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Progress and Problems in the Search for a Cure for HIV

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Leading experts discussed the latest developments in the search for an HIV cure at a January 13 Center for AIDS Research symposium in San Francisco, following a year of disappointing setbacks in the field. Researchers are increasingly focusing on a "functional cure" -- or remission -- that would allow people with HIV to remain off antiretroviral therapy (ART) for prolonged periods, as the hopes for true viral eradication have dimmed.

National Institute of Allergy and Infectious Diseases director Anthony Fauci kicked off the symposium, sponsored by UCSF and the Gladstone Institute for Virology and Immunology's Center for AIDS Research (CFAR), with an overview of the rationale for and feasibility of an HIV cure.

The rationale includes the fact that 35 million people are living with HIV worldwide, including 1.2 million in the U.S., and it is economically and logistically unfeasible to treat all of them for their entire lives. In addition, even people with well-controlled HIV on ART still have higher rates of chronic conditions such as cardiovascular disease and some cancers.

Fauci reviewed our current understanding of viral latency. Starting from the earliest days after infection, HIV enters resting CD4 T-cells, where it establishes a long-lasting reservoir. Latent HIV genetic material in these cells is hidden from the immune system and not susceptible to antiretroviral drugs. While combination ART is very effective at suppressing viral replication, it usually comes roaring back soon after treatment is stopped.

Cure strategies explored to date include very early antiretroviral treatment, drugs to reverse HIV latency, gene therapy to make immune cells resistant to HIV, stem cell transplants, monoclonal antibodies, and therapeutic vaccines to stimulate immunity. Most experts expect that multiple simultaneous approaches will be needed.

Fauci cautioned, however, that long-term viral remission may turn out not to be enough. Recent studies have shown that "elite controllers" -- the rare group of HIV-positive people who are naturally able to maintain undetectable viral load without ART -- still have signs of immune activation and higher rates of cardiovascular disease and more frequent hospitalizationthan HIV-negative people.

Early Antiretroviral Treatment

There have been glimmers of hope that starting HIV treatment very early might limit the size of the viral reservoir and improve the prospects for a cure.

At the 2013 Conference on Retroviruses and Opportunistic Infections (CROI), Deborah Persaud first reported on a baby born to an HIV positive mother in Mississippi who did not receive antiretrovirals to prevent mother-to-child transmission. Due to the risk of infection, the infant was started on combination ART at around 30 hours after birth. The baby continued on ART for more than a year with good viral suppression, but then was taken off treatment by her caretakers. When she was brought back into care at age 2, her viral load was unexpectedly still undetectable despite being off antiretrovirals for several months. Extensive testing failed to find HIV RNA in her blood plasma or HIV DNA in peripheral blood cells, leading many to hope that this very early treatment had led to a cure.

Unfortunately, after two years of sustained remission, researchers reported before last summer's International AIDS Conferencethat the child -- now age 4 -- was found to have detectable HIV viral load during a routine clinical visit. She was then put back on ART, her viral load was again suppressed, and she remains in generally good health.

Katherine Luzuriaga from the University of Massachusetts Medical School discussed this case at the CFAR symposium, along with research on other children who received early therapy. The Mississippi child showed that even very early treatment does not prevent the establishment of a latent HIV reservoir. However, the shorter the time a baby is exposed to ongoing HIV replication before starting ART, the smaller the viral reservoir, she explained.

But early ART may not be sufficient. "Many of us feel antiretrovirals alone won't lead to an HIV cure in infants, so now we're looking at 'ARV plus' using immunotherapy or a vaccine," Luzuriaga said.

Jintanat Ananworanich from the U.S. Military HIV Research Program also discussed the role of very early ART in HIV remission. She previously headed up a team at the Thai Red Cross that put together the SEARCH cohort of 230 people with acute HIV infection who started very early ART.

Ananworanich noted that people who started treatment very early -- during a stage known as Fiebig I -- had less lymph node fibrosis or hardening, which allowed better CD4 cell recovery. However, she cautioned, "there may be some irreversible immune damage" even if ART is started within 3 weeks, since depletion of CD4 cells in the gut and evidence of inflammation are seen soon after infection.

The SEARCH team is now conducting a studyin which a small number of these Thai patients will interrupt treatment. Some will receive latency-reversing drugs and others will get a therapeutic vaccine. Their viral load will be monitored every 3 days and they will immediately resume treatment if found to have detectable HIV.

