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IAS 2017: Why Curing Cancer May Be Like Curing HIV -- and May Be As Difficult


For the last few years, a specialist symposium on HIV cure research has preceded the annual International AIDS Society meetings, and this year was no exception, with a 2-day forum at the Curie Institute in Paris before the opening of the 9th IAS Conference on HIV Science (IAS 2017).

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But this time around, there was a difference: this year's meeting was called the IAS HIV Cure and Cancer Forum. This is due to the dawning recognition that curing HIV and curing cancer have aspects in common, and that established or experimental cancer drugs may also have a part to play in curing HIV.

HIV and Cancer: Similarities and Differences

There are many differences between HIV and cancer, of course, as Monsef Benkirane of France’s Institute of Human Genetics said in an opening lecture. HIV is caused by an infection and cancer by spontaneous misbehavior of cells (though in some cancers, this may be set off by infections).

Down in the heart of the cell, however, the issue is the same: cancer cells and HIV-infected cells harbor rogue genetic material that leads cells either to grow uncontrollably (cancer) or to derange the immune system (HIV). This means that they are both hard to cure: potentially, just 1 HIV-infected cell or 1 cancer cell can lead to a relapse.

It also means that the same tools that are now leading to a dramatic improvement in cancer cure and remission rates, including sophisticated drugs that target markers specific to cancer cells, could be used against HIV.

HIV-infected and cancer cells share a deadly trick. Cells with their rogue DNA can "de-differentiate" when they are under attack, whether by drugs or the immune system. This means they retreat to an earlier stage of cellular evolution where they are invisible to the immune system. Benkirane said, "When you treat, you actually create new cancer stem cells."

In HIV, something similar happens: energized immune cells that actively produce virus swiftly burn out, but a proportion return to a quiescent state, ready to spring into action again as soon as the pressure from antiretroviral therapy (ART) is eased. This is the HIV reservoir, and its identification and destruction (for a complete cure) or reduction or containment (for long-term remission) is the central barrier to be overcome if we are to find a cure.

The line of attack taken furthest by HIV cure researchers has used HDAC (histone deacetylase) inhibtors, drugs that "kick" the sleeping genes in reservoir cells back into a state of wakefulness. The full strategy has been called "kick and kill," as it has been hoped that the reservoir cells, once reactivated and visible to the immune system, could be killed naturally by immune responses or purged by antibody-based drugs that target them.

But repeated experiments with different HDACs have shown that, while they certainly wake up reservoir cells and turn them into short-lived virus-producing ones, they are unable to prevent new cells being "seeded" with HIV and then returning to a quiescent state. The size of the reservoir cells therefore does not change significantly.

Immune Checkpoint Inhibitors

The drug targets we really need to work on are the cellular molecules that prompt the cell to stop whatever immune job it is doing and revert to its quiescent state. Both cancer cells and HIV-infected cells are particularly rich in these so-called immune checkpoint receptors. It is thought that their function is, when the body is facing a hostile environment ranging from viral proliferation to chemical attack, to sequester a proportion of the immune system away, so that not all of it is permanently damaged.

There are a number of different immune checkpoint molecules. Ones already targeted by some cancer drugs include CTL-4 (cytotoxic T-lymphocyte-associated protein 4), PD-1, where the PD stands for "programmed death" (one of the things PD-1 can do is make cells self-destruct), TIGIT (T-cell immunoreceptor with Ig and ITIM domains), and JAK (Janus kinase). These are all inhibitory molecules that put cells into the reservoir state, though some like the TLR (toll-like receptor) family are excitatory, as the HDACs are, and TLR agonists continue to be under investigation as cell activators.

As with the HDACs, a number of CTL4, PD-1, and JAK inhibitors already exist as cancer drugs. These include the CTL-4 antagonist ipilimumab (Yervoy), the PD-1 antagonists nivolumab (Opdivo) and pembrolizumab (Keytruda), and the JAK inhibitors baricitinib (Olumiant) and ruxolitinib (Jakafi), which are approved for some cancers and are also used for auto-immune disorders such as rheumatoid arthritis and psoriasis. Some of these drugs have shown life-prolonging effects in cancers that used to be rapidly terminal.

HIV Cure and Cancer Forum attendees heard about several experiments using these agents in cancer patients with HIV. Timothy Henrich of the University of California at San Francisco, a researcher who has previously produced spells of undetectable HIV off ART in 2 patients given bone marrow transplants, presented data from 3 patients with lung cancer and HIV who were given multiple doses of pembrolizumab.

In all 3 patients, measures of T-cell activation decreased and in 1 patient, who was on ART, the amount of intracellular DNA (a measure of how many cells in the reservoir are infected) went down transiently. In a third patient, who was not on ART, both his general T-cell function and his blood plasma viral load decreased.

