Are medical ethics stopping people from being cured of HIV using CRISPR-Cas9?

Nasya Soraya

The human immunodeficiency viruses (HIV) are extremely hard to eradicate completely
from the body. Typically, HIV is managed through the use of antiretroviral therapy (ART) –
often a cocktail of drugs that target different stages of the HIV life cycle. These drugs are
able to keep the viral load of the patient low enough so that it is ‘undetectable’; this also
means the chances of virus transmission is extremely low. [1] However, this only functionally
cures the patient, as the viral load would begin to increase again after discontinued use of
ART.[2] Somatic gene therapy using CRISPR-Cas9 is an alternative that will be discussed, as
well as some ethical concerns and why there is not more support for this technology.

HIV infects by fusing its viral envelope with the target immune cell’s surface membrane.
This occurs through the interaction of the glycoproteins on the virus and CD4 and
chemokine co-receptors (mainly CCR5 or CXCR4) on the immune cell. Once fused, the
virus releases its RNA, along with an enzyme known as reverse transcriptase. The enzyme
uses the RNA as a template to make a copy of the HIV’s DNA inside the host cell. The
newly made DNA is transported to
the nucleus where it is broken out of
the capsid shell that encases it.
Another enzyme, integrase, then cuts
a section of the host cell’s DNA and
replaces it with the HIV DNA. After
activation, this host cell will become
a virion factory.[3] HIV-infected
immune cells that are not activated
are collectively known as the latent
HIV reservoir. This is the main
problem with ART; it only affects
the viral load of the patient and not
the latent reservoir. These cells can
be activated at any time with no
warning and so are of a particular
concern for long-term treatment.[4] Fig. 1: infection mechanism of HIV[5]

The origins of HIV are believed to be two species-jumps of simian immunodeficiency virus
(SIV). SIV is widespread amongst non-human primates but has rarely been observed to
cause serious illness. HIV-1 is most closely related to the SIV in chimpanzees and gorillas in
West Central Africa whilst HIV-2 resembles the SIV in wild sooty mangabeys in West
Africa. As to how the virus actually made the jump, there is only speculation. Butchering
and eating of infected meat as well as blood transfer from fighting are plausible causes. [6]
The reverse transcription process outlined previously is extremely prone to error and thus
genetic mutations. This easily explains SIV’s mutation into HIV. It also helps to explain why
the virus is so hard to target; little mutations mean it has multiple infection pathways that
must be considered when attempting to treat or cure.
CRISPR-Cas9 is a genome editing technology that was developed from the naturally
occurring immune response of bacteria. When a bacterium is infected with a bacteriophage,
it will cut small sections of the virus’ DNA and insert it into its own. This allows the
bacterium to “remember” the attack, thus when reinfection arises, it produces RNA segments
that recognise and attach to the corresponding DNA sections in the virus. An enzyme, such
as Cas9, will then cut the DNA apart, immobilising the bacteriophage. [7] This is essentially
how CRISPR-Cas9 works for scientists now; using RNA segments to guide Cas9 to the
particular locus where it will make a cut. From there, new genetic material can be inserted
into the sequence, or the cell’s own repair mechanisms can be manipulated to add or delete
DNA.[8]

Somatic cells are cells that are not gametes or undifferentiated stem cells. Therefore, somatic
gene therapy only alters the adult living cells in a patient. [9] Germline therapy, on the other
hand, is the editing of early-development embryos or gametes. This would produce changes
that would be passed onto the patient’s descendants. [10] Many stereotypical arguments against
genetic modification centres around germline editing. This is unsurprising despite the
uncontroversial nature of somatic editing – ultimately somatic gene therapy is just another
drug delivery system – as the average person is not expected to know the difference.

Undeniably, there are many valid concerns regarding germline editing. A popular opinion
held is that there is an aspect of “playing God”, in that it would actually change the human
gene pool and force evolution. Nonetheless, selective breeding in humans has already been
done multiple times to decrease the incidence of disease. Cyprus has one of the highest
frequencies of -thalassemia carriers in the world.[11] -thalassemia is an inherited disease
that lowers the number of functional haemoglobins in the blood, thus reducing the oxygen-
carrying capacity of the carrier. This causes a whole slew of problems that can lead to early
death. In the 1970-80s, all couples seeking to get married by the Cypriot Orthodox Church
were required to get screened for -thalassemia.[12] Although carriers were not forbidden
from marrying or having children, the screening allowed people to make informed decisions
on if they wanted to pass on this life-threatening disease. Screening during pregnancy also
allowed for terminations if the offspring was homozygous for -thalassemia. Additionally,
prenatal screening for other diseases such as Down syndrome has become increasingly
popular, in most cases also leading to termination. It can be then argued that germline editing
is no different to this. The aim of selective breeding is to select diseases out of the human
population; germline editing has the exact same goal.

