Wikipedia

Viral vector

Viral vectors are tools used to deliver genetic material into cells. This process can be performed inside a living organism or in cell culture. They have widespread applications for use in basic research, therapies, and vaccines.

A 2021 U.S. Centers for Disease Control and Prevention poster on the COVID-19 viral vector vaccines

Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect. Delivery of genes or other genetic material by a vector is termed transduction and the infected cells are described as transduced.

Molecular biologists first harnessed this machinery in the 1970s. In 1972, Paul Berg demonstarted the first viral vector, a modified SV40 virus. However, recombinant DNA research was temporarily suspended following the Asilomar Conference. Following the creation of formal policies by the National Institutes of Health, work proceeded. The 1980s saw both the first recombinant viral vector gene therapy and the first viral vector vaccine. Although the 1990s saw significant advances in viral vector design and genetics, viral vector clinical trials had a number of setbacks, culminating in the death of patient Jesse Gelsinger.

In addition to their use in molecular biology research, viral vectors are used for gene therapy and the development of vaccines. Vectors can either integrate into a cell's genome or transiently express a gene with non-integrative vectors.

Characteristics edit

 
Structure of a virus, specifically the hepatitis C virus

Viruses, infectious agents composed of a protein coat that encloses a genome, are the most numerous biological entities on Earth.[1][2] As they cannot replicate independently, they must infect cells and hijack the host's replication machinery in order to produce copies of themselves.[2] Viruses do this by inserting their genome—which can be DNA or RNA, either single-stranded or double-stranded—into the host.[3] Some viruses may integrate their genome directly into that of the host in the form of a provirus.[4]

This ability to transfer foreign genetic material has been exploited by genetic engineers to create viral vectors, which can transduce the desired transgene into a target cell.[2] Viral vectors consists of three components:[5][6]

  1. A protein capsid and sometimes an envelope that encapsidates the genetic payload. This determines the range of cell types that the vector infects, termed its tropism.
  2. A genetic payload: the transgene that results in the desired effect when expressed.
  3. A "regulatory cassette" that controls transgene expression, whether integrated into a host chromosome or as an episome. The casette comprises an enhancer, a promoter, and auxiliary elements.

Applications edit

 
Mice transduced by a lentiviral vector fluoresce under UV-illumination[7]

Basic research edit

Viral vectors are routinely used in a basic research setting, and can introduce genes encoding, for instance, complementary DNA, short hairpin RNA, and CRISPR/Cas9 for gene editing.[8] Viral vectors can be used for cellular reprogramming, for instance, inducing pluripotent stem cells or differentiating adult somatic cells into different cell types.[9] They are also frequently used to create transgenic mice and rats for experiments.[10] Viral vectors can be used for in vivo imaging, via the introduction of a reporter gene. Further, transduction of stem cells can allow for the tracking of cell lineage during development.[9]

Gene therapy edit

Main article: Gene therapy
 
Viral vector transduction of a cell for gene therapy

Gene therapy is a technique for correcting defective genes responsible for genetic disorders via the introduction of a therapeutic transgene. Gene therapy by viral vectors can be performed by in vivo delivery by directly administering the vector to the patient, or ex vivo by extracting cell from the patient, transducing them, and then reintroducing the modified cells into the patient.[11]

There are four broad categories of gene therapy: gene replacement, gene silencing, gene addition, or gene editing.[11][12] Relative to other non-integrative gene therapy approaches, transgenes introduced by viral vectors offer multi-year long expression.[13]

Vaccines edit

Main article: Viral vector vaccine
 
Shipments of the Russian-made Sputnik V COVID-19 vaccine, an adenoviral vector, are seen in Guatemala in 2021.

