Scientists from around the world met to review the future of HIV scientific research at the Institut Pasteur in Paris, last week – 30 years after the discovery of HIV by a team based at the institute.The prospects for a cure for HIV infection were a major theme of the meeting, which attracted around 500 scientists, chiefly from France and the United States.
“We’ve had some very interesting little lights at the end of the tunnel from individual studies regarding the possibility of a cure,” said Dr Tony Fauci, director of the US National Institutes of Allergy and Infectious Disease, referring to two recently reported cases and two studies. In the first case, Timothy Brown, the so-called 'Berlin patient', was cured of HIV infection after a bone marrow transplant from a donor with genetic resistance to HIV infection.
Professor Steve Deeks of the University of California San Francisco, who took part in extensive tests to determine whether Timothy Brown was free of HIV, told the conference: “We have concluded that he is as cured as you are going to get.”
In the second case, an infant treated almost immediately after delivery was reported to be controlling HIV infection after nearly 18 months off treatment. Researchers are describing this case as a functional cure.
Hints of success among some people treated very soon after infection
In two other small studies, there have also been hints that very early treatment, as in the case of the baby, might also lead to an ability to control HIV indefinitely without medication. French researchers have reported on a group of 14 patients – the Visconti cohort – they describe as 'in remission' after each having been off treatment for an average of 7.5 years. All these people started treatment within ten weeks of infection and were on treatment for an average of three years.
A group of Thai patients also treated very soon after infection but still remaining on treatment show almost no signs of HIV infection within long-lived cells that form the reservoir in which the virus is able to persist within the body, according to findings presented at the Conference on Retroviruses and Opportunistic Infections in March 2013. The levels of HV DNA within these cells fell as treatment went on, suggesting that very early treatment might both contain the infection of cells and then diminish HIV levels to such an extent in infected cells that these people might be able to control HIV without medication.
This question must still be answered. It is possible that a functional cure – long-term HIV control without medication – may only be possible for those who start treatment very soon after infection.
“The SPARTAC data [from a study of early treatment for 12 or 48 weeks within six months of infection] are consistent with the fact that you need early treatment and long treatment,” said Steve Deeks. The study found lower HIV DNA levels in individuals who initiated treatment within 12 weeks of infection and remained on it for 48 weeks.
Professor David Margolis of the University of North Carolina at Chapel Hill pointed to the failure to find people who controlled HIV after stopping treatment in other cohorts of people treated soon after infection, while Steve Deeks drew attention to a case of a patient followed by Tony Fauci's laboratory at the US National Institutes of Allergy and Infectious Disease who appeared to be a promising candidate for viral control, but who experienced viral rebound after two months off treatment.
“I think it is about 50/50 that the Visconti cohort is showing a real effect,” he said. In other words, researchers still need to know more about the Visconti patients, and how widespread post-treatment control of HIV might be. To this end, the French HIV research agency ANRS is seeking collaborators to create an international cohort of people who initiated treatment in primary infection and who have subsequently stopped treatment for at least 12 months without viral rebound.
What the participants in the Visconti cohort have in common apart from very early treatment is surprising. They exhibit hardly any of the characteristics associated with long-term viral control in people who have never been treated – so-called 'elite controllers' – and they have at least one genetic trait that should put them in line for fast disease progression, an HLA B57 allele.
The only trait they do share with elite controllers is a lack of HIV infection of central memory cells, the long-lived group of cells that form a stubborn component of the reservoir of infected cells, said Dr Deeks. “Are central memory cells relatively hard to infect compared to other cells?” he asked.
Chronic HIV infection: many puzzles to solve in order to make progress for the vast majority of people with HIV
The recent rash of new findings all refer to individuals diagnosed and treated very soon after infection. For people with established, or chronic, HIV infection, these findings may raise hopes of a cure, but as yet there is no well-documented case of a cure in a chronically infected person apart from the unusual case of the 'Berlin patient', Timothy Brown.
