CAN HIV BE CURED BY GENE THERAPY? Jiayi (Ariel) Cao (LVI

The World Health Organisation had estimated that around 680,000 people had died due to HIV-related illness in 2020 (WHO, 2020). Although numbers are declining, HIV is still responsible for over half a million deaths across the globe. Over the course of medical and scientific advancement, there has been developmental drug treatments and post-exposure prophylaxis, but the battle against HIV has not stopped as there is still no cure.

Excision BioTheraputics. (2021). Excision Receives FDA Clearance of IND for Phase 1/2 Trial of EBT-101 CRISPRBased Therapeutic for Treatment of HIV.

Joanna Smolen-Dzirba, e. a. (2017). V-1 Infection in Persons Homozygous for CCR5-delta 32 Allele: The Next Case and the Review.

Qiaoqiao Xiao, e. a. (2019). Application of CRISPR/Cas9-Based Gene Editing in HIV-1/ AIDS Therapy.

Contrasting the turmoil of HIV patients, around 10% of Europeans are naturally resistant to HIV infection. The consensus is that this is caused by a mutation in the gene that codes for the membrane protein receptor (CCR5) that HIV virus binds to to enter and infect human immune cells, which prevents the entry of HIV by taking away the ‘door handle’ to HIV’s target cells.

More specifically, HIV virus binds to the CD4 receptor of the target cell along with either CCR5 or CXCR4 membrane coreceptor depending on the viral strain. The HIV-1 R5 strains, which cause most HIV infections, binds to the CCR5 molecule (C-C chemokine receptor 5) on the host cell membrane. Among the lucky 10% of Europeans, they carry a genetic mutation termed CCR5-Δ32, which means a frame-shifting deletion of 32 nucleotides in the DNA sequence that codes for the protein CCR5. This mutation changes the shape of the CCR5 receptor and prevents it from presenting on the outside of the cell, which impedes the binding of HIV on the membrane receptor and consequently blocks the entry of HIV into the immune cell.

Recent studies have shown that although homozygous CCR5-Δ32 is highly protective against HIV-1 R5, heterozygous CCR5-Δ32 has no effect on HIV immunity but is still related to the delayed progression of AIDS. (Joanna SmolenDzirba, 2017)

Timothy Ray Brown (often referred to as the Berlin Patient) had been diagnosed with acute myeloid leukaemia and tested positive for HIV infection. He was the first person on this planet to be cured of HIV after receiving a stem cell transplant (which is also a treatment for his leukaemia) from a donor who possessed homozygous CCR5-Δ32. Although this is the first and currently only case of successful cure for HIV using stem cell transplantation, this idea can be considered when treating all HIV patients. Could we artificially induce this gene into HIV patients to induce immunity? The answer is that scientists are working on it.

The 2020 Nobel Prize in Chemistry was awarded to scientists who pioneered the genetic engineering technique CRISPR/cas9, which has proven to be one of the most effective techniques in gene editing. This provides potential opportunities to edit the CCR5 gene in HIV patients to intentionally induce CCR5-Δ32 and thus HIV immunity. In lab research conducted by Xiaoqiao Xiao, et al., an application of gene editing to inhibit HIV infection had been successful in vitro and in mouse models, which could potentially be performed on HIV patients to induce HIV immunity or even HIV prevention. (Qiaoqiao Xiao, 2019)

Excitingly, the first-in-human phase 1 and 2 clinical trial of CRISPR-based therapy in chronic HIV was approved by FDA (Food and Drug Administration) in September 2021. The safety, adverse effects and efficacy of the CRISPR-based one-time gene therapy on HIV patients will be evaluated. (Excision BioTheraputics, 2021) Here, we anticipate for encouraging results from the clinical trials.

Unfortunately, there has been reported cases of patients with homozygous CCR5-Δ32 (which was thought to be protective against HIV infection) who had been infected by HIV. (Joanna Smolen-Dzirba, 2017). This means that even if we induce CCR5-Δ32 gene through CRISPR/cas9, there is still no guarantee of 100% HIV immunity. As mentioned above, the entry of HIV into human immune cells not only involve CCR5, but other strains of HIV-1 may enter via another coreceptor CXCR4. Why don’t we just edit the gene coding for CXCR4 as well, just like what we are doing to CCR5 gene? The problem lies with the fact that studies have shown mice without CXCR4 die as embryos, which raises questions of whether it is safe to edit the gene. Therefore, whether CRISPR-based gene therapy that aims to edit CCR5 gene could protect us from HIV infections remains a question and is constantly being challenged with new cases and evidence.

Throughout the battles against diseases, scientific and medical advancements have undoubtedly saved millions of lives, yet we still have a long way to go. In the combat against HIV, the understanding of CCR5 and CXCR4 in HIV entry pathway has laid the basis of much research that is finding a cure and prophylaxis of HIV, and the new discovery of CRISPR/cas9 has brought exciting new opportunities and approaches to HIV treatment and prevention. Whether promising or not, every piece of new evidence adds a piece of the puzzle to the grand picture of our knowledge base and understanding of the world we live in. Although the complex living world never gives a straightforward answer to anything, scientists have never stopped striving for improvements and breakthroughs that both satisfy our curiosity and improve our lives.

The Chemistry Olympiad took place during the Lent term 2022. It is a really challenging paper for any Sixth Form student (and teachers!) and Downe House open it up to all our A level chemistry students. It relies not only on an excellent understanding of chemistry concepts, but also on resilience and the ability to problem solve novel and totally unfamiliar chemistry problems. Many of these are based on application of content from the UVI year of the A-level syllabus.

To achieve a gold in the Olympiad is extremely difficult, let alone in your first term of Lower Sixth – this is in fact exactly what Ariel achieved! Scoring in the top 9% of all candidates that sat the paper this year.

The chemistry department would like to say a huge well done to Ariel for her truly awesome achievement. Congratulations, Ariel – we are really proud of you!