For use as vaccine platforms, viral vectors can be engineered to carry a specific antigen associated with an infectious disease or a tumor antigen.[14][15] Conventional vaccines are not suitable for protection against some pathogens due to unique immune evasion strategies and differences in pathogenesis.[16] Viral vector-based vaccines, for instance, could eventually offer immunity against HIV-1 and malaria.[17]

While traditional subunit vaccines elicit a humoral response,[18] viral vectors allow for intracellular antigen expression that activates MHC pathways via both direct and crosspresentation pathways. This induces a robust adaptive immune response.[19][20] Viral vector vaccines also have intrinsic adjuvant properties via innate immune system activation and the expression of pathogen-associated molecular patterns (PAMPs), negating the need for any additional adjuvant.[21][14] In addition to a more robust immune response in comparison to other vaccine types, viral vectors offer efficient gene transduction and can target specific cell types.[18] Pre-existing immunity to the virus used as the vector, however, can be a significant issue.[17]

Prior to 2020, viral vectors were widely administered in but confined to veterinary medicine.[21] In the global response to the COVID-19 pandemic, viral vector vaccines played a fundamental role and were administered to billions of people, particularly in low and middle-income nations.[22]

Types edit

Retroviruses edit

Main article: Retroviruses

Retroviruses—enveloped RNA viruses—are popular viral vector platforms due to their ability to integrate genetic material into the host genome.[2] Retroviral vectors comprise two general classes: gamma retroviral and lentiviral vectors. The fundamental difference between the two are that gamma retroviral vectors can only infect dividing cells, while lentiviral vectors can infect both dividing and resting cells.[23] Notably, retroviral genomes are composed of single-stranded RNA and must be converted to proviral double-stranded DNA, a process known as reverse transcription—before it is integrated into the host genome via viral proteins like integrase.[24]

The most commonly used gammaretroviral vector is a modified Moloney murine leukemia virus (MMLV), able to transduce various mammalian cell types. MMLV vectors have been associated with some cases of carcinogenesis.[25] Gammaretroviral vectors have been successfully applied to ex vivo hematopoietic stem cell to treat multiple genetic diseases.[26]

Lentiviral vectors edit

Further information: Lentiviral vector in gene therapy
 
Packaging and transduction by a lentiviral vector.

Most lentiviral vectors are derived from human immunodeficiency virus type 1 (HIV-1), although modified simian immunodeficiency virus (SIV), the feline immunodeficiency virus (FIV), and the equine infectious anaemia virus (EIAV) have also been utilized.[23] As all functional genes are removed or otherwise mutated, the vectors are not cytopathic and can be engineered to be non-integrative.[27]

Lentiviral vectors are able to carry up to 10 kb of foreign genetic material, although 3-4 kb was reported as optimal as of 2023.[23][27] Relative to other viral vectors, lentiviral vectors possess the greatest transduction capacity, due to the formation of a three-stranded "DNA flap" during retro-transcription of the single-strand lentiviral RNA to DNA within the host.[27]

Although largely largely non-inflammatory,[28] lentiviral vectors can induce robust adaptive immune responses by memory-type cytotoxic T cells and T helper cells.[29] This is largely due to lentiviral vectors' high tropism for dendritic cells, which activate T cells.[29] However, they can infect all types of antigen-presenting cells.[30] Moreover, as they are the only retroviral vectors able to efficiently transduce both dividing and non-dividing cells, make them the most promising vaccine platforms.[30] They have also been trialed as vaccines against cancer.[31]

Lentiviral vectors have been used as in vivo therapies, such as directly treating genetic diseases like haemophilia B, and for ex vivo therapies like the the transduction of immune cells in CAR T cell therapy.[23] In 2017, the FDA approved tisagenlecleucel, a lentiviral vector, for acute lymphoblastic leukaemia.[32]

Adenoviruses edit

Main article: Adenovirus
 
Adenoviruses (visualized via electron micrograph at left and right and depicted graphically at center) are commonly used as viral vector platforms. Note the icosahedron capsid structure.

Adenoviruses are double-stranded DNA viruses belonging to the family Adenoviridae.[33][34] Their relatively large genomes, of approximately 30-45 kb, make them ideal candidates for genetic delivery;[33] newer adenoviral vectors can carry up to 37 kb of foreign genetic material.[35] Adenoviral vectors display high transduction efficiency and transgene expression, and can infect both dividing and non-dividing cells.[36]

