The 22nd Conference on Retroviruses and Opportunistic Infections that took place last month in Seattle is one of the largest scientific conferences on HIV and hepatitis C virus (HCV) research in the world. While HIV cure was a highlighted topic, addressed by dozens of presentations as well as at a Community Cure pre-conference, the overall picture from CROI of the state of actual progress toward an HIV cure was mixed at best.
The conference is vast. Over the course of four days, there were some 1,100 scientific presentations related to HIV and HCV. Headlines from the conference deservedly focused on new data showing that pre-exposure prophylaxis (PrEP) using Gilead's Truvada was extremely effective at preventing HIV infection in men even for unprotected anal sex when actually used and that on-demand use, where an uninfected person takes two pills two to 24 hours before first having receptive anal sex and one pill on each of the two days afterwards, was also extremely effective.
Other headlines showed HCV could be effectively cured in virtually all cases, but by using drugs that remain prohibitively expensive.
Regarding HIV cure research, one bottom line from CROI is that former San Francisco resident Timothy Ray Brown (also known as the Berlin patient) remains the only person ever cured of HIV infection. Brown was not an attendee at this year's conference, but was invited to give a public presentation of his story, along with his doctor who performed the curative treatment, Gero Hutter, at the Seattle Public Library during the conference. The presentation was sponsored by the Martin Delaney Collaboratory of AIDS Research for Eradication at the Fred Hutchinson Cancer Research Center in Seattle. Brown reported that his health remains good and he is HIV free despite taking no anti-HIV medication since 2008.
Replicating the Brown cure
Brown's cure is an example of a "cellular" therapy, one of two major approaches under investigation as an HIV cure. (The other major approach involves activating resting infected cells so they can be recognized and killed by the immune system. This "kick and kill" approach is further discussed below.)
Cellular therapies in general involve giving patients genetically modified cells, either bone marrow stem cells or CD4/CD8 cells. In Brown's case, the genetic modification was due to a naturally occurring mutation of a gene that makes CCR5, one of the two molecules on CD4/CD8 cells and other immune cells that most HIV strains need to enter and infect cells. Brown required a bone marrow transplant to treat an aggressive leukemia and received the naturally mutated cells from a donor whom his doctor identified. Because his leukemia was not stopped by the first transplant, Brown actually received two a second round of oblation and a second bone marrow transplant with the naturally genetically-modified donor stem cells.
Since publication of Brown's cure, there have been reports of six further HIV-positive patients with aggressive cancers that received bone marrow stem cells from donors who naturally had the CCR5 mutation in an effort to replicate Brown's results. One report involved cord blood cells. None has been a success as all six treated patients died as a result of their cancer or cancer treatment before definitive results about whether the transplant cured their HIV were known.
CXCR4
One presentation by a medical team led by Jens Verheyen reported further results regarding one of those six patients. This patient, shortly after transplant, was not able to control his HIV virus without anti-viral drugs and subsequently died from the blood cancer. Further analysis, presented at CROI, found that the patient's continuing virus after transplant was a different variety of HIV that uses CD4 and a different co-receptor, known as CXCR4, to enter and infect cells. The presentation suggested that because this different HIV virus does not use the CCR5 co-receptor, the transplant with cells lacking CCR5 not only did not prevent HIV from reproducing, but also selected for CXCR4 using HIV virus.
Treatment with artificially genetically modified cells
The failures to replicate the Brown case using naturally mutated donor cells were in contrast to reports from Sangamo BioSciences Inc. regarding a human clinical trial using artificially genetically modified cells. In this case the cells are not from a donor, but from the patient being treated. At present, Sangamo has not used genetically modified stem cells in human trials, but instead used a patient's own CD4 and CD4/CD8 cells that taken out of the body, genetically modified to lack CCR5, expanded, and then transfused back to the patient. At present, the clinical trials are Phase 2 safety studies, but Sangamo also reported efficacy.
The Sangamo trials involve testing the safety of preconditioning and the safety of using modified CD8 cells with the modified CD4 cells. The first presentation related to the preconditioning needed to get a patient's body able to accept and grow the genetically modified cells. This is similar, but less drastic than, the chemical oblation done before a bone marrow transplant and depletes the body's CD4 and CD8 cells so that the modified transfused cells will have room to expand. In its presentation, Sangamo reported that the preconditioning agent Cyclophosphamide (CTX) was both safe and effective to enhance acceptance (engraftment) of the genetically modified CD4 cells. Sangamo additionally reported that including genetically modified CD8 cells with the modified CD4 cells was as safe as previous studies using only CD4 cells and that modified CD8 cells did grow in the patient's body.