Stem Cell Transplants

Symposium attendees also heard an update on another recent disappointment: a pair of stem cell transplant recipients in Boston who experienced HIV rebound after having viral suppression for weeks or months off ART.

At the 2012 International AIDS Conference, Timothy Henrich from Harvard Medical School first reported on 2 men who underwent bone marrow transplants for lymphoma using stem cells from normal donors and mild chemotherapy that allowed them to stay on ART. After showing no detectable HIV in their blood plasma, peripheral blood cells, or gut tissue for a few years, they agreed to try a careful experimental treatment interruption.

As Henrich reported in late 2013 and at the 2014 CROI, HIV did come back, after 12 weeks off treatment in one man and after 8 months in the other. Both men quickly reached high viral loads but were able to regain viral suppression after restarting ART.

"The hardest thing I ever had to do as a physician was to call these patients and tell them their HIV had come back," Henrich said at the symposium.

Given the inability to detect HIV while the men were still on ART, he suggested that "long-lived tissue reservoirs inaccessible to sampling" are responsible for HIV rebound after stem cell transplantation.

Robert Siliciano from Howard Hughes Medical Institute is perhaps the foremost expert on finding hidden HIV, having developed highly sensitive detection techniques. More than one speaker noted that he had foiled numerous cure research attempts by detecting the virus where others could not.

Siliciano also echoed Henrich's concern about not being able to detect low-level hidden virus in cure studies. "We will have HIV patients where we can't measure anything, but we won't know if they're cured -- we have to figure out how to follow them," he said.

One Known Cure

Given the disappointing HIV rebound seen in the Mississippi child and the two Boston bone marrow transplant patients, only 1 person still appears to be cured of HIV: Timothy Brown, formerly known as the Berlin Patient.

In 2006 Brown, who was then on ART with good viral suppression, developed leukemia and he underwent 2 bone marrow transplants after other treatment failed. Brown's doctor, Gero Hütter, had the idea to use bone marrow from a donor with a double CCR5-delta-32 mutation, meaning their stem cells were missing the CCR5 co-receptor that most types of HIV use to enter T-cells. Brown received intensive chemotherapy that killed off his cancerous immune cells, and his immune system was rebuilt from the donor's stem cells. (This differs from Henrich's patients, who received stem cells from normal donors and used milder chemotherapy that did not destroy all their immune cells.)

Although Brown stopped ART when he received the chemotherapy and bone marrow transplants, his HIV did not return. Despite 7 years of poking and prodding, researchers have not been able to detect replication-competent HIV in his blood plasma, peripheral blood cells, or anywhere else they have looked.

CFAR presented an award to Brown at the symposium recognizing his contribution to HIV research for undergoing extensive testing in an effort to learn how he controls the virus.

Presenter Steven Deeks from UCSF described how Brown moved to San Francisco in 2011 and showed up at his clinic.

"There were lots of issues to deal with that I didn't know how to handle," Deeks joked. "In all the paperwork in an HIV clinic, you have to basically say whether the patient is HIV positive or negative. I never could quite figure out how to answer that question."

"I asked him to come in for a blood draw, and he said yes," Deeks continued. "Then I said, we need a lot of blood, how about leukapheresis, and he said yes. Then I said, we really don't think the virus is in your blood, we think it's in your gut, how about a rectal biopsy, and he said yes. Then we told him we don't really think it's in your rectum, we think it's in your ileum, about 20 feet up in your gut, and he said yes. Then we thought maybe it's in your brain, and he had a lumbar puncture. Then we said, we can't find it anywhere else, how about a lymph node biopsy, and he said yes...And he never complained."

Accepting the award, Brown said, "I want to accept this award on behalf of the millions of people who are infected with HIV, those who have died of the disease, and also the patients who have made an effort in trying to help find a cure."

Henrich and other speakers at the symposium noted that Brown's unique case had helped inspire their work on an HIV cure.

It remains unclear whether Brown's cure is due to using stem cells missing CCR5, the intensive chemotherapy, a graft-versus-host reaction (in which the donor cells attack the recipient's body), or some other unknown factors. However,Hütter recently reportedthat 6 other HIV-positive cancer patients have undergone bone marrow transplants from CCR5-delta-32 donors, and none have experienced a cure like Brown's (1 experienced rebound with HIV that uses the alternate CXCR4 co-receptor, and all died from cancer progression or complications).

