1226849

review-article20242024
CLLXXX10.1177/09636897241226849Cell TransplantationZhou et al

Review

Cell Transplantation

Mitigating Cross-Species Viral Infections

Volume 33: 1­–9
© The Author(s) 2024
Article reuse guidelines:
in Xenotransplantation: Progress, sagepub.com/journals-permissions
DOI: 10.1177/09636897241226849
https://doi.org/10.1177/09636897241226849

Strategies, and Clinical Outlook journals.sagepub.com/home/cll

Yenong Zhou1 , Shuyu Zhou2, Qian Wang3, and

Bing Zhang1

Abstract
Xenotransplantation holds great promise as a solution to address the critical shortage of organs, but it raises concerns
regarding the potential transmission of porcine viruses to recipients, leading to infections and even zoonotic diseases. Data
used in this review were mainly from literature of Pubmed database. Keywords included xenotransplantation, infection, virus,
and epidemiology. The original articles and critical reviews selected were relevant to this review’s theme. We review the
major viral infections of concern in xenotransplantation, their risk of transmission, diagnosis, treatment, and ways to prevent
infection. Then, we pivot to a comprehensive overview of the current status of xenotransplantation. In addition, we offer our
own insights and recommendations for propelling xenotransplantation forward, transitioning from preclinical experiments to
the critical phase of clinical trials. Viral infections pose considerable safety concerns within xenotransplantation, particularly
with the possibility of emerging or currently unidentified viruses. Clinical trials serve as a crucial platform to progress the
safety standards of xenotransplantation. However, further studies and dedicated efforts are required to effectively translate
findings into practical applications that can improve safety measures in this field.

Keywords
xenotransplantation, infection, virus and epidemiology

Introduction these infections and their pathogenic effects may be even

more pronounced, given the imperative need for immuno-
A persistent worldwide shortage of organs from deceased suppression in xenotransplantation11.
human donors for transplantation plagues patients with end-
stage organ failure1. For instance, a survey by the International
Society for Heart and Lung Transplantation (ISHLT) high- Viruses
lights the stark reality that a vast number of end-stage heart Drawing from experiences in allotransplantation and insights
failure patients eagerly await a heart transplant, with fewer from preclinical models, viral infections loom as our fore-
than 4% fortunate enough to receive one2. Xenotransplantation, most concern, with the potential to even trigger zoonotic
the transfer of living cells, tissues, or organs from genetically transmissions. This concern finds stark confirmation in the
engineered pigs, emerges as a promising alternative to allevi-
ate this organ shortage crisis3–5. In 2022, a historic milestone
1
was achieved at the University of Maryland Medical Center,  epartment of Cardiovascular Surgery, Xijing Hospital, Air Force
D
where the first-ever gene-edited pig heart was successfully Medical University, Xi’an, China
2
Inner Mongolia Autonomous Region Hospital of Traditional Chinese
transplanted into a human recipient, yielding encouraging Medicine, Hohhot, China
data6. This remarkable achievement has significantly bol- 3
Nutriology Department, Qingdao Special Servicemen Recuperation
stered the confidence of scientists in the field. Nevertheless, Center of PLA Navy, Qingdao, China
the successful application of xenografts carries an inherent Submitted: September 24, 2023. Revised: January 2, 2024.
risk—viral infection7. Infections can have dire conse- Accepted: January 3, 2024.
quences, impacting survival rates, exacerbating inflam­
Corresponding Author:
matory responses, and triggering immune rejection in Bing Zhang, Department of Cardiovascular Surgery, Xijing Hospital, Air
allotransplantation8–10. Anticipating the prevalence of infec- Force Medical University, 127 Changle West Road, Xi’an 710032, China.
tions in xenotransplantation, it is crucial to recognize that Email: 15771793132@163.com