Though, it would be ignorant to deny that germline editing presents opportunities for
exploitation. Historically, selective breeding in humans has been used as a means of
discrimination and oppression. Eugenics aimed to improve the gene pool of a population, for
example, by forced sterilisation or anti-miscegenation laws. [13][14] Allowing for diseases such
as HIV to be edited out of the gene pool could be a slippery slope into editing for phenotypes
that are deemed superior. Even with inherited diseases such as Down syndrome, there is an
implication in wanting to eradicate the mutation that people with Down syndrome are
inferior, or that their lives are somehow worth less. Regulatory bodies also in this sense
cannot be trusted to ensure that germline editing is only authorised for ‘appropriate’ causes
as this is subjective. Governments are also likely to do what is profitable for them, and if the
people are demanding designer babies when the technology is already legal, there is no
guarantee that CRISPR would not be used for eugenics. In fact, it would speed the process
up by a very large margin.

Dr. He Jianku made headline news in late 2018 due to his illegal experiments that produced
3 babies born to HIV-1 positive fathers that he claimed are HIV resistant. [15] He did this by
removing the gene that codes for the CCR5 co-receptor, one of the pathways that HIV-1 uses
for infection. He was jailed for 3 years and fined 3 million yuan. Moreover, he received
widespread condemnation for his reckless actions; none of his work was peer-reviewed as it
was all done in secrecy. There were also concerns that Dr. He’s clients were underinformed
on the risks of unproven stem cell intervention. Partly in response to the scandal and the
criticisms, WHO published a guide on human genome editing that recommends all types of
gene editing only be pursued by countries that have rigorous regulatory bodies with
committed transparency report schemes.[16] This whole controversy also worked to heighten
the fears surrounding gene editing and CRISPR-Cas9 specifically. For many people this
event would have been the first and only time they heard of CRISPR-Cas9 and its relation to
HIV cures. Hence, there is an unfair representation in the media of what a gene therapy HIV
cure could look like.

The Nuremberg Code outlines the standard

for ethical medical research. The very first
principle established in the Code is that
“the voluntary consent of the human
subject is absolutely essential”.[17] It can
then be argued that germline editing is
unethical due to the impossibility of getting
an embryo’s consent. This is yet another
aspect of the debate with much subjectivity
to it – whether there is life in a 5-day old
Fig. 2: amongst religious Americans
embryo is really up to personal opinion.
Religious beliefs also commonly influence opinions when determining the morality of
curing, or conferring immunity to, a baby of a disease before it is born. A survey conducted
in the USA by the Pew Research Centre in 2016 (see Fig. 2) indicates how, the more
religious a person is, the less likely they are to want disease-curing gene editing for their
children.[18] Another question asked in the survey
(see Fig. 3) demonstrated how ignorance paired
with misinformation can discourage people from
supporting gene editing. The unknown posits a
fear in people, not entirely falsely as well. There
is always a risk in CRISPR-Cas9 editing of an
undesirable mutation, the expression of which
could harm the patient.

Public support and opinion are very important

when it comes to medical studies as it determines
Fig. 3: informed vs uninformed how much funding a study is likely to secure. It
also affects how likely governments are willing to approve any applications for clinical
trials. The technology for somatic gene therapy has existed for ~35 years, and yet the first in
human study to treat HIV was just begun in late 2021 and will conclude in 2024. [9][19]
Medical ethics is not what is stopping potential patients from being cured of HIV. Ignorance
paired with misinformation and damning representations of CRISPR-Cas9 in the media is
what is delaying the process of clinical trials for possible cures via somatic gene therapy. In
terms of germline editing, I believe it should be used for medical purposes such as curing
HIV and that it is ethical when done so. Nonetheless, I also do not trust that its legalisation
would not be exploited.
References, all retrieved 22 June 2022
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196576/
2. http://www.aimspress.com/article/doi/10.3934/Allergy.2021015
3. https://www.cell.com/cell/fulltext/S0092-8674(00)81430-0?_returnURL=https%3A
%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii
%2FS0092867400814300%3Fshowall%3Dtrue
4. https://hivinfo.nih.gov/understanding-hiv/fact-sheets/what-latent-hiv-reservoir
5. https://commons.wikimedia.org/wiki/User:Jmarchn
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234451/
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553049/
8. https://youtu.be/2pp17E4E-O8
9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327547/
10.https://bmcmedethics.biomedcentral.com/articles/10.1186/s12910-020-00487-1
11.https://pubmed.ncbi.nlm.nih.gov/24006929/
12.https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.c.30202
13.https://www.ushmm.org/collections/bibliography/nazi-racial-science
14.https://www.law.cornell.edu/supremecourt/text/388/1
15.https://www.technologyreview.com/2018/11/25/138962/exclusive-chinese-scientists-
are-creating-crispr-babies/
16.https://www.who.int/publications/i/item/9789240030381
17.https://media.tghn.org/medialibrary/2011/04/
BMJ_No_7070_Volume_313_The_Nuremberg_Code.pdf
18.https://www.pewresearch.org/science/2016/07/26/u-s-public-opinion-on-the-future-
use-of-gene-editing/
19.https://clinicaltrials.gov/ct2/show/NCT05144386