The search for a broadly useful HIV cure continues

DURBAN, South Africa – So far, there has been exactly one person who has been cured of AIDS – Berlin patient Timothy Brown. And his treatment, due to both its dangers and its costs, is definitely not suitable for scale-up. (See BioWorld Today, July 19, 2016.)

But especially in the continued absence of a vaccine, the search for a cure that could be broadly applicable has become a major part of the AIDS research agenda. And the belief in a cure, which once seemed like optimism verging on foolishness, now seems like a reasonable one to hold.

Not that it's clear whether a cure is feasible. Speaking at the 21st International AIDS conference this week, Anthony Fauci, director of the National Institute of Allergy and Infectious diseases (NIAID), said that a cure is "not impossible, but very challenging."

One issue is that there are no examples of the immune system winning its battle against HIV. Once infected, people do not clear the infection. The vast majority either gets treatment or dies.

And while there are rare examples of elite controllers that can keep the virus in check for many years without antiretroviral therapy (ART), even those individuals do not cure themselves – they remain infected. That lack of understanding of what sort of an immune response to aim for hampers both vaccine and cure research.

In his talk, Fauci distinguished between a true elimination cure, where the virus is no longer in the body, and sustained control, where viral levels remain undetectable in the absence of antiretroviral treatment.

Patients, obviously, would prefer an elimination cure, both for reasons of stigma and because only an elimination cure can truly guarantee that the virus is not coming back.

Timothy Brown was cured by a bone marrow transplant with cells that were genetically resistant to HIV infection because they have a deletion in the surface molecule CCR5, which HIV uses as a co-receptor to enter cells.

At the meeting, researchers from the European EpiStem consortium presented data on 15 additional HIV-positive individuals that received bone marrow transplantations for life-threatening hematological conditions. The team reported that bone marrow transplantation reduced the size of the HIV reservoir, and that the virus had remained undetectable for more than a year after transplantation in two of three patients where long-term data are available. Because the patients remain on ART, however, it is not possible to say whether they are in remission.

Bone marrow transplantation is too dangerous to provide an acceptable risk-benefit balance to HIV-infected individuals. But a possible alternative is to genetically engineer patient's T cells to mimic the CCR5 mutation that makes cells resistant to HIV. (See BioWorld Today, March 6, 2014.)

Sangamo Biosciences Inc. is testing that approach in the clinic with cells edited using zinc finger nucleases.

And the general approach, Fauci said, is "especially promising in the age of CRISPR. . . . The tools are at least there to pursue it."

Another possibility is the use of latency-reversing agents to drain the HIV reservoir that is responsible for viral rebound, likely in combination with immune-stimulating agents. (See BioWorld Today, July 19, 2016.)

There is also potentially the use of passively transferred antibodies in therapeutic vaccines. While antigens that can rapidly produce broadly neutralizing antibodies (bnAbs) have eluded researchers to date, the same is not true of the antibodies themselves. There are now a number of such antibodies, and one particularly promising one, VRC01, is being tested both for its ability to prevent HIV acquisition and as therapy.

Trials in infected individuals have shown that therapeutically administered VRC01 could delay rebound – "not a home run of any sort. But it tells us that there was an influence, albeit very transient," Fauci said.

Several strategies could lead to more sustained effects, including finding more potent antibodies, extending the half-lives of the antibodies themselves, using gene therapy for in vivo production of antibodies, and combining different antibodies.

The latter approach worked for antiretroviral drugs, Fauci pointed out. Since the introduction of three-drug ART, "we can get to undetectable [viral loads], and it can be indefinitely."

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