Why is AIDS incurable?
Acquired ImmunoDeficiency Syndrome (AIDS) is caused by Human Immunodeficiency Virus (HIV). After a successful HIV invasion, people may undergo a long asymptomatic period up to 15 years, during which HIV targets human T cells expressing CD4 and keeps proliferating inside [1]. Eventually sufficient HIV leads to AIDS, by then the human immune system has been greatly compromised or destroyed. In spite of several approaches to slow down HIV proliferation, there is no cure for AIDS and the damage to immune system is irreversible. Cocktail therapy is a common antiretroviral therapy (ART), which refers to the combination of three or more antiretroviral medicines to suppress the viral loads without generating drug resistance [2]. This therapy however, cannot eradicate existing HIV so that ART must be taken every day. When medical intervention stops, the remaining HIV can still replicate and eventually leads to AIDS [3].
The “Berlin Patient”, the world’s first patient cured of HIV
Though no cure, there are two cases in which patients are surprisingly cleaned of HIV. Timothy Ray Brown, a male American known as the “Berlin Patient”, was the world’s first person cured of HIV [4]. He was diagnosed HIV positive in 1995 when attending university in Berlin. He adopted ART and lived for the next 10 years. Then in 2006, he was diagnosed of acute myeloid leukemia. Four rounds of chemotherapy he adopted did not stop the caner for long so he accepted the bone-marrow transplant.
His blood sample was sent to the stem cell bank with the German Red Cross to find a match and luckily, there were 267 matches. More luckily, a donor from the bank had a mutation on the CCR5 Δ32 site on the CD4+ T cells. Three months after the first transplant, HIV was no longer found in his blood but the leukemia came back. So he accepted the second transplant in 2008 and had been through a 6-year rehabilitation before fully recovered. In conclusion, the transplant of stem cells with a CCR5 mutation cured both his leukemia and HIV.
The “London Patient”, the world’s second patient cured of HIV
Soon a second case emerged. In March 2020, scientists completed the 30-month observation and announced that Mr. Adam Castillejo, known as the “London Patient”, was cured of HIV. He shared a lot of common with Mr. Brown, both had been diagnosed of HIV and a cancer, been through several rounds of chemotherapy, adopted stem cell transplant and an arduous rehabilitation [5].
Growing up in Venezuela, Mr. Castillejo moved to London in 2002 and was diagnosed HIV positive next year, when he was 23. He had been receiving ART since then. In 2011, bad luck got him again. He had been experiencing fevers, which turned out the result of a Stage IV lymphoma. His HIV status complicated the treatment because there was little information on how to treat a patient with both diseases. Each time his oncologists adjusted his cancer treatment, the infectious-disease doctors had to recalibrate his HIV medications. The endless chemotherapies continuously weakened his body and finally in the spring of 2015, his doctor told him he might not survive the Christmas this year.
Running out of other options, he reached Dr. Ian Gabriel, an expert in bone-marrow transplants for treating cancer, including in people with HIV. Luckily, Dr. Gabriel found several donors in the stem cell bank that were compatible with Mr. Castillejo’s immune system. A German donor in particular, carries the CCR5-Δ32 mutation, as does the donor of Mr. Brown. The transplant was conducted on May 13, 2016 and it took years for Mr. Castillejo to recover. He underwent severe loss of weight, hearing and motility. When he was allowed to leave the hospital, the only exercise he could do was walking. He took his last set of antiretroviral drugs in October 2017, and no signs of existing HIV were ever found since then. Therefore scientists changed his status from “Long-term remission” to “Cured” [6].
How does CCR5 mutation bring HIV immunity?
Both patients are cured of HIV after the transplant of stem cells carrying CCR5-Δ32 mutation. So how does this mutation bring immunity to HIV infection? In 1996, Paxton et al. reported 25 individuals who were highly resistant to HIV-1 infection, under high-risk sexual exposures with HIV carriers. They correlated this resistance to a group of mutated C-C chemokines on CD4+ T cell membranes [7]. These receptors were involved in the human immune system. In the same year, Deng et al. identified a major co-receptor that acted like a doorway of HIV entry [8], first named fusin, then CC-CKR-5 and finally CCR5. CCR5 refers to C-C chemokine receptor type 5, a membrane-bound protein of white blood cells.