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(https://us.sagepub.com/en-us/nam/open-access-at-sage).
2 Cell Transplantation
case of the recipient of the world’s first pig heart xenotrans-
plantation, whose unfortunate demise was suspected to result
from a porcine cytomegalovirus (PCMV) infection12. This
sobering event underscores the inherent perils of viral infec-
tions in xenotransplantation. Following the guidelines out-
lined by the American Society of Transplantation, we focus
our analysis on three key viruses: PCMV, porcine lympho-
tropic herpesvirus (PLHV), and porcine endogenous retrovi-
rus (PERV)13. Our investigation spans a comprehensive
exploration of these viruses, encompassing their epidemiol-
ogy, modes of transmission, monitoring techniques, and
more.
Porcine Cytomegalovirus
PCMV, officially known as suid beta herpesvirus 2 (SuBHV2)
in accordance with the classification by the International
Committee on Taxonomy of Viruses (ICTV), belongs to the
Roseolovirus genus, signifying its place within the Beta her-
pesvirinae subfamily14,15. Analysis of its genome sequence
has revealed a total length of 128,367 base pairs, encompass-
ing 79 predicted open reading frames (ORFs)14. PCMV
exhibits a widespread presence among pig populations
worldwide. For instance, in the Hunan and Sichuan prov-
inces of China, the prevalence of PCMV-positive pigs stands
at 96.4% and 84.4%, respectively16,17. PCMV has been
linked to various ailments in pigs, including pneumonia, rhi-
nitis, small body size, miscarriages in female pigs, and edema
of the heart and other organs18. Notably, PCMV has been
associated with consumptive coagulopathy in a recent
study19. In the context of xenotransplantation, PCMV infec-
tions have proven detrimental, leading to a reduction in graft
survival time. Previous investigations have demonstrated
that the presence of PCMV during porcine heart transplanta-
tion in baboons resulted in a significant decrease in survival
times, with durations dwindling from 33 days to 20 days and
from 195 days to 30 days, respectively20,21. Moreover, in
2022, a groundbreaking xenotransplantation at the University
of Maryland in Baltimore involved a pig heart transplant into
a human patient. This case raised concerns that PCMV may
have contributed to the patient’s unfortunate demise, given
that the virus potentially entered the recipient’s body along
with the transplanted organ12. Similar to other herpesviruses
known for their resilience within host organisms, PCMV can
undergo reactivation in vivo under conditions of stress22. The
study had reported the presence of antibody cross-reactivity
between PCMV and human herpesvirus 6 (HHV-6)23. While
PCMV is unlikely to infect human cells or replicate within
the human body, uncertainties persist regarding its potential
to induce diseases akin to HHV-6, like roseola infantum, or
reduce the survival time of the pig transplant24. These find-
ings underscore the critical significance of PCMV in the con-
text of xenograft survival.
Numerous polymerase chain reaction (PCR) methods are
at our disposal for the detection of PCMV, some of which
yield longer amplicons, enhancing our ability to sequence and
classify the detected PCMVs effectively25. However, it is
important to note that certain PCR methods may occasionally
yield false negatives26. Therefore, there is a need for the adop-
tion of more sensitive PCR techniques. New diagnostic
approaches, such as nested PCR and duplex real-time PCR
systems, have been developed with improved parameters,
significantly bolstering their sensitivity and accuracy25,27. In
addition to PCR-based methods, immunological techniques
for PCMV detection have also seen advancements. Using
recombinant proteins corresponding to the two domains of
PCMV glycoprotein gB as antigens, researchers have
employed Western blot technology to analyze the presence of
PCMV-specific antibodies28. Furthermore, an indirect-block-
ing enzyme-linked immunosorbent assay (ELISA) method
designed to detect the gB epitope has demonstrated impres-
sive specificity at 98% and remarkable sensitivity at 97.8%29.
In terms of the detection timeframe, real-time PCR offers a
distinct advantage, as it facilitates the early detection of
PCMV presence in piglets compared to antibody testing12,26.
Porcine Lymphotropic Herpesvirus
PLHV-1, PLHV-2, and PLHV-3 belong to the gamma her-
pesvirus family and are prevalent among pigs. A survey con-
ducted in a densely populated pig area in Northern Italy
