results of our trial suggest that very early treatment in newborns may not have to mean within hours of birth,” said Louise Kuhn, PhD, Columbia Mailman School professor of epidemiology (in the Sergievsky Center). “We learned that we must be more attune to basing decisions about how quickly to start ART on optimizing maternal adherence with treatment rather than with just focusing on speed. While we certainly do not want to introduce undue delay, starting ART within the first two weeks of life led to similar outcomes to starting within the first two days of life.”

The study was designed shortly after the report of the infant in Mississippi who started antiretroviral treatment within 30 hours of birth and who was able to maintain viral suppression off treatment for over two years. This case report led to optimism that ART started within hours of birth may lead to protection of critical immune processes and smaller viral amounts, making possible remission in a sizable minority of infants treated in this way. “The outcome in Mississippi raised the tantalizing possibility that we may be able to facilitate remission in infants if we start ART very early in life,” noted Kuhn.

To yield the target population for the trial, clinical protocols were established at Rahima Moosa Mother and Child Hospital (RMMCH), Johannesburg, South Africa. The analysis included 73 children who were born between March 1, 2015 and September 30, 2017 with confirmed HIV infection and ART initiated within 14 days. The initial ART regimen consisted of nevirapine, lamivudine and zidovudine; nevirapine was replaced with lopinavir-ritonavir once the child reached 42 weeks post-menstrual age, usually about 4 weeks of age in calendar time. ART was initiated based on results of the first round of diagnostic testing and was continued throughout the study.

Of those surviving during the study, 75 percent attained viral load <50 copies/ml on ART but not all of these sustained this low level of virus. Dividing the group into the 46 infants who started ART less than two days old and the 27 infants starting ART between 2 and 14 days old, showed a similar percent achieving and sustaining viral load <50 copies/ml on ART. In the very early treated infants (less than 2 days old), 51 percent achieved and sustained viral suppression; in the early treated infants (2 to 14 days old), 53 percent achieved and sustained viral suppression.

“Viral suppression rates, especially to more stringent cut-offs than required by our protocol were lower than expected, and we concluded that very early ART on its own, with routinely-available regimens, is unlikely to lead to remission in a sizable minority of early-treated infants,” said Kuhn. This is most likely explained by the significant challenges of adequate maternal adherence with ART for neonates and infants including major practical difficulties of sustaining adherence with twice-daily, poorly-palatable liquids for infants. Moreover, most of the study participants’ caregivers live in impoverished economic circumstances with complex social problems and experience a high degree of HIV-related stigma.

“We need to find interventions to treating newborns that are reasonable for mothers to fully adhere to,” said Kuhn. Long-acting formulations and/or alternative interventions may be more adherence-friendly and need to be investigated. These may enable more rapid and sustained viral control and immune recovery in a larger proportion of early treated infants as a stepping stone to achieve remission.

Co-authors are Stephanie Shiau, Elaine Abrams, and Wei-Yann Tsai, Columbia Mailman School; Yanhan Shen, Columbia Sergievsky Center; Renate Strehlau, Faeezah Patel, Karl-Günter Technau, Megan Burke, Gayle Sherman, Ashraf Coovadia, Rahima Moosa Mother and Child Hospital and University of the Witwatersrand, Johannesburg; Grace M. Aldrovandi, UCLA; Rohan Hazra, Eunice Kennedy Shriver National Institute of Child Health and Human Development; and Caroline Tiemessen, National Institute for Communicable Diseases, National Health Laboratory Services, and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

UNAIDS is calling on governments to ensure that the right to health is realized by all by prioritizing public investments in health. At least half of the world’s population cannot access essential health services. Every two minutes a woman dies while giving birth. Among the people being left behind are women, adolescents, people living with HIV, gay men and other men who have sex with men, sex workers, people who inject drugs, transgender people, migrants, refugees and poor people.

“The right to health is eluding the poor and people trying to lift themselves out of poverty are being crushed by the unacceptably high costs of health care. The richest 1% benefit from cutting-edge science while the poor struggle to get even basic health care,” said Winnie Byanyima, Executive Director of UNAIDS.