HIV uses CCR5 to specifically identify and infect CD4+ T cells. Note that individuals carrying a CCR5 homozygous mutation (Δccr5/Δccr5) are the most resistant to HIV-1 infection. Heterozygous CCR5 mutation (CCR5/Δccr5) carries a dominant allele so that partial CCR5 can be expressed, therefore the HIV resistance is partly compromised. Among known sites of CCR5 mutations, Δ32 is a hotspot. Generally speaking, CCR5-Δ32 mutation is rare among humans, most found among north Europeans (~10%) and western Asians (~5%), the ratio of Δccr5/Δccr5 was less than 1%. Even heterozygous CCR5 mutation is barely detectable among Eastern Asians and Africans.
CCR5 secondary structure and location. [Source: https://en.wikipedia.org/wiki/CCR5]
Two gene-edited girls immune to HIV caused controversy
In November 2018, two girls named Lulu and Nana were born in China, whose CCR5 genes were knocked out via the Crispr/Cas9 gene-editing technique by Prof. Jiankui He. Lulu was deleted one the two copies of CCR alleles while Nana was deleted both copies. According to He, Nana was carrying innate immunity of HIV because her CD4 cells would not be expressing CCR5 co-receptor so that HIV cellular entry would be a failure. This behavior however, arose worldwide escalating debate, on human ethnical, healthy and technical aspects.
Human gene editing is dangerous. One reason is that these changes are lifelong, no turning back. If the two girls can make their lives to adulthood, not allowing them to have their children is inhuman. However, they will definitely pass on edited genes to the children, which is also inhuman to the children [9]. We can eliminate an engineered animal if things go wrong, but how can we kill an engineered living person? Another reason is that the functions of CCR5 are not extensively studied so that its deletion may be associated with potential risks. Though no solid experimental or medical evidences, CCR5 deletion was found associated with some negatives, including more severe diseases when infected with West Nile Virus, Japanese Encephalitis virus, etc.
Crispr/Cas9, one of the most prevailing gene-editing techniques, has been found of high-frequency off-target mutagenesis, meaning that there are genes being unexpectedly altered and we don’t know about these alterations, according to an article published on Nature Biotechnology [10]. Perhaps some crucial genes of Lulu and Nana have already been altered but yet discovered. If the breach of gene editing is not fixed, people will eventually have one more discrimination apart from sex and race, which is gene discrimination. Imaging that people carrying “defect” genes will be biased in jobs and marriage. No country in the world allows researches concerning reproductive human embryo gene edition, and Jiankui He was therefore banned from continuing his research and sentenced three years in prison.
Patients cleaned of HIV by transplant of stem cells with CCR5-Δ32 mutation does not mean this treatment can be generalized, given the fact of several failures already happened. The 5-year survival rate after transplant is often less than 50%. Even if patients are cleaned of HIV, they may still die from cancer, transplant rejection or other diseases. In conclusion, stem cell transplant ranks the lease option to treat HIV unless running out of any other option. Besides, ART has achieved long-term HIV remission and is free in most countries.
References
1. https://www.who.int/news-room/q-a-detail/hiv-aids
2. https://www.healthline.com/health/hiv-aids/understanding-the-aids-cocktail#takeaway
3. https://www.aids.gov.hk/pdf/g190htm/11.htm
4. Brown, T. R. (2015). I Am the Berlin Patient: A Personal Reflection. AIDS Research and Human Retroviruses, 31(1). doi: 10.1089/aid.2014.0224
5. https://www.nytimes.com/2020/03/09/health/hiv-aids-london-patient-castillejo.html
6. Gupta, R. K., Peppa, D., Hill, A. L., Gálvez, C., Salgado, M., Pace, M., … Olavarria, E. (2020). Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report. The Lancet HIV, 7(5). doi: 10.1016/s2352-3018(20)30069-2
7. Paxton, W., Martin, S., Tse, D. et al. Relative resistance to HIV–1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high–risk sexual exposures. Nat Med 2, 412–417 (1996). https://doi.org/10.1038/nm0496-412
8. Deng, H., Liu, R., Ellmeier, W. et al. (1996). Identification of a major co-receptor for primary isolates of HIV-1. Nature, 381. doi:10.1038/381661a0
9. https://www.thebodypro.com/article/designing-hiv-resistant-people-a-top-hiv-clinical-
10. Fu, Y., Foden, J., Khayter, C. et al. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol 31, 822–826 (2013). https://doi.org/10.1038/nbt.2623