Dr Tony Fauci commented, “It is a greater possibility that we aren’t going to have a pristine cure that is going to cure everybody.”
Something more than very early antiretroviral treatment will be needed to achieve a functional cure in people with chronic HIV infection, scientists at the meeting agreed. Chronic infection poses a challenge because HIV infects very long-lived immune system cells and forms a reservoir of latent, inactive virus that can restore viral load to pre-treatment levels within weeks if fully suppressive antiretroviral treatment is halted.
Flushing out virus from this reservoir of cells will require the identification of agents that can activate cells and deplete a substantial proportion of virus. One round of treatment is unlikely to be enough, and experiments with the use of candidate agents called HDAC inhibitors are still at an early stage.
“We also need to understand how to safely and repeatedly activate cells over time,” said Professor David Margolis, who has been studying the use of vorinostat and other agents to induce lately infected cells to produce HIV. It is likely that a combination approach to activation will be required, he went on.
Others have suggested that gene therapy – taking stem cells from a person with HIV and engineering them to become resistant to HIV infection – may pave the way for a functional cure in people with fully suppressed HIV. This hope is based on the Timothy Brown, the 'Berlin patient', who received a bone marrow transplant from a donor who lacked the CCR5 receptor used by HIV to gain entry to CD4 cells.
“Is the Berlin patient proof of concept for gene therapy? Not really, because he had chemotherapy which wiped out his immune system,” said Paula Cannon of the University of Southern California. “If we don’t completely ablate [eliminate] with chemotherapy, the patient’s immune system needs to be re-populated gradually [by repeat infusions of genetically modified cells], so a suitable conditioning treatment is needed in order to help infused modified cells to home to the bone marrow."
Further advances may also be necessary in order to maximise the contribution of antiretroviral treatment to curing HIV infection. For example, scientists need to know more about how different combinations of antiretroviral drugs compare in reducing immune activation, which could be important in preparing people for curative interventions, said Professor Judith Currier of the University of California Los Angeles. If virus in the central nervous system proves to form an important reservoir, drugs with a greater capacity to penetrate into the cerebrospinal fluid might be needed, she said.
Scientists also need better tools to help them evaluate whether efforts to rid the body of HIV have worked, said Professor Sharon Lewin of Monash University, Melbourne, Australia. Researchers will need to be able to measure whether cells are producing infectious virus in response to interventions designed to flush out HIV from latently infected cells, and what proportion of cells respond to the intervention.
Gregg Gonsalves, who presented an HIV community perspective on HIV cure research at the meeting, warned that budget cuts in Europe and North America are “a dagger at the heart of biomedical research”. He noted that, in the United States, federal funding for scientific research and development will fall back to 2002 levels as a result of recent funding cuts. “Austerity is killing the great biomedical enterprise that marked the second half of the twentieth century,” he said.
He called on scientists to become activists in order to stand up for HIV and other biomedical research in the face of public spending cuts.
Warnings against over-optimism
Patient advocates also expressed concern about recent media reporting of HIV cure research, especially in a Sunday Telegraph news report published in April, which suggested that an HIV cure was months away. The Danish researchers interviewed in the article subsequently issued a correction in order to explain that their research is a preliminary study of an HDAC inhibitor in 15 patients, and that an HIV cure will take many years.
Advocates and scientists were highly critical of reporting which misleads people with HIV and the general public about the prospects of an imminent HIV cure. “It is time to challenge scientists about the danger of over-optimistic communication especially in non-scientific media,” said Eric Fleutelot of French advocacy group Sidaction.
“It has become very trendy to talk about an HIV cure but we must be very honest about this, it is going to be a very long road,” said Professor Brigitte Autran, a French researcher into therapeutic vaccines that can stimulate the immune system to control HIV in infected people.
“A safe, scaleable cure may prove impossible and will take years to decades to develop even if it is possible,” said Steve Deeks.