Nearly 100 million people are pushed into extreme poverty (defined as living on US$ 1.90 or less a day) because they have to pay for health care, and more than 930 million people (around 12% of the world’s population) spend at least 10% of their household budgets on health care. In many countries, people are denied health care or receive poor quality health care because of unaffordable user fees. Stigma and discrimination denies poor and vulnerable people, especially women, their right to health.

Every week, 6000 young women around the world become infected with HIV. In sub-Saharan Africa, four out of five new HIV infections among adolescents are among adolescent girls and AIDS-related illnesses are the biggest killer of women of reproductive age in the region. Despite significant progress in reducing AIDS-related deaths and new HIV infections, there were 1.7 million new HIV infections in 2018 and nearly 15 million people are still waiting to receive HIV treatment.

“Publicly financed health care is the greatest equalizer in society,” said Ms Byanyima. “When health spending is cut or inadequate, it is poor people and people on the margins of society, especially women and girls, who lose their right to health first, and they have to bear the burden of caring for their families.”

Delivering health care for all is a political choice that too many governments are not making. Thailand has reduced mortality rates for children under the age of five years to 9.1 per 1000 live births, while in the United States of America the rate is 6.3 per 1000 live births, even though Thailand’s gross domestic product per capita is about one tenth of that of the United States. Thailand’s progress has been achieved through a publicly financed health-care system that entitles every Thai citizen essential health services at all life stages and leaves no one behind.

South Africa had just 90 people on antiretroviral therapy in 2000, but in 2019 had more than 5 million on HIV treatment. South Africa now has the largest HIV treatment programme in the world. Countries such as Canada, France, Kazakhstan and Portugal have strong publicly financed health systems, yet some other richer countries do not.

Health investments in many countries remain very low compared to their gross domestic product. The United Nations Conference on Trade and Development estimates that developing countries lose between US$ 150 billion and US$ 500 billion every year owing to corporate tax avoidance and profit shifting by big companies. If this lost money were invested in health, health expenditure could triple in low-income countries and could double in lower-middle-income countries. The race to the bottom on corporate tax cheats denies developing countries of much needed revenue and robs ordinary people of vital health services. The countries of the Economic Community of West African States lose an estimated US$ 9.6 billion each year to numerous tax incentives.

“It is unacceptable that rich people and big companies are avoiding taxes and ordinary people are paying through their ill health,” said Ms Byanyima. “Big companies must pay their fair share of taxes, protect employee rights, provide equal pay for equal work and provide safe working conditions for all, especially women.”

Debt is posing a serious threat to Africa’s economy, health and development, resulting in big cuts in social spending to ensure debt repayment. According to the International Monetary Fund, as of April 2019 half of low-income countries in Africa were either in debt distress or at a high risk of being so. Beyond low-income countries, in Zambia there was a 27% drop in health-care investments and an increase of debt servicing by 790% between 2015 and 2018. Similar trends were seen in Kenya, where debt servicing increased by 176% and health investments declined by 9% between 2015 and 2018. “There is an urgent need to manage debt in ways that protects people’s health. That means ensuring new financing focuses on social investments, debt repayments being halted for a period if needed to allow economic recovery and debt restructuring under a coordinated mechanism to protect spending on HIV, health and development,” said Ms Byanyima.

A major factor of ill health is the denial of human rights. According to the World Bank, more than one billion women lack legal protection against domestic violence and close to 1.4 billion women lack legal protection against domestic economic violence. In at least 65 countries, a same-sex sexual relationship is a crime. In recent years in some countries, crackdowns and restrictions on lesbian, gay, bisexual, transgender and intersex people have increased. Sex work is a criminal offence in 98 countries. Forty-eight countries and territories still maintain some form of HIV-related restrictions on entry, stay and residence. A recent study of sex work policies in 27 countries concluded that those that decriminalized some aspects of sex work have significantly lower HIV prevalence among sex workers.