The adenoviral capsid, an icosahedron, features a fibre "knob" at each of its 12 vertices. These fibre proteins mediate cell entry—greatly affecting efficacy and contribute to its broad tropism—notably via coxsackie–adenovirus receptors (CARs).[33][36] Adenoviral vectors can induce robust innate and adaptive immune responses.[37] Its strong immunogenicity is particularly due to the transduction of dendritic cells (DC), upregulating the expression of both MHC I and II molecules and activating the DCs.[38] They have a strong adjuvant effect, as they display several pathogen-associated molecular patterns.[37] One disadvantage is that pre-existing immunity to adenovirus serotypes is common, reducing efficacy.[36][39] The use of chimpanzee adenoviruses may circumvent this issue.[40]

While the activation of both innate and adaptive immune responses is an obstacle for many therapeutic applications, it makes adenenoviral vectors an ideal vaccine platform.[34] The global response to the COVID-19 pandemic saw the development and use of multiple adenoviral vector vaccines, including Sputnik V, the Oxford–AstraZeneca vaccine and the Janssen vaccine.[41]

Adeno-associated viruses edit

Main article: Adeno-associated virus
 
Lentivirus (upper panel) – To produce lentiviruses with the gene of interest as the lentiviral DNA construct, first transfect cells with a packaging plasmid and the envelope vector (VSVG). Adeno Associated Virus (AAV) (lower panel) – To produce AAV, package a gene of interest into the AAV-ITR vector and transfect cells with a Helper vector and the Rep/Cap DNA integration vector.

Adeno-associated viruses (AAVs) are relatively small single-stranded DNA viruses belonging to Parvoviridae and, like lentiviral vectors, AAVs can infect both dividing and non-dividing cells.[42] AAVs, however, require the presence of a "helper virus" such as an adenovirus or herpes simplex virus to replicate within the host, although it can do so independently if cellular stress is induced or the helper virus genes are carried by the vector.[43]

AAVs insert themselves into a specific site in the host genome, particularly AAVS1 on chromosome 19 in humans. However, recombinant AAVs have been designed that do not integrate. These are instead stored as episomes that, in non-dividing cells, can last for years.[44] One disadvantage is that they are not able to carry large amounts of foreign genetic materials. Furthermore, the need to express the complementary strand for its single-stranded genome may delay transgene expression.[44]

As of 2020, 11 different AAV serotypes—differing by capsid structure and consequently by tropism—had been identified.[42] The tropism of adeno-associated viral vectors can be tailored by creating recombinant versions from multiple serotypes, termed pseudotyping.[42] Due to their ability to infect and induce longlasting effects within nondividing cells, AAVs are commonly used in basic neuroscience research.[45] Following the approval of the AAV Alipogene tiparvovec in Europe in 2012,[46] in 2017, the FDA approved the first AAV-based in vivo gene therapy—voretigene neparvovec—which treated RPE65-associated Leber congenital amaurosis.[47] As of 2020, 230 clinical trials using AAV-based treatments were either underway or had been completed.[46]

Vaccinia edit

Main article: Vaccinia
 
An electron micrograph of vaccinia

Vaccinia virus, a poxvirus, is another promising candidate for viral vector development.[48] Its use as the smallpox vaccine—first reported by Edward Jenner in 1798—led to the eradication of smallpox and demonstrated vaccinia as safe and effective in humans.[49][48][note 1] Moreover, manufacturing procedures developed to mass-produce smallpox vaccine stockpiles may expedite vaccinia viral vector production.[51]

Vaccinia possesses a large DNA genome and can consequently carry up to 40 kb of foreign DNA.[49][52][53][52] Further, vaccinia are unlikely to integrate into the host genome, decreasing the chance of carcinogenesis.[52] Attenuated strains—replicating and non-replicating—have been developed.[49] Although widely characterized due to its use against smallpox, as of 2019 the function of 50 percent of the vaccinia genome was unknown. This may lead to unpredictable effects.[53]

As a vaccine platform, vaccinia vectors display highly effective transgene expression and create a robust immune response.[51] The virus fast-acting: its life cycle produces mature progeny vaccinia within 6 hours, and has three viral spread mechanisms.[53] Vaccinia also has an adjuvant effect, activating a strong innate response via toll-like receptors.[51] A significant disadvantage that can reduce its efficacy, however, is pre-existing immunity against vaccinia in those who received the smallpox vaccine.[51]