revealed the widespread presence of PLHVs, with preva-
lence rates of 28.97%, 10.79%, and 4.54% for PLHV-1,
PLHV-2, and PLHV-3, respectively. These viruses were not
only detected in various pig tissues but were also associated
with specific clinical conditions30. PLHV confirmed to infect
persistently porcine B cell line L2331,32. While PLHV is gen-
erally benign in its natural host, it can pose a significant
health threat when transmitted to other species, causing
severe diseases33. Surprisingly, no direct link between PLHV
and swine diseases has been established thus far. However,
research has indicated that PLHV-1 can induce posttrans-
plant lymphoproliferative disease (PTLD) in minipigs34,35.
The primary mode of PLHV transmission is horizontal, but
there is also a risk of vertical transmission from parent to
offspring33,36. Currently, no treatments or vaccines are avail-
able for these three PLHVs.
Even strategies like early weaning and colostrum feeding
have proven ineffective in eliminating PLHV37. Although
practices such as cesarean section and barrier maintenance
have reduced PLHV infection rates from 80% to as low as
3% to 12.8%, they are not foolproof38, necessitating the
development of sensitive detection methods and novel
approaches for PLHV elimination.
PLHV presence has been systematically examined and
quantified using PCR assays, with a particular focus on spe-
cific real-time PCR techniques30,39. These assays have strate-
gically employed primers and probes targeting key regions
within the DNA polymerase gene and the gene responsible
for encoding glycoprotein B33. In addition to PCR-based
Zhou et al
approaches, the detection of antibody responses to recombi-
nant glycoprotein B of PLHV-1 has been explored using both
Western blot assays and ELISA methods40,41. These compre-
hensive techniques have significantly contributed to our
understanding of PLHV dynamics and its impact on host
organisms.
Porcine Endogenous Retroviruses
Numerous viruses have been identified in both pigs and
humans, with PERVs standing out as particularly noteworthy.
PERVs are known to be transmissible from pig cells to human
cells, making them a subject of significant concern42. There
are three types of PERVs: PERV-A and PERV-B, which are
integrated into the genome of all pigs, and PERV-C, which is
present in most, but not all, pigs. While PERV-A and PERV-B
are polytropic and capable of infecting various human cell
types, PERV-C is ecotropic and exclusively infects porcine
cells. Intriguingly, PERV-A and PERV-C can combine to form
PERV-A/C recombinants. These recombinants exhibit a simi-
lar ability to infect human cells as PERV-A but have been
shown to have a higher replication rate than PERV-A alone43.
PCR amplification technology has proven effective in detect-
ing PERVs in the genomes of four major miniature pig breeds
in China44. Over time, PERVs have been observed to remain
active within their host organisms, with the number of copies
increasing 45. Notably, PERVs carry the potential to induce
various health issues, including the development of tumors,
leukemias, and neurodegenerative diseases46,47. Recent
research has also revealed that PERVs can stimulate the pro-
duction of the pro-inflammatory chemokine CXCL10 in
human monocytes and monocyte-derived primary cells,
thereby enhancing the innate immune response within the
host48. To date, no transmission of PERVs has been observed
in clinical trials or preclinical trials49,50. There are several pos-
sible explanations for this absence of transmission. It is con-
ceivable that PERVs are not released from the graft, or they
may be suppressed by intracellular restriction factors and the
innate immune response within the recipient51.
The patients selected for the clinical porcine islet xeno-
transplantation were nonimmunocompromised individuals
with diabetes. This characteristic might have contributed to
preventing the spread of PERV50. It has been demonstrated
that PERVs can infect human cells52,53 and integrate into
human genome in cell culture54. This raises concerns regard-
ing the possibility of PERVs being transmitted through a
transplant patient and potentially becoming infectious to
individuals in contact with that patient, posing a potential
source for a widespread epidemic13,55. In addition, microchi-
merism, which can be challenging to distinguish from PERV
infection, has been reported in the initial human xenograft
trials and in most preclinical trials involving nonhuman pri-
