SEATTLE – Ten years after "Berlin patient" Timothy Ray Brown, a second patient has achieved long-term undetectable viral load in the absence of antiretroviral treatment (ART) after receiving a bone marrow transplant with hematopoietic stem cells with a nonfunctional version of the CCR5 receptor, a surface molecule on helper T cells that is used as an entry co-receptor by HIV.

A team from the University of Cambridge presented the London patient's data at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) on Tuesday, with concomitant online publication in Nature.

At the meeting, the excitement about the second case was palpable, particularly since the treatment that the new patient received was milder than of Timothy Ray Brown, who received two separate transplants and total body irradiation with each. The London patient received only a single transplant, and was not irradiated.

Even that milder conditioning will not make bone marrow transplant an acceptable treatment for HIV infection. Still, the researchers concluded in their paper that "CCR5 gene therapy strategies using stem cells could conceivably be a scalable approach to remission."

At the meeting, one example of such gene therapy strategies was reported by Pablo Tebas, director of the University of Pennsylvania's AIDS clinical trial unit. In a group of 14 HIV-positive patients, autologous transplantations of cells that had been edited to disrupt CCR5 functioning led to delayed viral rebound after ART interruption in HIV-positive patients.

The delay was "more a shift to the right" than a dramatic prevention of rebound, Tebas told reporters at the press conference.

But the study showed that electroporation, rather than viral vectors, could be used to modify the CCR5 receptor, potentially enabling higher doses.

"When you use a viral vector, it is immunogenic, and so you cannot give multiple doses of the product," Tebas said.

Primate studies of a different kind of gene editing were presented by Tricia Burdo, associate professor at Temple University's Center for Neurovirology. Rather than editing the genes of the host immune cells, Burdo and her colleagues are using CRISPR to try and edit the integrated HIV.

In the context of latent HIV, she explained, "our idea is that HIV... is more of a genetic disorder. So we are really trying to excise the bad gene."

In primates on antiretroviral treatment, treating the animals with CRISPR/Cas9 targeting several different HIV genes, the team was able to demonstrate that the system excised the virus in every tissue they have looked at so far.

Burdo was unwilling to call the animals "cured," noting that at a minimum, there would need to be analytical treatment interruption to test whether the virus would rebound.

Cure, remission, prevention

With the London patient's case report, questions of what should count as a cure were an area of lively discussion at the meeting.

Tebas told an anecdote that illustrated the challenges that cure research faces, recounting that some HIV patients feel that they are cured already because their treatment regimen consists of one pill a day, which effectively suppresses the virus.

Technically speaking, those patients are certainly not cured, as viral suppression depends on ongoing treatment.

Additionally, ART is not effective in all patients, and not everybody feels cured on a one-pill-a-day regimen. "There are some people who feel cured with one pill a day, and there are some people who feel very sick with one pill a day," Tebas told BioWorld.

Since Brown's transplant, there have been several other case reports of individuals who had prolonged periods of undetectable HIV after ART interruption. Two men, the Boston patients, achieved long-term remissions after bone marrow transplants with wild-type CCR5. Both, however, eventually rebounded.

There are also three reports of children who have been able to discontinue ART after a period of treatment, if HIV infection was diagnosed and treatment started within hours of birth. Only one of the three, however – known as the South African Boy – has no detectable virus and is thus potentially cured. A second child, the French Girl, has replication-competent virus that can be detected via extremely sensitive assays, as well as through occasional blips of increased viral load. The third child, the Mississippi Baby, rebounded after 27 months.

Early initiation of ART likely enables long-term remissions by preventing the establishment of a viral reservoir in the first place, while in Timothy Ray Brown and now in the London patient, those reservoirs were fully established. The reservoir is widely seen to be the key obstacle to an HIV cure that will be applicable more broadly. Even the gentler procedure used in the London patient does not have an acceptable risk benefit in the era of effective antiretroviral therapy, where patients can be HIV-positive but clinically healthy for decades.

The challenge of having to compete with highly effective ART is not unique to bone marrow transplants, but to other so-called "kick and kill strategies," which collectively aim to rouse latently infected cells so that ART, which can only work on dividing cells, is effective.

Some of those strategies, such as HDAC inhibitors, have been insufficiently effective so far. The meeting brought more disappointments in that regard, with the report that multiple I.V. doses of HDAC inhibitor romidepsin were insufficient to reverse latency.

But others, such as checkpoint inhibitors, have been effective at rousing latently infected cells, but stumbled over safety issues in the form of autoimmune problems. "The toxicity we are willing to tolerate differs between a basically healthy HIV-positive individual who is suppressed on ART, and someone with, for example, metastatic melanoma," Katharine Bar, assistant professor of medicine at the University of Pennsylvania's Center for AIDS Research, told the audience in an overview of data on cure strategies that will be presented at the meeting.

No Comments