In 91 countries, adolescents require the consent of their parents to take an HIV test and in 77 countries they require the consent of their parents to access sexual and reproductive health services, creating barriers to protect young people from HIV infection. One of the consequences of this is that the HIV incidence rate among young women and girls in eastern and southern Africa is twice that of their male peers.

“In the next decade, we can end AIDS as a public health threat and achieve universal health coverage. Governments must tax fairly, provide publicly funded quality health care, guarantee human rights and achieve gender equality for all—it is possible,” said Ms Byanyima.

In October 2019, the US Food and Drug Administration approved a second medication for use as HIV preexposure prophylaxis, also known as PrEP, sparking controversy about which drug should be prescribed. Gilead Sciences, which manufactures both approved drugs, has argued that the new drug is safer and more effective than the old drug. But these claims are overstated, say a team of clinical and public health experts.

Their commentary, “Tenofovir Alafenamide for HIV Preexposure Prophylaxis – What Can We DISCOVER About Its True Value?”, appears in the January 14 issue of Annals of Internal Medicine.

PrEP, which is 99% effective in preventing HIV, exists in two forms: tenofovir disoproxil fumarate with emtricitabine (TDF/FTC) – best known as Truvada, its brand name in the US – and tenofovir alafenamide with emtricitabine (TAF/FTC), known as Descovy. TDF/FTC has been used for PrEP for more than 7 years, with ample evidence of its safety and effectiveness.

“These drugs are equally effective when used for PrEP in gay and bisexual men and transgender women, and the potential safety benefits of TAF/FTC over TDF/FTC have not yet been shown to be clinically significant,” said lead author Douglas Krakower, MD, Assistant Professor at the Harvard Pilgrim Health Care Institute, Beth Israel Deaconess Medical Center, and Harvard Medical School.

The high cost of PrEP medications, around $24,000 per year in the US, has been a major barrier to PrEP use. Activists have argued that taxpayer money funded the development of PrEP medications, and the US Department of Health and Human Services recently sued Gilead Sciences over patent infringement.

The older PrEP medication, TDF/FTC, will be available as a generic as early as 2020, which could reduce costs and increase access. But Gilead Sciences holds the exclusive rights to manufacture TAF/FTC until 2022 and has requested a patent extension to 2025. If the generic version of TDF/FTC is perceived to be less safe, uptake of TAF/FTC would presumably rise – with cost ramifications.

“With the exorbitant cost of these drugs, there are huge public health and economic implications if most PrEP users begin to use the newer TAF/FTC pill rather than TDF/FTC for PrEP,” said senior author Julia Marcus, PhD, Assistant Professor in the Department of Population Medicine at Harvard Pilgrim Health Care Institute and Harvard Medical School. “Gilead is asking us to ‘update’ our PrEP to TAF/FTC, but that’s not a clinically necessary or cost-effective choice for the vast majority of PrEP users.”

The authors examined the available data on the safety, efficacy, and public health context for the two PrEP medications. Robust data show the effectiveness of TDF/FTC in all priority populations at risk for HIV, including gay and bisexual men, transgender women, people who inject drugs, and heterosexuals whose partners are living with HIV. In contrast, the only efficacy data for TAF/FTC come from the DISCOVER trial, which enrolled solely gay and bisexual men and a small number of transgender women.

“In the DISCOVER study, TDF/FTC was associated with small changes in renal and bone biomarkers, while TAF/FTC was linked to weight gain and changes in cholesterol,” noted Dr. Krakower. But there were no differences between the groups in clinical events or the number of people who stopped the drug for safety reasons, suggesting that these small changes may not be clinically important. “Given the available clinical evidence and public health context, TDF/FTC should remain the first choice for the vast majority of PrEP users,” he said.

In addition to Drs. Krakower and Marcus, authors of the commentary included Demetre Daskalakis, MD, Deputy Commissioner at the New York City Department of Health and Mental Hygiene, and Judith Feinberg, MD, Professor of Medicine at West Virginia University and Chair of the Board of Directors of the HIV Medicine Association.