mates56,57. These findings underscore the critical importance
of continuous monitoring and accurate identification of
PERVs in xenotransplantation research.
3
Given the significant variation in PERV copy numbers
across different pig breeds, employing PCR to quantify
PERV copy numbers in various pig breeds becomes invalu-
able for selecting the most suitable candidates for xenotrans-
plantation44,58. Among the available techniques, droplet
digital PCR (ddPCR) stands out as the most commonly used
method44. Furthermore, the presence of PERV particles can
be visually confirmed through electron microscopy, provid-
ing an additional means of detection59. An innovative
approach proposed in a study is the immunoperoxidase assay
(IPA), designed to detect viral proteins in infected cells and
antibodies against PERV in the serum of the infected host60.
These diverse methodologies offer essential tools for assess-
ing and managing the risk associated with PERVs in xeno-
transplantation settings.
Elimination of Porcine Viruses
Control of Pig Donors
Selection of pig herds. Notably, not all pigs harbor specific
pathogens, underscoring the critical need to identify and
assess the pathogens present in pigs for the purpose of select-
ing suitable donors in xenotransplantation endeavors. Estab-
lishing an “exclusion list” serves as a fundamental foundation
for the screening of potential pig donors, and it necessitates
periodic revision in response to evolving global swine infec-
tion epidemiology and evolving clinical experience7. As an
illustrative example, the selection of pigs with diminished
expression of PERV-A and PERV-B or those lacking PERV-
C can be a proactive measure to prevent the binding of
PERV-A and PERV-C61. Such negative pigs represent viable
candidates for direct use in xenotransplantation procedures,
thus mitigating the risk associated with PERV transmission.
Medicines. In situations where negative pigs are not readily
available, an alternative approach involves the selection of
pigs with low viral loads, followed by treatment using vac-
cination or antiviral drugs62. Specifically, PCMV can be
effectively inhibited by various antiviral drugs, including
ganciclovir (a synthetic analogue of 20-deoxy-guanosine),
cidofovir (employed in the treatment of HCMV-induced reti-
nitis in humans), foscarnet (functioning as a structural mimic
of the anion pyrophosphate, selectively inhibiting the pyro-
phosphate binding site on viral DNA polymerase), acyclovir
(a guanosine analogue), and valaciclovir (a prodrug of acy-
clovir)63. Studies have demonstrated that both ganciclovir
and cidofovir exhibit superior efficacy in inhibiting PCMV
replication when compared to foscarnet and acyclovir64. It is
worth noting that as of now, there have been no reports of
successful anti-PCMV vaccines. Conversely, for PERV,
inhibitors targeting viral reverse transcriptase and integrase
have shown effectiveness. Among these, azidothymidine
(AZT) stands out as the most potent inhibitor of reverse tran-
scriptase, while integrase inhibitors have demonstrated
4 Cell Transplantation
significant efficacy against PERV65–67. Effective neutralizing
antibodies can be induced when different animal species are
immunized with PERV’s recombinant transmembrane enve-
lope protein p15E and envelope glycoprotein gB7068. These
antibodies recognize an epitope in the p15E fusion peptide
proximal region (FPPR), termed E1, and an epitope in the
membrane proximal external region (MPER), termed E269,70.
Nonetheless, it is imperative to conduct extensive analyses
using diverse animal models to comprehensively evaluate
the impact and effectiveness of PERV vaccines.
Cesarean delivery, colostrum deprivation, and early weaning.
When negative animals are not available and vaccines or
antiviral drugs prove ineffective against viruses with low
viral loads, there are alternative methods for virus elimina-
tion. Some viruses are transmitted vertically, highlighting the
importance of preventing the vertical transmission of viruses
from sows to piglets. Studies have confirmed that practices
such as early weaning, colostrum deprivation, and cesarean
delivery can effectively eliminate the PCMV virus in
pigs37,71. However, it is important to note that these methods
do not result in complete clearance of the PLHV virus, as
experimental results have indicated the continued presence
of PLHV viral DNA in early weaned pigs36,37.
Biosecurity of pig farms. Once the virus is successfully elimi-
