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A Cure to HIV/AIDS: Where are we now?

A Cure to HIV/AIDS: Where are we now?

August 16, 2022

By Dylan Roussouw

Figure 1: Logo of the 2022 International AIDS Conference. (1)

The 2022 International AIDS Conference, convened by the International AIDS Society, began on 29 July in Montreal, Canada. Their purpose is to provide education on HIV/AIDS as well as advocate for “a world in which HIV no longer presents a threat to public health and individual well-being.”1 The society consists of over 13,000 professionals spanning 170 countries and focusing on creating dialogue between the fields and disciplines partaking in the fight against HIV/AIDS. They perform research into potential new treatment modalities for HIV and present these developments through the Journal of the International AIDS Society. The International AIDS Society also work on public perception of HIV through their Hearts of Stigma programme. The International AIDS Conference is one of many HIV conferences the Society hosts, the others being the IAS Conference on HIV Science and the HIV Research for Prevention Conference.2

One case presented at the Montreal Conference – that of a 66-year-old cancer patient, nicknamed the “City of Hope Patient” (after the Los Angeles cancer centre he was treated at) – offers insight into a potential cure for HIV. This patient was diagnosed with both AIDS as well as Acute Myeloid Leukaemia (AML). To treat both he underwent a stem cell transplant from an HIV-resistant donor (a common genetic anomaly occurring in about 1% of people of northern European descent). It has been 3½ years since the transplant and 17 months since discontinuing antiretroviral therapy. The patient currently has no viable copies of the HIV virus present in his body, meaning he is in complete viral remission. This poses the possibility that stem cell transplantation could present a possible cure for HIV in other patients.3

 

South Africa’s HIV prevalence

According to the Stats SA4 2022 Mid-year report: The estimated overall HIV prevalence rate is approximately 13,9% This equates to around 8,45 million people living with HIV in South Africa. As illustrated in figure 2, globally there was approximately 38,4 million people living with HIV.5 This implies that South Africa contains 22% of the world’s HIV-positive population. Progress in the field of HIV research could mean more people achieve viral suppression, possibly even viral eradication.

Figure 2: 2022 Global HIV Data from UNAIDS. (5)

 

Why is HIV so difficult to cure?

Unlike other viruses that can either be cured or vaccinated against, HIV only has suppressive treatment. This is because of HIV’s high genetic variability. This variability stems from two sources: a fast replication cycle and a high mutation rate. A virus’s replication cycle describes the rate at which copies of the virus can be produced. HIV’s replication cycle comes in at 1010 virions (whole virus particles) per day. The mutation rate is the rate per nucleotide at which mutations occur when replicating or recombining viral DNA. The mutation rate for HIV is around 3 x 10-5 per nucleotide base per cycle.5 These characteristics result in multiple variants of HIV being produced within one patient. Although antiretroviral (ARV) medication can block the various functions that allow the HIV virus to replicate, variants of the virus may arise that are able to reproduce in the presence of ARVs.6 Figure 3 illustrates the basic steps in the life cycle of HIV as well as the drug classes commonly used to prevent HIV infection and proliferation.7 HIV also forms reservoirs in the T cells and other lymphoid tissue of the body. These reservoirs are resistant to ARV therapy as well as clearance by host immunity.8 These factors combine to form a major roadblock in the path to curing HIV.

Figure 3: The steps in the HIV lifecycle and the medication that can inhibit these steps. (7)

 

Research and Advancements

Up to 2022 research into cures for HIV have focused on stem cell therapies and gene therapies. Gene therapy has largely been focusing on the genes responsible for C-C chemokine receptor 5 (CCR5) and CXC receptor 4 (CXCR4) expression in CD4 positive T cells and CD34 positive hematopoietic stem cells. CCR5 and CXCR4 are receptors on immune cell surfaces that HIV utilises to infect these immune cells.9,10 Elimination of the loci responsible for encoding these receptors has the potential to prevent HIV infection of these cells, thereby preventing its proliferation. This effect has been demonstrated in the first patient to be cured of HIV, Timothy Brown, otherwise known as the “Berlin Patient”. In 2007 Brown was undergoing treatment for a relapse in AML, much like the City of Hope Patient. Brown received an allogenic haematopoietic stem cell transplant from a donor who had a “homozygous mutation for the D32-null mutation in CC chemokine receptor 5.” That means that all the donor’s stem cells did not express the CCR5 receptor on their cell surface and neither would the T cells produced from those cells. This transplant both eliminated Brown’s cancer and gave him an in-built defence mechanism against HIV.9