Other Approaches to a Cure

Several other experts at the CFAR symposium discussed the nuts-and-bolts basic science underpinning HIV cure research.

Siliciano discussed efforts to reverse latency and bring HIV out of hiding. Several research teams have used various compounds -- including HDAC inhibitors such as vorinostat, panobinostat, or romidepsin -- to activate resting T-cells and flush out the virus, dubbed the "shock and kill" approach. Stimulating too many T-cells and over-activating the immune system is a potential risk of this strategy.

Romas Geleziunas from Gilead Sciences and Martin Tolstrup from Aarhus University in Denmark described various latency-reversing compounds, most of which have demonstrated no more than modest success. Underlining the difficulty of this research, Geleziunas noted that screening a library of more than 400,000 potential latency-reversing agents turned up just one likely small-molecule candidate (GS-46).

While some compounds do activate cells and spur virus production, they have not been shown to shrink the viral reservoir. "We can't assume that T-cells will die if we simply reverse latency -- they may just sit there and continue to produce HIV," Siliciano cautioned.

Nicolas Chomont from the University of Montreal described the role of T-cell homeostasis in maintaining HIV persistence. He noted that early ART, started within the first 2 weeks after infection, resulted in a restricted HIV reservoir in memory T-cells. However, he said, even after more than 15 years on ART, HIV DNA is still detectable in 3 memory cell subsets, and these cells "still have the ability to produce HIV RNA when stimulated."

Chomont also noted that "the more memory T-cells you have, the larger the HIV reservoir, and the older you are, the more memory cells you have" -- perhaps helping explain why some of the best results using very early ART have been seen in babies.

James Mullins from the University of Washington discussed HIV integration sites and maintenance of reservoirs, Jeffrey Lifson from Leidos Biomedical Research discussed non-human primate research on therapeutic vaccines -- including a promising CMV-vectored vaccine -- and Dan Barouch from Harvard Medical School presented research on monoclonal antibodies against HIV

"It takes 30 seconds to ask an HIV vaccine question, but a million dollars and about 2 years to answer it in primate studies," Lifson quipped.

Barouch described a monkey study using the monoclonal antibody PGT121 in combination with antiretroviral drugs. Monkeys receiving the cocktail showed a decline in their viral reservoir, which was greatest in animals that started with the lowest viral loads. However, PGT121 plus ART did not prevent eventual viral rebound, suggesting that only a subset of reservoir cells were targeted.

"We can potentially tickle the reservoir, perhaps reduce it, and delay viral rebound, but we have not seen eradication or prevention of rebound," Barouch summarized.

He added, however, that a new broadly neutralizing antibody, PGDM1400, appears "extraordinarily potent," especially when combined with PGT121. "No vaccine candidate can even come close to inducing responses like these monoclonal antibodies," he said.

Finally, W. David Hardy from Calimmune described research using gene therapy to remove the CCR5 or CXCR4 co-receptors from stem cells -- in effect, using gene modification to mimic Brown's stem cell transplant from a donor with missing CCR5.

Previous research using gene therapy to modify CD4 T-cells (Sangamo's SB-728-T zinc finger technique) has shown that the procedure is safe and leads to substantial and long-lasting CD4 cell gains. In addition, a small number of study participants were able to maintain viral suppression during experimental ART interruption. Modifying stem cells instead of existing T-cells could provide a longer-lasting benefit since stem cells give rise to all immune cells in the body.

The CFAR symposium provided a good overview of where we've been and where we're going with HIV cure research. Some of the strategies discussed, including latency-reversing agents and monoclonal antibodies, are still in early stages of research and not ready for widespread clinical use. Others, like gene therapy, may be too high-tech and expensive to scale up. Stem cell transplants are a risky procedure with a high mortality rate, making them appropriate only for HIV positive people who need them for cancer treatment. Very early ART is promising, but it is challenging to find people during the first days or weeks after infection.

"A cure for HIV "has got to be simple, with no tertiary care, safe, that is, no worse than antiretroviral therapy, and scalable to millions of people," Fauci concluded.

2/20/15

Source

UCSF/GIVI Center for AIDS Research. HIV Persistence: Progress and Problems in the Search for an HIV Cure. Annual Scientific Symposium. January 13, 2015.