nated, it is imperative to maintain the animal in strict isolation
to prevent de novo infections or re-entry of the virus. For
instance, certain viruses like Hepatitis E virus (HEV) can per-
sist in drinking water, feces, and buildings72,73. Therefore,
donor pigs should be raised and kept in biosecure facilities
that isolate them from the external environment. These facili-
ties should provide filtered air, sterilized water, and irradiated
food certified to be free of any mammalian protein. All mate-
rials entering these facilities must undergo autoclaving, and
personnel should enter through showers and wear specialized
clothing74. Only through rigorous supervision and control of
all aspects can donor pigs attain the status of designated
pathogen-free (DPF).
RNA Interference
RNA interference (RNAi) represents a swift and efficient
method for gene expression suppression. This process
involves two primary steps: initially, double-stranded RNA
(dsRNA) is cleaved into small interfering RNAs (siRNAs)
through the activity of bacterial ribonuclease III (RNase
III)-like enzymes. Subsequently, these siRNAs associate
with the RNA-induced silencing complex (RISC) and facili-
tate the degradation of target messenger ribonucleic acid
(mRNA)26,75. In the context of PERV, its expression can be
significantly reduced through the use of siRNA molecules
that correspond to various segments of viral genes such as
gag, pol, and env. The most potent sequences are carefully
selected and expressed as short hairpin RNA (shRNA) using
the polymerase III vector system. This approach enables the
continuous inhibition of PERV replication76–78. PERV-
specific shRNA has demonstrated the ability to reduce
PERV expression both in vitro (within PERV-producing
human cells) and in vivo (in transgenic pigs engineered to
express PERV-specific shRNA)79. Such interventions con-
tribute to enhancing the safety of xenotransplantation proce-
dures. In addition, some research findings suggest that
certain immunosuppressant agents can reduce PERV expres-
sion in vitro without synergistic or antagonistic effects on
RNAi-mediated PERV suppression80.
Gene Editing
Gene editing stands out as an ideal approach for inactivating
viruses embedded within the genome. Technologies such as
Zinc finger nuclease (ZFN) or clustered regularly interspaced
short palindromic repeats–associated RNA-guided DNA
endonuclease Cas9 (CRISPR/Cas9) can be harnessed to deac-
tivate the PERV gene81. ZFN technology, designed to target
multiple proviral sequences of PERV, exhibited high expres-
sion within the nucleus and effective interactions. However,
its implementation induced extreme cytotoxicity in PERV-
infected cells82. In contrast, CRISPR/Cas9 has shown greater
success. In 2015, Yang and her research team employed
CRISPR/Cas9 to eliminate 62 PERV copies in porcine kidney
epithelial cell line (PK15), resulting in a reduction of PERV
transmission to humans by more than 1,000 times53.
Subsequently, in 2017, Yang and her team used CRISPR-
Cas9 to inactivate all PERV instances in pig primary cell lines
and generated PERV-inactivated pigs through somatic cell
nuclear transfer42. Furthermore, in 2021, the team demon-
strated that CRISPR-Cas9 and transposon technology could
be used to engineer pigs with inactivated PERV, eliminating
three xenoantigens and enabling the expression of nine human
transgenes. This advancement enhanced the pig’s immune
compatibility and coagulation compatibility with humans,
successfully addressing the issue of PERV safety in xeno-
transplantation83. However, a notable challenge persists in the
form of a highly sensitive method for measuring PERV copy
numbers and expression levels45,53,82. Recent studies have
explored the use of cytosine base editors (CBEs), which do
not induce DNA double-strand breaks (DSBs) like CRISPR-
Cas9, offering a means to edit PERV with reduced cytotoxic
effects. In addition, the plasmids employed for PERV editing
are not integrated into the host genome, and they do not
impact the karyotype of modified cells84.
Current Status and Prospects for
Clinical Trails
Over the past decade, nonhuman primate models have wit-
nessed remarkable advancements, thanks to the emergence
of gene editing technologies and refined immunosuppres-
sive regimens. These innovations have propelled research to
new heights, as evidenced by documented achievements in
xenotransplantation outcomes. Researchers have reported
Zhou et al
