Heavyweight! The Lancet officially issued: confirmed the world's 2nd case of HIV cure 2020-03-10 Heavy!
I play Gordo Clove yesterday
On March 10, 2020, Ravindra K. Gupta's team published a study in Lancet HIV entitled Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report [2], following up on last year's treatment update of the amazing 'London patient'.
In this latest study, the authors changed their assessment of the patient's improvement from "long-term remission" to "cure" and confirmed that the "London patient" is the second person in the world to be cured of HIV.
Image source: Lancet HIV
"The Berlin Patient is no longer alone
In 1995, a man named Timothy Ray Brown was diagnosed with AIDS. Eleven years later, poor Brown was diagnosed with Acute myeloid leukemia (AML), and the scythe of death was finally waved at this lingering AIDS patient.
An optimistic Timothy smiling in the street
But Brown and his doctors didn't just give up. Gero Hütter, a doctor from Berlin, decided to make a bold move by selecting a special donor from among 60 bone marrow donors who carried the CCR5-Δ32 mutation.
CCR5 was previously shown by Professor Hongkui Deng, now at Peking University, to be the primary receptor for HIV virus invasion of Τ cells. One percent of Europeans are born with the CCR5-Δ32 mutation. Later studies found that this mutation makes them innately immune to the CCR5 (R5)-tropic HIV virus.
Previous paper by Professor Hongkui Deng, source: Nature
Brown's bone marrow transplant was a success, and his leukemia was immediately cured. Even more surprisingly, the ΗΙV virus in his body dropped to undetectable levels, eliminating the need for antiretroviral (ART) to suppress the ΗΙV virus, and Brown has survived to this day.
Until March 8, 2019, Brown was believed to be the first and only person in the world to be cured of HIV, and was therefore known as the "Berlin patient.
On March 8 last year, Professor Ravindra K. Gupta of Cambridge University led a team that published a paper in Nature entitled HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation [1], giving the lonely Berlin patient patients with companionship.
Image source: Nature
The article reports that within 16 months after a patient in London, England, who had both Hodgkin's lymphoma and AIDS received a CCR5-Δ32-derived hematopoietic stem cell transplant, not only did the Hodgkin's lymphoma recover, but the patient's blood was free of HIV.
The patient then stopped taking ΑRT medication for 18 months and no HIV was found in his blood before the paper was submitted. The researchers concluded that the "London patient" was in "long-term remission" of his AIDS and that he was likely to become the second patient to be cured of AIDS.
A year later, the London patient was finally recognized as the second person in the world to be cured of AIDS.
"The London Patient" recreates miracle in 30 months
Image source: Lancet HIV
In a previous Nature article, researchers reported HIV viral loads in plasma only 18 months after stopping ART medication. This article follows up by reporting progress between March 19 and March 20, extending the time to 30 months.
During the additional 12 months, plasma HIV viral loads remained undetectable below the detection limit. Chimerism from transplanted hematopoietic stem cells was still possible at 99%; the patient's CD4 cell count also returned to normal levels.
The same Epstein-Barr virus (EBV) and cytomegalovirus (CMV) as reported in Nature continued to be present during this period, but the CMV viral load decreased 18 months after transplantation.
Patients did not take immunosuppressive drugs during this period and did not develop graft versus host disease. Droplet Digital PCR showed no detectable HIV1 provirus long terminal repeat (HIV-1 LTR) in CD4 T cells, but a small amount of HIV-1 LTR was detected in memory T cells.
Building on the detection of plasma in the Nature study, the researchers in this study deliberately tested for the presence of HIV virus in multiple HIV latent reservoirs. HIV viral loads in semen, cerebrospinal fluid and puncture tissue biopsies were all below the detection limit and negative.
Small amounts of HIV membrane glycoprotein genes (env), LRT and structural protein genes (gag) were detected in lymph nodes, but no DNA integrase was detected, demonstrating a low and incomplete HIV genome. RT-PCR showed similar results, along with evidence for the absence of the HIV packaging signal ψ. This implies that these small amounts of HIV genes are not sufficient to cause HIV relapse.
Image source: Lancet HIV
The researchers then examined the specific immune responses of the patient's CD4 and CD8 T cells to HIV gag, EBV and CMV. The patient's T cells were found to produce an immune response only to EBV and CMV, but not to HIV gag.
