Popular culture celebrates firsts. Everyone knows the first person on the Moon, the first person to fly across the Atlantic and the first African American major league baseball player, while few can name the second. But in some contexts, such as science, the second is arguably far more important. A one-time event can be a fluke, while a second is replication and confirmation.
Such is the case with the London patient, the second patient to have been apparently cured of HIV (the first being the Berlin patient). The Lancet HIV has just published a 30 month follow up of the London patient, finding that they are still free of intact HIV – apparently cured. What does this mean for the prospects of an HIV cure?
The two patients were treated in a similar way, with total bone marrow replacement. This is considered a high-risk treatment only suitable for desperate situations, and will not become a standard treatment. The Berlin patient was treated with total body irradiation followed by two rounds of bone-marrow transplant and then chemotherapy. The transplant came from a donor with the CCR5 variant that is resistant to HIV (they do not express CCR5, which is a T-cell receptor HIV uses to infect cells). The Berlin patient remains HIV free off anti-retroviral drugs.
The London patient was treated with one round of bone marrow transplantation and a milder form of chemotherapy, with no whole-body irradiation. So they represent not only a second case of apparent cure of HIV, but a demonstration that a less aggressive and risky treatment can be effective.
The current study sampled serum and multiple tissues to detect HIV. Specifically:
We used ultrasensitive viral load assays of plasma, semen, and cerebrospinal fluid (CSF) samples to detect HIV-1 RNA. In gut biopsy samples and lymph-node tissue, cell-copy number and total HIV-1 DNA levels were quantified in multiple replicates, using droplet digital PCR (ddPCR) and quantitative real-time PCR. We also analysed the presence of intact proviral DNA using multiplex ddPCR targeting the packaging signal (ψ) and envelope (env). We did intracellular cytokine staining to measure HIV-1-specific T-cell responses. We used low-sensitive and low-avidity antibody assays to measure the humoral response to HIV-1.
What they found was no intact HIV. They did find HIV remnants, which are essentially fragmentary “fossils” of HIV, but not intact HIV capable of infecting. Even though this is pretty thorough, it is still sampling, so they had to use a mathematical model to predict the probability of cure, which they estimate at greater than 99%. Whether or not this cure is permanent remains to be seen, as both patients will have to be followed, but these results are extremely encouraging.
What does this mean for HIV treatment going forward? Not much directly, as even the less aggressive treatment is still high risk and will only be used in extreme cases, such as life-threatening blood cancer. For most patients with HIV, standard anti-retroviral drug cocktail is still the standard of care. But these cases are an important proof of concept that has implications for future research.
One big lesson is that the CCR5 HIV resistant variant is an effective treatment for those already infected with HIV. So the next obvious question is – can we do gene therapy on HIV patients to give them the resistant variant? Will CRISPR come to the rescue?
If you recall, the two Chinese “CRISPR babies” were altered to have the CCR5 variant to make them resistant to HIV, because one of the donor parents was HIV positive. The researcher, He, is now in prison, and there is general consensus that this process was unethical and premature. But the concept is valid.
One of the early applications for CRISPR treatment involves autologous bone marrow transplants. The two HIV-cured patients were treatment with allogenic transplants, from another donor. But we could take the bone marrow out of a patient, use CRISPR to alter their genes, and then give them back to the patient. This would reduce the risk of graft failure due to rejection or graft-vs-host disease.
Even better, we could potentially use CRISPR inside patients, rather than on cells taken out of a patient. In fact, this was just reported for the first time one week ago. The treatment involved patients with a genetic form a blindness (Leber congenital amaurosis), and the CRISPR vector was injected just beneath the retina. Whether or not the treatment was successful remains to be seen.
To be clear, we are a long way away from routinely using CRISPR on HIV patients to give them the CCR5 resistant variant. But we do have some important proof-of-concept successes. The necessary clinical research will still take years, but there is a path forward. CRISPR is proving safe, so far, and the technology itself is still improving fairly rapidly.
In many ways the London patient HIV cure is a bit of a side show, but it does point the way to a potential cure for HIV in the future. It’s also another demonstration of how basic science research can pay off in unexpected ways, but that years of clinical research are necessary to translate these basic advances into practical treatments.