instances of remarkable survival in pig-baboon heterotopic
heart xenografts, with some cases extending up to an impres-
sive 945 days, and in orthotopic xenografts, survival periods
of up to 195 days have been achieved85–87. In a groundbreak-
ing development, the University of Maryland School of
Medicine disclosed the successful transplantation of gene-
edited pig hearts into baboons. These modified pig hearts,
with six genes edited, exhibited remarkable resilience,
surviving in baboons for a remarkable 264 days with the
assistance of life support88. Furthermore, in a significant
milestone in 2022, scientists achieved the transplantation of
gene-edited pig hearts into two recently deceased humans.
Notably, there were no early signs of rejection observed in
either transplanted organ. The transplanted hearts func-
tioned normally with the application of standard post­
transplant medications, obviating the need for additional
mechanical support89. These groundbreaking successes
underscore the promising prospects of xenotransplantation
as a viable solution to address the critical shortage of human
donor organs. The successes in kidney xenotransplantation
have also been nothing short of impressive, with the longest
recorded survival period extending to an astounding 499
days90. Notably, in 2021, several scientific research teams
achieved significant milestones by transplanting gene-
edited pig kidneys into two brain-dead human recipients.
Remarkably, no instances of hyperacute rejection were
observed in these groundbreaking procedures91,92. In addi-
tion, substantial strides have been made in the field of liver
xenotransplantation. In a noteworthy development in 2020,
13 gene-edited pig-rhesus monkeys demonstrated remark-
able resilience, surviving for 26 days following heterotopic
auxiliary liver transplantation93. Building on this progress,
in 2023, a gene-edited pig-macaque orthotopic auxiliary
liver transplant achieved a survival period of 34 days,
marking another significant advancement in the field94. In
our center, we successfully conducted multiorgan xeno-
transplantation procedures in both 2020 and 2022, marking
significant milestones in the field of xenotransplantation95,96.
Notably, in 2022, we achieved a remarkable feat by trans-
planting three organs (liver, kidney, and heart) and three tis-
sues (cornea, skin, and bones) from a 6-gene edited pig into
four rhesus monkeys. In these groundbreaking procedures,
the heterotopic heart transplant recipients exhibited a sur-
vival period of 20 days, while the monkey receiving a com-
bined liver and kidney transplant survived for 14 days96.
While the successful outcomes of preclinical experiments
in recent years have fueled optimism about the progression
of xenotransplantation to clinical applications, it is important
to note that the Food and Drug Administration (FDA) has not
yet granted approval for clinical trials. The world’s first pig
heart transplant was conducted under the FDA’s “compas-
sionate use” provision, which allows for experimental treat-
ments when a patient is facing a serious or life-threatening
medical condition6. Using deceased models for xenotrans-
plantation research also poses certain limitations. Studies
show hearts procured after brain death manifest distinct
5
pathological changes. The adverse effects of brain death on
myocardial function, marked by substantial anaerobic meta-
bolic and hemodynamic decline, trigger a catecholamine
storm resulting in heightened tachycardia and hypertension.
This escalation drives increased cardiac output and myocar-
dial oxygen consumption, worsening underlying myocardial
ischemia, and significantly elevating the risk of postopera-
tive transplant failure97–100. But xenotransplantation studies
from recently deceased donors are critical to gathering the
additional human data needed to advance the field. Several
crucial steps must be completed before FDA approval can be
obtained, including the testing of a clinical immunosuppres-
sion model, ensuring the genetic modifications of xenografts
are appropriate, and establishing a robust viral surveillance
protocol with confirmation of biocompatibility101–104. Several
institutions have announced their intentions to initiate clini-
cal trials in kidney xenotransplantation, with a phase I clini-
cal trial of gene-edited pig-human kidney transplantation
registered in 2023, pending U.S. FDA authorization105.
Despite the substantial progress made, the absolute risk of