Brigitte Autran of Hôpital Pitié Salpêtrière in Paris gave data from 12 patients with non-small-cell lung cancer who had been given nivolumab. They were a diverse group. One was a cisgender and another a transgender woman, the others were gay men. They were between age 40 and 77 and had been diagnosed with HIV between 1980 and 2005. CD4 counts ranged from 60 to 700 cells/mm3. Most had viral loads below 20 copies/mL, though in 2 cases they were marginally detectable, at 34 and 53 copies/mL.

In one patient -- the one with the lowest CD4 count -- there was a significant T-cell rise and an increase in the proportion of cells showing an HIV-specific immune response. In another patient, an increase in the HIV-specific immune response was accompanied by a significant decrease in intracellular HIV DNA. However, he was the only one who showed indications of a shrunken HIV reservoir and other immunological effects that continued after the course of treatment. Effects in other patients were slight and transient.

Christina Gavegnano of Emory University in Atlanta presented data from animal studies of baracitinib in recently infected monkeys and found that, compared with treatment with lamivudine, there was a 700-fold reduction in the number of non-dividing latent CD4 T-cells established in the body. The drug could possibly be used as an addition to ART that would slowly shrink the HIV reservoir to the point where a treatment interruption could be considered. A human trial of ruxolitinib in 60 adults (A5336) is underway.

Results with PD-1 and CTL-4 antagonists, and JAK inhibitors, have so far not been impressive, with only a minority of patients demonstrating strong or durable responses, if any. Sharon Lewin of the University of Melbourne said that interpreting PD-1 blocker studies in people with cancer is already difficult because cancers are heterogeneous, and people with HIV who have cancer may not be representative of other HIV-positive people.

"We need to do studies in HIV-positive patients without cancer," she said. "And we need to study combination therapies. But combinations of immune checkpoint inhibitors, while proving to have more powerful results in some cancers, are too toxic to use with people who only have HIV."

In some studies of patients with melanoma, as many as 50% of patients had experienced severe or life-threatening side effects or even death from the drugs when they were used in combination.

Reservoir Cell Signal Found

One thing that would help efforts to cure HIV and to use new types of drugs to eradicate HIV-infected cells would be if reservoir cells could be identified more easily. The proportion of central memory resting T-cells that are infected with HIV  ranges from 1 per thousand to 1 per million. So far, however, we have had no clear way to identify them -- and that means no way to target these cells alone with drugs, and no other cells, which is the way to reduce toxicity.

In what might be the biggest news in cure research at the conference, it looks like that marker might have been found. Two different studies presented at the Cure Forum and at the main conference found that reservoir cells express much higher levels of a cellular receptor molecule called CD32a than other cells. While reservoir cells also express somewhat higher levels of other proteins, including immune checkpoint receptors and the CD2 molecule, this is the first time such a strong association has been found.

Genevieve Martin of the University of Oxford reported at the Forum and in a conference presentation that levels of CD32a were no higher generally in people with HIV than in HIV-negative people, with about 1.5% of immune cells in general expressing it. But in people with HIV, reservoir cells had from 100 to 1000 times as much of the molecule expressed on their surface, and these cells were also likely to be enriched with PD-1 and other immune checkpoint receptors.

Getting the Body to Ignore HIV

What if we are asking the wrong, question, though? What if trying to destroy or at least expose and inactivate every cell containing HIV is not the way forward and instead the answer is to teach the body to simply either ignore HIV or develop an immune response that controls it?

One of the most widely reported stories of the main IAS conference was the discovery of a South African child who had been born and started treatment early but who had now been off ART for 8.5 years without developing a detectable viral load. There has always been a very small proportion of adults who have either always been able to control HIV or who, like this child, started ART early but subsequently came off it, and found their HIV did not reappear, or did so only after a prolonged period.

Nicolas Noël of the South Paris Hospital at Le Kremlin-Bicêtre talked about a French cohort of HIV controllers -- people who maintain an undetectable viral load off treatment. He found 178 patients who controlled HIV with occasional "blips" (transient detectable viral load) and 52 patients who never had blips. The former group had an average viral load of 21 copies/mL by an ultrasensitive viral load test, while the non-blippers had a viral load lower than this test’s lower limit of detection of less than 4 copies/mL.

He found evidence that the blippers had very slowly declining CD4 counts, while the non-blippers did not; their CD4s stayed resolutely stable, at an average count of 700, on the low side of normal.