Herpesviruses edit

Main article: Herpesviruses
 
Herpes simplex virus I

Of the nine herpesviruses that infect humans, herpes simplex virus 1 (HSV-1) is the most well characterized and most commonly used as a viral vector.[54] HSV-1 offers several advantages: it had broad tropism and can deliver therapeutics via specialized expression systems.[55] Moreover, HSV-1 can cross the blood brain barrier if medically-disrupted, enabling it to target neurological diseases. Also, HSV-1 does not integrate into the host genome and can carry large amounts of foreign DNA. The former feature prevents harmful mutagenesis, as can occur with retroviral and adeno-associated vectors. Replication-deficient strains have been developed.[56]

In 2015, talimogene laherparepvec—an HSV-1 vector that triggers an anti-tumor immune response—was approved by the US Food and Drug Administration to treat melanoma.[57] As of 2020, HSV-1 vectors have been experimentally applied against sarcomas and cancers of the brain, colon, prostate, and skin.[58]

Cytomegalovirus (CMV), a herpesvirus, has also been developed for use as a viral vector.[59] CMV can infect most cell types and can thus proliferate throughout the body. Although a CMV-based vaccine provided significant immunity against SIV—closely related to HIV—in macaques, development of CMV as a reliable vector was reported to still be in early stages as of 2020.[60][61]

Plant viruses edit

Main article: Plant virus

Plant viruses are also engineered viral vectors for use in agriculture, horticulture, and biologic production.[62] These vectors have been employed for a range of applications, from increasing the aesthetic quality of ornamental plants to pest biocontrol, rapid expression of recombinant proteins and peptides, and to accelerate crop breeding.[63]

Replicating virus-based vectors are typically used.[64] RNA viruses used for monocots include wheat streak mosaic virus (WSMV) and barley stripe mosaic virus (BSMV) and, for dicots, tobacco rattle virus (TRV). Single-stranded DNA viruses like geminiviruses have also been utilized.[64] Viral vectors can be administered to plants via several pathways termed "agro-inoculation", including via rubbing, a biolistic delivery system, agrospray, agroinjection, and even via insect vectors.[65][63] However, Agrobacterium-mediated delivery of viral vectors—in which bacteria are transformed with plasmid DNA encoding the viral vector construct—is the most common approach.[66]

History edit

 
 
Paul Berg's creation of the first viral vector in 1972 led to the Asilomar Conference, which established a moratorium on recombinant DNA research.

In 1972, Stanford University biochemist Paul Berg developed the first viral vector, incorporating DNA from the lambda phage into the polyomavirus SV40 to infect monkey kidney cells maintained in culture.[67][68][69] The implications of this research troubled scientists like Robert Pollack, who convinced Berg not to insert DNA from SV40 into E. coli via a bacteriophage vector. They feared that introducing the purportedly cancer-causing genes of SV40 may have created carcinogenic bacterial strains.[70][71] These concerns and others in the emerging field of recombinant DNA led to the Asilomar Conference of 1975, where attendees agreed to a voluntary moratorium on cloning DNA.[72]

In 1977, the National Institutes of Health (NIH) issued formal guidelines confining viral DNA cloning to rigid BSL-4 conditions, practically preventing such research. However, the NIH loosened these rules in 1979, permitting Bernard Moss to develop a viral vector utilizing vaccinia.[72] In 1982, Moss reported the first use of a viral vector for transient gene expression.[17] The following year, Moss used the vaccinia vector to express a hepatitis B antigen, creating the first viral vector vaccine.[21]

Every realm of medicine has its defining moment, often with a human face attached. Polio had Jonas Salk. In vitro fertilization had Louise Brown, the world's first test-tube baby. Transplant surgery had Barney Clark, the Seattle dentist with the artificial heart. AIDS had Magic Johnson. Now gene therapy has Jesse Gelsinger.