infection in xenotransplantation remains uncertain. Early clin-
ical trials will provide valuable insights into the most suitable
monitoring and prophylaxis strategies for xenotransplantation.
Given the immunosuppressed state of organ recipients, the
anticipation of infections is crucial. Conducting routine pre-
transplant screenings for recipients will help identify latent
infections that necessitate ongoing surveillance or the imple-
mentation of prophylactic therapies. Screening source animals
for latent and active infections using available assays can help
restrict donor-derived infections to a certain extent. Regular
monitoring following FDA and other relevant guidance docu-
ments involves employing microbe-specific assays. In addi-
tion, the implementation of advanced unbiased metagenomic
sequencing methods can aid in surveillance for both known
and unknown organisms106,107. Advancements in microbiol-
ogy, such as quantitative molecular assays for viruses and
unbiased metagenomic sequencing, enable the screening and
monitoring of recipients and donors for infections, even in the
absence of symptoms. But these methods have not yet been
validated or approved for clinical use and are known to incur
high costs108. Blood samples collected from recipients and
contacts can be systematically archived at standard intervals.
This archival practice serves the purpose of facilitating future
epidemiological studies or advancements in unbiased metage-
nomic sequencing techniques. Xenotransplantation recipients
displaying signs of infection, such as fever, hypotension, or
graft dysfunction, may undergo various diagnostic procedures.
These include blood, urine, and/or sputum cultures, alongside
relevant radiological examinations and invasive diagnostics
involving microbiological and histopathological analyses109.
Implementing stringent infection control measures is crucial
throughout this process. We believe that as clinical data con-
tinue to emerge, regulatory, and control guidance on infection
will evolve accordingly.
Based on our experiences, we offer the following recom-
mendations for future clinical trials: First, involve virologists
6 Cell Transplantation
in the research design phase to provide valuable insights62.
Second, given the presence of numerous new or unfamiliar
viruses in donor animals, the development of more sensitive
detection and elimination methods is imperative26. Third,
considering that the use of immunosuppressants in xenograft
recipients can exacerbate infection symptoms, it is essential to
assess and optimize the recipient’s condition prior to surgery.
Finally, implementing meticulous infection control measures
tailored to various groups such as xenotransplant recipients,
healthcare workers, contacts, and others is essential.
Conclusions
Recent discoveries have underscored the paramount impor-
tance of viral safety in ensuring the success of xenotrans-
plantation. In recent years, significant strides have been
made in developing highly sensitive and specific methods
for detecting swine viruses, effectively eliminating the
majority of known viral threats. Nevertheless, the ongoing
emergence of new and latent viruses poses an ongoing chal-
lenge to the safety of xenotransplantation, as these viruses
carry the potential to infect humans or even trigger fresh out-
breaks of disease in pig populations. Looking ahead, our ulti-
mate aspiration is to comprehensively address and resolve
the issue of microbiological safety in xenotransplantation.
This ambitious goal will require ongoing vigilance, research,
and the continuous development of cutting-edge strategies to
safeguard the health of both recipients and donor animals.
Authors’ Contributions
YZ, SZ, and QW worked together to supply a dynamic perspective
of xenotransplantation in this review article. BZ provided critical
feedback and revised the article. YZ, SZ, and QW contributed
equally to this work.
Ethical Approval
This study was approved by our institutional review board.
Statement of Human and Animal Rights
This article does not contain any studies with human or animal
subjects.
Statement of Informed Consent
There are no human subjects in this article and informed consent is
not applicable.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was supported by grants from the National Natural Science
Foundation of China (grant no. 82000227).
ORCID iD
Yenong Zhou https://orcid.org/0009-0006-5727-301X
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