The non-blippers had very low levels of anti-HIV antibodies of the type called IgG. This may appear to be a paradox, as in studies of HIV vaccines, a strong HIV IgG response has been found to be protective. But the point is that in most people with HIV, the IgG response is turned on all the time -- even in people who take ART -- and the virus learns very quickly to mutate around it. The battle between HIV and the antibodies that attack it is an arms race that HIV nearly always wins. What is needed is a situation where the "antigenic signal" of the virus is so low that the IgG response, simply because it is rarely called on, remains effective when it is needed.

Another hint that this might be an ideal virus-controlling situation came from a study comparing the HIV response in Rhesus macaques with that in African green monkeys.

Michaela Müller-Trutwin of Paris’s Pasteur Institute told Forum attendees that Rhesus macaques can be infected with SIV, the monkey equivalent of HIV, develop high viral loads, experience CD4 cell declines, get sick, and die. African green monkeys, on the other hand, can be infected with SIV, develop high viral loads, and experience an initial loss of CD4 cells in their gut. But they do not experience the chronic T-cell activation or inflammation that leads to immune system derangement and CD4 cell loss. The difference appears to be that African green monkeys do not establish reservoirs; SIV remains a circulating virus but not an archived one.

How does this happen? The SIV appears to stop at the gut level because the central memory T-cells that live in the lymph nodes, and whose infection is the last stage in the establishment of a chronic, integrated infection, are much less likely to become infected.

How are these lymph node cells protected? It appears that in the early stages of infection -- the first few days or even hours -- a strong immune response snaps into action but then quickly closes itself down once its job is done. That response is characterized by a large proliferation of a different kind of immune cell, the natural-killer or NK cell, which bears a large number of CXCR4 receptors.

The job of cells with this receptor is normally to attract cells to the lymph nodes and in this case, it may efficiently place infected cells in proximity to the cells that are most likely to kill them, and do so rapidly. In addition, green monkey central memory cells largely lack the CCR5 receptors on their surface that make them vulnerable to infection.

When cells with HIV do manage to get to the lymph nodes, they can only attach to the parts of nodes that have high levels of the circulating immune chemical IL-15, and several monkey studies presented at the conference and the forum found that treatments that combine either IL-15 or IL-21, another cytokine (immune system modulator) with alpha-interferon, produce animals with many fewer infected CD4 and CD8 cells and lower anti-SIV responses.

These results are very suggestive, especially as HIV vaccine researchers have found that an NK-type response is the one that may make all the difference between HIV infection and lack of it. However, they are probably more useful to people as vaccines to stop infection in the first place, as everything suggests that once the reservoir is established, it is much more difficult to generate an immune response that shrinks it.

Not "Kick and Kill" but "Block and Lock"

One possibility is the idea of keeping the reservoir in a state of permanent lockdown: to find a drug that could detect the few HIV-infected cells and then not activate and kill the cells, but do something to their DNA that ensured they never get reactivated.

At the forum Jonathan Karn of Case Western University in Cleveland said there was such a mechanism: DNA could be methylated or effectively immobilized permanently, in the way that it was temporarily shut down in the process of immune checkpoint-induced de-differentiation. To do this would be to use exactly the opposite strategy of those that aim to activate the reservoir cells and expose them to drugs or a vaccine-enhanced immune reaction.

However, in order not to damage the rest of the cell’s DNA, only the parts surrounding the HIV genes should be immobilized. This is more difficult than with cancer, where the rogue genes’ location in the DNA are known; HIV can integrate itself at a number of different sites along the genome, though certain locations appear more favored than others.

At the main conference, Susana Valente of the Scripps Research Institute in La Jolla presented more data on an oral inhibitor of the HIV protein tat. Lab-dish experiments on human cells announced in 2015 showed that the tat inhibitor didehydro-cortistatin A (dCA) drastically reduced viral expression in HIV-infected reservoir cells, and this effect seemed to last for weeks to months even when dCA therapy was stopped, indicating that the drug had produced a persistent state of lockdown in the cells.

"You could call this strategy 'block and lock' instead of 'kick and Kill'," Valente said.

Tat is one of the first proteins expressed by HIV after infection and sets in motion other events, including integration into host DNA. It also appears to play a role in maintaining the slow, "behind the scenes" ongoing replication of HIV that keeps the reservoir topped up.

At IAS 2017, Valente presented the results of experiments in mice adapted so they can be infected with human HIV. Adding dCA to standard ART resulted in a significant 1.5-fold to 10.5-fold reduction in viral expression from reservoir cells and showed a degree of persistence when ART was withdrawn. However, Valente warned that even adapted mice were not the same as humans, and the tricks HIV uses to co-opt the human immune system into making more HIV could in theory neutralize the effect of dCA. Human studies are planned.

Can We Achieve a Complete HIV Cure in More Patients?

What all these different approaches have in common is that they aim to put HIV infection into persistent remission. But they do not completely remove HIV from the body.