Donors with mutations that grant HIV-resistance are not the only option available. Through CRISPR (clustered regularly interspaced short palindromic repeats) genome editing haematopoietic stem cells can be specifically engineered to not express CCR5 or CXCR4. This can be applied to donor stem cells, or to the patient’s own CD34 stem cells. However, methodology for sorting cells to edit them is limited. In a 2019 study, a study published in the New England Journal of Medicine utilised CRISPR-edited donor stem cells in the treatment of a patient with HIV and Acute Lymphocytic Leukaemia (ALL). In sorting 28,8% of the sorted cells were CD34 positive, while the remainder was CD34-depleted. Only the CD34 positive cells were able to be edited, and the combination of edited and depleted cells was transfused into the patient. After monitoring for 19 months the overall disruption of CCR5 expression was only 5%. At 4 weeks after the cessation of retroviral therapy the patient’s HIV viral load had reached 3 x 107 and ARVs were resumed.11

Roadblocks to the Treatment of HIV

Although gene therapy and stem cell therapy have the potential to cure HIV, there are still problems preventing their use in the general HIV-infected population. Each case discussed above has involved a patient with both HIV and a life-threatening cancer, either: acute myeloid leukaemia or acute lymphoid leukaemia. In each case these patients were unlikely to survive and consented to trying these experimental treatments. For implanted stem cells to have an effect they must replace the user’s immune system. This means that the patients underwent myeloablative therapy using chemotherapy medication such as cyclophosphamide.11 The intention of myeloablative therapy in AML is to destroy the host’s defective stem cells, while the intention of the transplant is to allow the donor stem cells to take over the host’s immunity. This suggests that the cases of Brown and the City of Hope patient were ideal candidates on which to recommend this experimental treatment on. However, myeloablative therapy in preparation for stem cell transplantation has several complications and risks associated with it. The stem cells destroyed leads to anaemia (deficiency of haemoglobin and/or red bled cells), neutropenia (deficiency in neutrophils, another type of immune cell), and thrombocytopenia (deficiency in platelets required for clotting). Elimination of immune cells results in an increased risk of infection, as well as no way to deal with infections once infected other than antibiotic treatment.11

The CRISPR stem cell case also demonstrates that current methodology has significant room for improvement when it comes to sorting, editing, and implanting stem cells.11 However, achieving 5% CCR5 receptor disruption supports the hypothesis that stem cell therapy has potential to augment the management of HIV, allowing for ARV therapy to be tapered.9

Conclusion

Stem cell therapy, gene therapy, and gene-editing all show promise as routes to create a cure for HIV/AIDS. However, they are still in the experimental phase in which their use is not safe to study and test in the general population. As the field develops, and research advances, these techniques will gradually become accessible for testing within the general population. At the epicentre of the HIV pandemic, South African participation in this research is vital to accelerate the development of a solution.

To read more about the most recent HIV research and developments: International AIDS Society

Bibliography

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  2. Home | International AIDS Society (IAS) [Internet]. Iasociety.org. 2022 [cited 6 August 2022]. Available from: https://www.iasociety.org/
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  7. The power of partnership takes on HIV | Laboratory News [Internet]. Labnews.co.uk. 2022 [cited 6 August 2022]. Available from: https://www.labnews.co.uk/article/2026519/the_power_of_partnership_takes_on_hiv
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  9. Peterson C, Younan P, Jerome K, Kiem H. Combinatorial anti-HIV gene therapy: using a – ProQuest [Internet]. Proquest.com. 2013 [cited 6 August 2022]. Available from: https://www.proquest.com/docview/1381856400/fulltext/DD4AA1344E7C4EB0PQ/1?accountid=14717
  10. Kandula U, Wake A. Promising Stem Cell therapy in the Management of HIV and AIDS: A Narrative Review [Internet]. National Library of Medicine. 2022 [cited 6 August 2022]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9275675/
  11. Xu L, Wang J, Liu Y, Xie L, Su B, Mou D et al. CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia | NEJM [Internet]. New England Journal of Medicine. 2019 [cited 6 August 2022]. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1817426
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