— Sheryl Gay Stolberg, The New York Times Magazine[73]

Although a failed gene therapy attempt utilizing wild-type Shope papilloma virus had been made as early as 1972, Martin Cline attempted the first gene therapy utilizing recombinant DNA in 1980. It proved unsuccessful.[74][11] In the 1990s, as genetic diseases were further characterized and viral vector technology improved, there was overoptimism about the capabilities the technology. Many clinical trials proved failures.[75] There were minors successes, such as the first effective gene therapy for severe combined immunodeficiency (SCID) in patient Ashanthi DeSilva. It employed a recombinant retrovirus.[11]

However, during a 1999 clinical trial at the University of Pennsylvania, Jesse Gelsinger died from a fatal reaction to an adenoviral vector-based gene therapy.[73][75] It was the first death related to any form of gene therapy.[76] Consequently, the FDA suspended all gene therapy trials at the University of Pennsylvania and investigated 60 others across the US.[76] An anonymous editorial in Nature Medicine noted that it represented a "loss of innocence" for viral vectors.[75] Shortly therafter, the field's reputation was further damaged when 5 children treated with a SCID gene therapy developed leukemia due to an issue with the retroviral vector.[75][note 2]

Viral vectors experienced a resurgence when they were employed for ex vivo hematopoietic gene delivery.[77] In 2003, China approved the first gene therapy for clinical use: Gendicine, an adenoviral vector encoding p53.[78][79] In 2012, the European Union issued its first approval of a gene therapy, an adeno-associated viral vector.[80] During the COVID-19 pandemic, viral vector vaccines were used to an unprecedented extent.[81] As of 2022, all approved gene therapies were viral-vector based and over 1000 viral vector clinical trials targeting cancer were underway.[77]

In popular culture edit

 
The film I Am Legend (set pictured) depicts a viral vector-created apocalypse.

In film, viral vectors are often portrayed as unintentionally causing a pandemic and civilizational catastrophe.[82] The 2007 film I Am Legend depicts a cancer-targeting viral vector as unleashing a zombie apocalypse.[83][84] Similarly, a viral vector therapy for Alzheimer's disease in Rise of the Planet of the Apes (2011) becomes a deadly pathogen and causes an ape uprising. Other films featuring viral vectors include The Bourne Legacy (2012) and Resident Evil: The Final Chapter (2016).[85]

Notes and references edit

Notes edit

  1. ^ Edward Jenner's use of material from cow blisters containing vaccinia was the basis for vaccinology and ultimately led to the eradication of smallpox from Earth.[50]
  2. ^ Ultimately, 1 child died. According to Cormac Sheridan, the backlash was unfair as the overall mortality rate for the viral vector therapy was lower than equivalent approaches.[75]

