CpG-depleted adeno-associated virus vectors evade immune detection
Open accessAbstract
Due to their efficient transduction potential, adeno-associated virus (AAV) vectors are leading candidates for gene therapy in skeletal muscle diseases. However, immune responses toward the vector or transgene product have been observed in preclinical and clinical studies. TLR9 has been implicated in promoting AAV-directed immune responses, but vectors have not been developed to circumvent this barrier. To assess the requirement of TLR9 in promoting immunity toward AAV-associated antigens following skeletal muscle gene transfer in mice, we compared immunological responses in WT and Tlr9-deficient mice that received an AAV vector with an immunogenic capsid, AAVrh32.33. In Tlr9-deficient mice, IFN-γ T cell responses toward capsid and transgene antigen were suppressed, resulting in minimal cellular infiltrate and stable transgene expression in target muscles. These findings suggest that AAV-directed immune responses may be circumvented by depleting the ligand for TLR9 (CpG sequences) from the vector genome. Indeed, we found that CpG-depleted AAVrh32.33 vectors could establish persistent transgene expression, evade immunity, and minimize infiltration of effector cells. Thus, CpG-depleted AAV vectors could improve outcome of clinical trials of gene therapy for skeletal muscle disease.
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The innate response to self-complementary AAV in mice required TLR9/MyD88.
“We confirmed with Tlr9−/− and Myd88−/− mice that the innate immune response to self-complementary AAV was indeed dependent on the TLR9/MyD88 pathway (Fig. 1D and 1E), as previously shown in the literature (15–17).”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [17]
The Results (page unavailable) show that Tlr9-deficient mice had a reduced innate cytokine and chemokine response to AAVrh32.33. The Introduction and Discussion (pages unavailable) connect TLR9 to self-complementary AAV and report TLR9/MyD88-dependent recognition of AAV2, but they do not establish that the innate response to self-complementary AAV in mice required both TLR9 and MyD88. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCD8+ T cell responses against rh32.33 capsid required MyD88 in mice.
“We confirmed with Myd88−/− mice that development of CD8+ T cell responses against rh32.33 capsid depended on MyD88(15, 17) (Fig. 2A, middle panel).”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [17]
The Results and Figure 2 caption (page unavailable) report reduced capsid-reactive CD8+ T-cell responses in Tlr9-deficient mice. They do not report an experiment in Myd88-deficient mice or establish MyD88 dependence for the rh32.33 capsid response; the Discussion mentions MyD88 only when describing another study’s broader AAV findings. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTLR9 and TLR2 have been demonstrated to detect AAV genomes and capsids, respectively.
“Microglia are the chief resident immune cells of the retina and are capable of inducing pro-inflammatory cytokine expression through TLR9- and TLR2-mediated responses,41 which have been demonstrated to detect AAV genomes and capsids, respectively.42, 43, 44”
From Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina (2021) · cites this paper as [43]
The Discussion states that TLR9 can recognize unmethylated CpG motifs in AAV expression cassettes, supporting the AAV-genome part of the claim. The passages found do not say that TLR2 detects AAV capsids; a search for TLR2 and capsid recognition found no supporting passage. Section page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe AAV vector genome triggers TLR9, a receptor that detects foreign DNA.
“the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [17]
Reduction of CpG islands in rAAV vectors increased transgene expression and reduced TLR9-mediated innate immune detection.
“Recent studies indicated that the reduction of CpG islands in rAAV vectors increased transgene expression and reduced TLR9-mediated innate immune detection [46,47].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [47]
Interpreting the effect of CpG depletion on transcription alone could be complicated by innate immune pathways such as TLR9.
“but interpreting this effect on transcription alone could be complicated by innate immune pathways such as TLR9.41,42”
From Adeno-Associated Virus Serotype-Specific Inverted Terminal Repeat Sequence Role in Vector Transgene Expression (2020) · cites this paper as [42]
Immune responses mounted by IFN induction resulted in a loss of transgene expression delivered by AAV in mice.
“Immune responses mounted by IFN induction resulted in a loss of transgene expression delivered by AAV in mice [34, 40].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [40]
Deletion of CpG dinucleotides in the AAVrh32.33 vector resulted in stable transgene expression and reduced infiltration of effector T cells.
“Deletion of the CpG dinucleotides exhibited stable transgene expression with reduced infiltration of effector T cells (Teff) when packaged in the immunogenic AAVrh32.33 vector [40].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [40]
The difference in responses would likely be more pronounced if more immunogenic DNA were used, for instance CpG-rich or self-complementary.
“It is likely that the difference would be more pronounced if more immunogenic DNA would be used, for instance CpG-rich or self-complementary (65–69).”
From Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood (2022) · cites this paper as [67]
Use of a CpG depleted expression cassette ablated CTL responses to the β-galactosidase transgene upon AAV gene transfer in mice.
“Additionally, Faust et al. demonstrated that use of a CpG depleted expression cassette ablated CTL responses to the β-galactosidase transgene upon AAV gene transfer in mice (23)”
From Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy (2021) · cites this paper as [23]
In a proof-of-principle study, absence of CpG sequences in the lacZ reporter transgene minimized CD8+ T cell infiltration and prolonged reporter transgene expression after AAV gene transfer in mice.
“In a proof-of-principle study, others have shown that absence of CpG sequences in the lacZ reporter transgene minimized CD8+ T cell infiltration and prolonged expression of a reporter transgene upon AAV gene transfer in mice (23).”
From Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy (2021) · cites this paper as [23]
Previous animal studies have shown immune-activating effects of CpG motifs in AAV.
“Previous animal studies have shown the immune-activating effects of CpG motifs in AAV (23, 150, 151).”
From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [151]
The TLR9-MyD88 pathway is an important component of innate immune sensing of AAV, driving early innate inflammation and IFN I production in tissue, promoting CD8+ T cell activation, and modifying antibody responses.
“Since this initial discovery, the TLR9-MyD88 pathway has been consolidated as an important component of innate immune sensing of AAV, driving early innate inflammation and IFN I production in the tissue, promoting CD8 + T cell activation, and modifying antibody responses.”
From Innate immune sensing of adeno-associated virus vectors (2024) · cites this paper as [24]
Preclinical and clinical studies have shown that AAV-associated cellular responses to both capsid and transgene product are inversely related to the number of CpG motifs.
“Indeed, preclinical and clinical studies have demonstrated that AAV-associated cellular responses to both AAV capsid and transgene product are inversely related to the number of CpG motifs, thereby further consolidating the role of TLR9 innate sensing of AAV.”
From Innate immune sensing of adeno-associated virus vectors (2024) · cites this paper as [24]
Development of CpG-depleted expression cassettes has become a major focus for clinical applications, while incorporation of TLR9 inhibitory sequences has been proposed as an alternative strategy.
“To circumvent recognition of the AAV genome by TLR9, development of CpG-depleted expression cassettes has become a major focus for clinical applications, while incorporation of TLR9 inhibitory sequences has been proposed as an alternative strategy.28,29,30”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [30]
Cross-priming of capsid-specific CD8+ T cells in mice depends on the TLR9>IFN-I pathway, and CpG depletion of vector genomes has been useful in reducing such responses in mice and humans.
“Cross-priming of capsid-specific CD8+ T cells in mice depends on the TLR9>IFN-I pathway (likely reflecting activation in lymphoid organs), and CpG depletion of vector genomes has been useful in reducing such responses in mice and humans.30,41,70”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [30]
Mouse muscle transduced with rAAVrh32.33 carrying a CpG-negative genome showed stable transgene expression.
“Mouse muscle transduced with rAAVrh32.33carrying the CpG negative genome had reduced CD4+, CD8+, and MHC II expression compared to the unmodified vector and showed stable transgene expression.”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [118]
Mouse muscle transduced with rAAVrh32.33 carrying a CpG-negative genome had reduced CD4+, CD8+, and MHC II expression compared to unmodified vector.
“Mouse muscle transduced with rAAVrh32.33carrying the CpG negative genome had reduced CD4+, CD8+, and MHC II expression compared to the unmodified vector and showed stable transgene expression.”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [118]
The immunogenicity of rAAVrh32.33 could be mitigated by the state of the genome.
“They found that the immunogenicity could be mitigated by the state of the genome.”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [118]
In Tlr9-deficient mice that received an immunogenic AAV variant (AAVrh32.33), IFN-γ T cell responses toward capsid and transgene were suppressed, resulting in minimal cellular infiltrate and stable transgene expression.
“In Tlr9-deficient mice, IFN-γ T cell responses toward capsid and transgene were suppressed, resulting in a minimal cellular infiltrate and stable transgene expression [94].”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [94]
The CpG-TLR9 interaction was demonstrated by inducing an immune response in WT mice by an immunogenic AAV variant, and this response was attenuated in TLR9-/- mice.
“This CpG-TLR9 interaction was demonstrated by inducing an immune response in WT mice by an immunogenic AAV variant, and this response was attenuated in TLR9-/-mice [94].”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [94]
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- Authors
- Faust, S. M., Bell, P., Cutler, B. J., Ashley, S. N., Zhu, Y., Rabinowitz, J. E., & Wilson, J. M.
- Affiliations
- University of Pennsylvania (US)
- Temple University (US)
- Corresponding author
- Wilson, James M.
- Venue
- Journal of Clinical Investigation
- Published
- 2013-06-17
- Volume
- 123
- Issue
- 7
- Pages
- 2994-3001
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3696560
- OpenAlex
- W2095942414
- Cited by
- 254
- References
- 27
- Citations by year
- 2026: 20 · 2025: 26 · 2024: 25 · 2023: 30 · 2022: 21 · 2021: 29 · 2020: 21 · 2019: 18 · 2018: 5 · 2017: 19 · 2016: 9 · 2015: 17 · 2014: 10 · 2013: 4
- FWCI
- 8.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL091096, T32HL007954)
- National Institute of Allergy and Infectious Diseases (T32AI007324)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- adeno-associated virus vectors, CpG depletion, TLR9, immune evasion, TLR9-deficient mice, IFN-γ T cell response, transgene expression
- MeSH terms
- Dependovirus, Animals, Capsid, DNA, Viral, Genetic Vectors, HeLa Cells, Humans, Mice, Inbred C57BL, Transduction, Genetic, Genetic Therapy, CD4-Positive T-Lymphocytes, Mice, Knockout, CD8-Positive T-Lymphocytes, Muscle, Skeletal, CpG Islands, Chemokines, Transgenes, Toll-Like Receptor 9, Mice, Adaptive Immunity, Immune Evasion
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