Glycoprotein G of Herpes Simplex Virus 2 as a Novel Vaccine Antigen for Immunity to Genital and Neurological Disease

Görander, Staffan; Harandi, Ali M.; Lindqvist, Madelene; Bergström, Tomas; Liljeqvist, Jan‐Åke

doi:10.1128/jvi.00186-12

Cited by 27 publications

(35 citation statements)

References 55 publications

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“…It is generally accepted that an ideal HSV-2 vaccine should be capable of protecting individuals against new infection, sterilizing circulating viruses in infected individuals, and eliminating latent viral reservoirs (11,41,46). We demonstrated that HSV-2 gB-CCL19 fusion constructs were highly effective in inducing systematic immune responses, in particular a Th1-based Ab response, which was different from the immune profile induced by HSV-2 gB alone (44).…”

Section: Discussionmentioning

confidence: 74%

“…It was well documented in animal models that an efficacious prophylactic HSV-2 vaccine will most likely induce a robust neutralizing-Ab response (11,41,46). Having demonstrated that fusion of CCL19 to gB at either end could significantly augment systemic and mucosal Ab responses to gB, we assessed the neutralizing activity of sera collected at days 14 and 49 postboost and at days 5, 9, and 11 postchallenge, as well as vaginal fluids tested at day 14 postboost.…”

Section: Gb-ccl19 Fusion Constructs Promote An Enhanced Virusneutralimentioning

confidence: 99%

“…However, most findings suggested that one glycoprotein or several glycoproteins in combination are still not sufficient to induce effective immune responses against HSV-2 infection. One major limitation to subunit protein vaccines or plasmid (p)DNA vaccines encoding such proteins is their poor immunogenicity compared with live-attenuated and inactivated viral vaccines (5,10,11). Adjuvantation is one of the simplest, but most effective, ways to improve the immunogenicity of vaccine candidates (5,12).…”

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confidence: 99%

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Immunization with HSV-2 gB-CCL19 Fusion Constructs Protects Mice against Lethal Vaginal Challenge

Yan

Deng

et al. 2015

The Journal of Immunology

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There is a lack of an HSV-2 vaccine, in part as the result of various factors that limit robust and long-term memory immune responses at the mucosal portals of viral entry. We previously demonstrated that chemokine CCL19 augmented mucosal and systemic immune responses to HIV-1 envelope glycoprotein. Whether such enhanced immunity can protect animals against virus infection remains to be addressed. We hypothesized that using CCL19 in a fusion form to direct an immunogen to responsive immunocytes might have an advantage over CCL19 being used in combination with an immunogen. We designed two fusion constructs, plasmid (p)gBIZCCL19 and pCCL19IZgB, by fusing CCL19 to the C- or N-terminal end of the extracellular HSV-2 glycoprotein B (gB) with a linker containing two (Gly4Ser)2 repeats and a GCN4-based isoleucine zipper motif for self-oligomerization. Following immunization in mice, pgBIZCCL19 and pCCL19IZgB induced strong gB-specific IgG and IgA in sera and vaginal fluids. The enhanced systemic and mucosal Abs showed increased neutralizing activity against HSV-2 in vitro. Measurement of gB-specific cytokines demonstrated that gB-CCL19 fusion constructs induced balanced Th1 and Th2 cellular immune responses. Moreover, mice vaccinated with fusion constructs were well protected from intravaginal lethal challenge with HSV-2. Compared with pgB and pCCL19 coimmunization, fusion constructs increased mucosal surface IgA+ cells, as well as CCL19-responsive immunocytes in spleen and mesenteric lymph nodes. Our findings indicate that enhanced humoral and cellular immune responses can be achieved by immunization with an immunogen fused to a chemokine, providing information for the design of vaccines against mucosal infection by HSV-2 and other sexually transmitted viruses.