Figure source: Lancet HIV
Further studies found that although the patient still had some amount of HIV antibodies, there was a significant decrease in the affinity of these antibodies, which together proved that the patient was clinically cured of HIV.
Image source: Lancet HIV
Using mathematical models to simulate the probability of remission, the researchers concluded that the probability of achieving "long-term remission" was higher than 99% at 90% chimerism. The patient's chimerism rate is now stable at 99% over time, and the authors concluded that the "London patient" had been cured of HIV based on the previous treatment history of the "Berlin patient".
This paper once again demonstrates the possibility of using CCR5 mutant hematopoietic stem cell transplantation to treat HIV, and provides experience and guidelines for the clinical implementation of related therapies in the future.
More importantly, at a time when HIV vaccine and drug research has repeatedly failed, the miracle of the "Berlin patient" has been revived by the "London patient", giving new hope to the 38 million people living with HIV worldwide.
The CCR5 Story Continues
Because there is no effective cure for AIDS, the perception of the disease has reached the point where people are afraid to talk about it. Every development in the AIDS epidemic generates a lively debate within and outside of academia, and the story of CCR5 has had its ups and downs in recent years.
Before the "London patient" was reported, Professor He Jiankui of the Southern University of Science and Technology (SUST) had used the growing CRISPR technology to genetically edit the fetuses of AIDS patients.
He knocked out CCR5 in the baby to give the baby immunity to AIDS similar to that of the "Berlin patient" and CCR5-Δ32 mutation carriers. But his adventurous actions caused a shock to the world's scientific community and the outcry of all scientists because of ethical controversies and falsified experimental ethics approval procedures. Last year, He Jiankui was sentenced to three years in prison for his work.
Image source: Nature Medicine
In the wake of the He Jiankui case and the announcement of the "London patient," the safety of the CCR5-Δ32 mutation has been studied by the academic community.
Rasmus Nielsen and Xinzhu Wei from the University of California, Berkeley published a paper in Nature Medicine titled CCR5-∆32 is deleterious in the homozygous state in humans [3], which reported that CCR5-∆32 pure congeners cause a 21% increase in all-cause mortality. of increased all-cause mortality. The paper generated a lot of controversy and was eventually retracted because of conflicting data and incorrect analysis methods.
Image source: Nature Medicine
In a dramatic turn of events, a few months later researchers, including the original authors of the paper, re-analyzed the data and published another article in Nature Medicine titled No statistical evidence for an effect of CCR5-∆32 on lifespan in the UK Biobank cohort [4 ], stating that there is no evidence that the CCR5-∆32 mutation affects the lifespan of carriers, partially clearing the way for the study.
Figure source: NEJM
In addition to using hematopoietic stem cells from CCR5-∆32 mutation carriers, the discoverers of CCR5, Professor Hongkui Deng's group at Peking University, Tiger Chen's group at the Fifth Medical Center of the PLA General Hospital, and Hao Wu's group at Beijing You'an Hospital, Capital Medical University, collaborated to publish a paper in ΝΕJM entitled CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphoma. with HIV and Acute Lymphocytic Leukemia [5], reported a method to use CRISPR technology to edit CCR5 in hematopoietic stem cells for transplantation to circumvent ethical and safety issues, which is expected to mass-produce "Berlin patients" and "London patients" to help more AIDS patients. Although the editing efficiency in the study was not high, the safety and potential of the technique has been demonstrated in the study.
The cure of the "London patient" is further proof that Professor Hongkui Deng and Professor Hu Chen, who sadly passed away after a long illness, have chosen the right path. (Responsible editors: Ivan, dxylc)
Title image credit: Tuworm Creative
Reference Sources.
1. Gupta, R.K., et al., HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature, 2019. 568(7751): p. 244-248.
2. Gupta, R.K., et al., Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical Lancet HIV, 2020.
3. Wei, X. and R. Nielsen, CCR5-∆32 is deleterious in the homozygous state in humans. Nature Medicine, 2019. 25(6): p. 909-910.
4. Maier, R., et al., No statistical evidence for an effect of CCR5-∆32 on lifespan in the UK Biobank cohort. Nature Medicine, 2020. 26(2): p. 178-180.
5. Xu, L., et al., CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia. New England Journal of Medicine, 2019. 381(13): p. 1240- 1247.