Yet that is what was achieved in what is still the one case of a person cured of HIV. Researchers have not managed to find any trace of HIV in the body of Timothy Ray Brown, who attended a symposium presenting the main data from the HIV Cure and Cancer Forum, nearly a decade after he was cured. How can we produce other Timothy Ray Browns?

Brown’s cure involved a hazardous bone marrow transplant to treat leukemia that made him very ill and left him with some permanent nervous system damage. Nonetheless, experiments continue to explore the complete removal of HIV using similar transplant technology in patients with cancer and HIV, but using techniques that will hopefully be less chancy.

In the HIV Cure and Cancer Forum, Maria Saldago of the IrsiCaixa AIDS Research Institute near Barcelona presented results from ICISTEM, a cohort of patients with HIV and advanced cancers (mainly leukemia and lymphoma) who have had bone marrow transplants. As such patients are rare, ICISTEM has only collected data on 23 patients, 11 of whom have died. Salgado presented data on the 6 patients among the remaining 12 who have had more than 2 years of follow-up.

In 5 of these 6 patients, the transplanted HIV-free bone marrow stem cells rapidly replaced the patient's cancerous and HIV-infected cells. Ultrasensitive tests can find no HIV RNA in the blood of these patients -- their viral load, in short, approaches zero -- and tests can also find no HIV DNA in their reservoir cells. In some patients, HIV DNA undetectability in reservoir cells happened within a month; in others, HIV DNA levels slowly declined over a period of up to a year.

The key to full replacement by new cells appeared to be graft-versus-host disease (GVHD), a condition in which the grafted bone marrow cells "reject" the body’s own cells as foreign -- essentially the reverse of what happens in typical transplant rejection. This is normally a condition transplant doctors try to avoid, as it creates severe and in some cases lethal inflammation.

In the case of these patients, and in Brown's case, GVHD appears to have been an essential part of the process whereby their HIV-infected immune system may have been replaced by a non-infected one. In fact, it may be the essential step. Although Brown was transplanted with cells from a donor who was naturally immune to HIV, only 6 out of the 23 ICISTEM patients have received cells from HIV-immune donors.

Are the ICISTEM patients cured? We don’t know. Although the researchers have failed to find a single copy of HIV DNA in one million resting reservoir cells in some of the patients, the test will be to take these patients off antiretroviral therapy (ART). We have had disappointments before, as when HIV reappeared, after a delay,in the so-called Boston patients even though their DNA became completely undetectable.

Salgado told the HIV Cure and Cancer Forum that treatment interruptions were planned for early next year. Then we will find out if Timothy Ray Brown finally has company.

Will Enough People Come Forward for Cure Research?

Finally, the limiting factor in cure research may not be the complexity of the science involved or the current lack of one strategy that looks more promising than others, but the reluctance of people with HIV to come forward for cure research. While previous surveys have shown a general altruistic interest in volunteering for HIV cure research, when possible consequences are spelled out, interest declines.

Michael Louella of the University of Washington AIDS Clinical Trials Unit has done research on community attitudes towards cure research. A lot of people with HIV, he said, are currently happily on 1-pill-a-day therapy and stable and do not want this disrupted.

One question that came up at the forum and its summary symposium was whether current HIV cure research is relevant for "typical" chronically infected, stable people with HIV. The current state of the science means that these chronically infected people are not the ones cure researchers seek out; the people they need are cancer patients or people with cancer in remission, people failing ART, or "controllers" who have never needed it, the few people treated within days of infection, the few who have voluntarily stopped ART, and the diminishing number who are virally suppressed but who fail to have adequate immune recovery.

Not only were there relatively few of these kinds of patients around, and they might not be at all typical of most people with HIV, but people's willingness to come forward and be HIV cure research guinea pigs may have been overestimated in the past.

Louella said that surveys of opinions about HIV cure research had pretty consistently found that people had "red lines" that would deter them from entering a study. These included clinical events such as the reactivation of genes that could cause cancer, CD4 count falls, and the possibility of drug resistance; uncomfortable procedures such as lumbar punctures (spinal taps) and bone marrow biopsies; and side effects ranging from vomiting to hair loss.

However, the single most often-cited reason that people might hesitate to join a trial was the possibility that they might become infectious again.

"People are loath to lose their hard-won viral undetectability," Louella commented.

In addition, the cure field itself is unclear about its goals and procedures. What should the ethical policy be on ART interruptions? How do we translate suggestive results from small groups of exceptional patients into larger studies? Is there a way of determining the most promising research avenues and eliminating those that are less fruitful? And how do we deal with the media, who threaten to create popular disillusion by portraying every small research advance as a "cure breakthrough"?

While that breakthrough will happen one day, the road towards it might be slower and less direct than many had thought when cure research was first focused on as a possibility.