In addition to this safety data, Sangamo reported that two of the four patients who received the transplants showed reduction of viral load even after long-term antiviral treatment interruptions (40-71 weeks), with one patient's viral load remaining below the limits of detection while not on antiviral drugs. If this patient continues to have sustained non-detectable viral load, the patient may be the second person in the world to have been functionally cured of HIV.
In addition to this ongoing Phase 2 clinical trial in HIV-infected humans, Sangamo announced that it is expanding its therapeutic approach to treat patients using essentially the gene modification therapy but with modified bone marrow stem cells. Sangamo reports that a Phase 1 clinical trial of this approach has been approved and will be undertaken along with City of Hope in Los Angeles. Treatment with modified stem cells (hematopoietic stem progenitor cells) will more closely replicate in patients the bone-marrow transplant that cured Timothy Brown and it is hoped may show stronger anti-HIV effect than treatment with modified CD4/CD8 cells.
Research on similar cellular therapies is taking place at a handful of other sites. Worldwide, a substantial majority of this research is located in California and involves two California companies, Sangamo and Calimmune, three Los Angeles academic research institutions, and funding from the California Institute of Regenerative Medicine.
Kick and Kill: First the kick
The other HIV cure approach, and the subject of the majority of presentations at CROI, is to activate latent long lived immune system cells that appear to harbor the HIV reservoir that is responsible for people who have HIV quickly rebounding within a few weeks of stopping anti-HIV therapy, even people who have been on drugs with undetectable viral load for close to 20 years. The approach has been nicknamed kick and kill. A drug or combination of drugs is used to activate or "kick" resting infected HIV cells, causing those cells to become active and produce HIV virus. Once the virus is being produced, the immune system, acting alone or aided by various immune enhancement therapies, can recognize and kill those cells.
Dozens of different drugs have been studied or proposed to activate latent HIV-infected cells and many of these drugs have been shown to activate cells in test tubes (in vitro) and to cause infected cells to emit HIV virus and in many cases to die. Prior to this year's conference, however, there was no demonstration that an activator could cause the amount of latently infected cells to be reduced in a living primate. This changed at CROI, where James Whitney from Harvard Medical School described results from research with rhesus monkeys using a Gilead experimental drug designed to reverse viral latency. The drug is an agonist of an immune system receptor protein called TLR7.
In the trial, rhesus monkeys infected with SIV (the monkey relative of HIV) who were virally suppressed with antiviral drugs were given the experimental drug. According to the data presented, the treatment showed evidence of activating latent cells because a transient increase in SIV was seen. The study further showed that when measured using currently available techniques, the viral DNA, indicating the size of the viral reservoir, was substantially reduced. Perhaps most notably, the study found that after discontinuation of antiretroviral therapy, SIV viral loads were lower among the monkeys that received the activator drug compared to the placebo group. This is the first demonstration in a living primate that a T-cell activating agent can reduce what is believed to be the HIV reservoir and reduce viral rebound.
While these results are interesting, the study was based on treatment of only four rhesus monkeys (with six monkeys used as a control) and the overall disease progression of SIV in rhesus monkeys is different from HIV in humans in many respects. Gilead has stated its intentions to begin human trials of the agent.
Kick and Kill remains an active area of research, with participation of multiple academic research centers and multiple pharmaceutical companies. One reason for this is that there is a long history of developing small molecule treatments and that is something that AIDS researchers and large pharmaceutical companies are comfortable with. There were a number of presentations related to using animal models for testing drugs that can kick latent cells into actively producing HIV.
Still too few dollars
The one issue not addressed at CROI that should be of great concern to people interested in an HIV cure remains how paltry funding for HIV cure research is compared to other areas of HIV research. The International AIDS Society estimated that last year worldwide funding for HIV cure research remains at a level of $100 million annually, not dramatically higher than the $60 million annually estimated to be spent before the Brown case was reported. This is a small percentage (2-3 percent) of the overall global HIV research budget, and a tiny, tiny fraction of annual worldwide spending on HIV. The science presented at CROI 2015 and previously suggests that a cure for HIV is scientifically possible, but the consensus of many scientists at the conference is that it will be decades before one is available. Given scientific results so far, this timeline could change, and will only be changed, if sufficient funding is made available for more directed research toward an HIV cure.
Stephen LeBlanc is a member of the AIDS Policy Project.