Citations edit

  1. ^ Pasin, Menzel & Daròs 2019, p. 1010.
  2. ^ a b c d Labbé, Vessillier & Rafiq 2021, p. 1.
  3. ^ Kayser et al. 2005, pp. 377–378.
  4. ^ Barth & Aylward 2024, p. 1.
  5. ^ Bulcha et al. 2021, pp. 1–2.
  6. ^ Nomaguchi et al. 2012, p. 1.
  7. ^ Moen et al. 2012, p. 2.
  8. ^ Lanigan, Kopera & Saunders 2020, pp. 1, 7.
  9. ^ a b Sakuma et al. 2012, p. 612.
  10. ^ Lanigan, Kopera & Saunders 2020, p. 1.
  11. ^ a b c d Bulcha et al. 2021, p. 1.
  12. ^ Li et al. 2023, p. 2.
  13. ^ Sasmita 2019, p. 29.
  14. ^ a b Wang et al. 2023, p. 1.
  15. ^ Larocca & Schlom 2011, p. 1.
  16. ^ Elkashif et al. 2021, p. 1.
  17. ^ a b c Ura, Okuda & Shimada 2014, p. 625.
  18. ^ a b Ura, Okuda & Shimada 2014, p. 624.
  19. ^ McCann et al. 2022, p. 2.
  20. ^ Ura, Okuda & Shimada 2014, p. 624-625.
  21. ^ a b c McCann et al. 2022, p. 1.
  22. ^ McCann et al. 2022, pp. 1, 6–7.
  23. ^ a b c d Labbé, Vessillier & Rafiq 2021, p. 2.
  24. ^ Milone & O'Doherty 2018, pp. 1530–1531.
  25. ^ Gruntman & Flotte 2018, pp. 1734.
  26. ^ Gruntman & Flotte 2018, pp. 1733.
  27. ^ a b c Nemirov et al. 2023, p. 1.
  28. ^ Nemirov et al. 2023, pp. 1, 4.
  29. ^ a b Nemirov et al. 2023, pp. 1–2.
  30. ^ a b Nemirov et al. 2023, p. 4.
  31. ^ Nemirov et al. 2023, p. 7.
  32. ^ Li & Samulski 2020, p. 255.
  33. ^ a b c Elkashif et al. 2021, p. 2.
  34. ^ a b Farhad et al. 2022, p. 2.
  35. ^ Nemirov et al. 2023, pp. 3–4.
  36. ^ a b c Ura, Okuda & Shimada 2014, p. 628.
  37. ^ a b Elkashif et al. 2021, p. 3.
  38. ^ Elkashif et al. 2021, pp. 3–4.
  39. ^ Elkashif et al. 2021, p. 8.
  40. ^ Ewer et al. 2017, p. 3020.
  41. ^ Elkashif et al. 2021, pp. 10, 11.
  42. ^ a b c Haggerty et al. 2019, p. 69.
  43. ^ Haggerty et al. 2019, pp. 69–70.
  44. ^ a b Haggerty et al. 2019, p. 70.
  45. ^ Haggerty et al. 2019, pp. 71–74, 78.
  46. ^ a b Haggerty et al. 2019, p. 75.
  47. ^ Li, Samulski & Rafiq 2020, p. 255.
  48. ^ a b Zhang et al. 2021, p. 1578.
  49. ^ a b c Ura, Okuda & Shimada 2014, p. 626.
  50. ^ Kaynarcalidan, Mascaraque & Drexler 2021, pp. 1–3, 5.
  51. ^ a b c d Ura, Okuda & Shimada 2014, p. 627.
  52. ^ a b c Kaynarcalidan, Mascaraque & Drexler 2021, p. 1.
  53. ^ a b c Guo 2019, p. 4.
  54. ^ Mody et al. 2020, p. 1.
  55. ^ Mody et al. 2020, pp. 3–4.
  56. ^ Mody et al. 2020, p. 4.
  57. ^ Khushalani et al. 2023, p. 1.
  58. ^ Hromic-Jahjefendic & Lundstrom 2020, p. 631.
  59. ^ Ura, Okuda & Shimada 2014, p. 631.
  60. ^ Sasso et al. 2020, p. 10.
  61. ^ Schaefer et al. 2005, p. 1446.
  62. ^ Abrahamian, Hammond & Hammond 2020, pp. 513–515.
  63. ^ a b Pasin, Menzel & Daròs 2019, pp. 1010–1011.
  64. ^ a b Zaidi & Mansoor 2017, p. 1.
  65. ^ Abrahamian, Hammond & Hammond 2020, pp. 520–523.
  66. ^ Abrahamian, Hammond & Hammond 2020, pp. 522–528.
  67. ^ Travieso et al. 2022, p. 1.
  68. ^ Lukiw 2023, p. 1.
  69. ^ Jackson, Symons & Berg 1972, pp. 2904–2909.
  70. ^ Carmen 1986, pp. 61–62.
  71. ^ Lukiw 2023, p. 2.
  72. ^ a b Moss 2014, p. 4220.
  73. ^ a b Stolberg 1999.
  74. ^ Wirth, Parker & Ylä-Herttuala 2013, p. 164.
  75. ^ a b c d e Sheridan 2011, p. 121.
  76. ^ a b Sibbald 2001, p. 1612.
  77. ^ a b Bezeljak 2022, pp. 2, 10.
  78. ^ Wirth, Parker & Ylä-Herttuala 2013, p. 165.
  79. ^ Bezeljak 2022, p. 23.
  80. ^ Wirth, Parker & Ylä-Herttuala 2013, pp. 166–167.
  81. ^ Bezeljak 2022, p. 2.
  82. ^ Sánchez-Angulo 2023, pp. 1, 16.
  83. ^ Reuters 2020.
  84. ^ Feldman & Clayton 2022, pp. 2, 5.
  85. ^ Sánchez-Angulo 2023, p. 16.

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Books edit

  • Carmen I (1985). Cloning and the Constitution: An Inquiry into Governmental Policymaking and Genetic Experimentation. University of Wisconsin Press. ISBN 9780299103408.
  • Kayser FH, Bienz KA, Eckert J, Zinkernagel RM (2005). Medical Microbiology (10 ed.). Thieme. ISBN 1588902455.
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