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Section: Discussionmentioning

confidence: 74%

Section: Gb-ccl19 Fusion Constructs Promote An Enhanced Virusneutralimentioning

confidence: 99%

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confidence: 99%

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Immunization with HSV-2 gB-CCL19 Fusion Constructs Protects Mice against Lethal Vaginal Challenge

Yan

Deng

et al. 2015

The Journal of Immunology

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“…The mixtures were then centrifuged at 20,000 ϫ g for 2 h (SW28.1 rotor) over the three-step discontinuous sucrose gradient consisting of 2 ml each of 50, 40, and 30% (wt/vol) sucrose in PBS, and 1-ml fractions were collected following side puncture of tube in the middle of the 50% sucrose layer. Each fraction was subjected to (i) titration of residual infectivity in the viral plaque assay, (ii) quantification of radioactivity in a scintillation counter, (iii) determination of the number of viral DNA copies based on quantitative PCR (qPCR) analysis (35), and (iv) determination of reactivity with mouse monoclonal antibodies against HSV glycoprotein B (gB) (clone B11D8; dilution, 1:100), gC (clone E5F7; dilution, 1:100), gE (clone B1E6; dilution, 1:100) and gG (clone O1C5; dilution, 1:100) and rabbit polyclonal antibody against the major capsid protein VP5 (NC1; dilution, 1:500) by an enzyme-linked immunosorbent assay (ELISA)-based method. The monoclonal antibodies were prepared and characterized in our laboratory (26,36,37), while polyclonal antibody NC1 was kindly provided by Gary Cohen and Roselyn Eisenberg (University of Pennsylvania).…”

Section: Methodsmentioning

confidence: 99%

The Cholestanol-Conjugated Sulfated Oligosaccharide PG545 Disrupts the Lipid Envelope of Herpes Simplex Virus Particles

Said

Trybala

Görander

et al. 2016

Antimicrob Agents Chemother

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bHerpes simplex virus (HSV) and many other viruses, including HIV, initiate infection of host cells by binding to glycosaminoglycan (GAG) chains of cell surface proteoglycans. Although GAG mimetics, such as sulfated oligo-and polysaccharides, exhibit potent antiviral activities in cultured cells, the prophylactic application of these inhibitors as vaginal microbicides failed to protect women upon their exposure to HIV. A possible explanation for this failure is that sulfated oligo-and polysaccharides exhibit no typical virucidal activity, as their interaction with viral particles is largely electrostatic and reversible and thereby vulnerable to competition with GAG-binding proteins of the genital tract. Here we report that the cholestanol-conjugated sulfated oligosaccharide PG545, but not several other sulfated oligosaccharides lacking this modification, exhibited virucidal activity manifested as disruption of the lipid envelope of HSV-2 particles. The significance of the virus particle-disrupting activity of PG545 was also demonstrated in experimental animals, as this compound, in contrast to unmodified sulfated oligosaccharide, protected mice against genital infection with HSV-2. Thus, PG545 offers a novel prophylaxis option against infections caused by GAG-binding viruses. Since the original finding of WuDunn and Spear (1) that ubiquitous and negatively charged glycosaminoglycan (GAG) chains of cell surface proteoglycans provide the binding sites for attachment of herpes simplex virus (HSV) to cells, these oligosaccharides have been reported to assist infection of cells by a number of different viruses, including respiratory syncytial virus (RSV) (2, 3), HIV-1 (4), and Ebola virus (5). In HSV, glycoprotein C (gC) (6) and/or gB (7) mediates virus binding to cell surface GAGs. Sulfated polysaccharides and other polysulfonated compounds that mimic the structure of GAG chains are well-known inhibitors of the virus-GAG interaction in cultured cells (3,8,9). Due to extensive sulfonation, these compounds efficiently outcompete the binding of cell surface GAGs to the viral attachment proteins, thus preventing infection of cells. Notably, the same GAG mimetics can inhibit infectivity of different 9). In spite of potent antiviral activity in cultured cells, these inhibitors, i.e., cellulose sulfate, carrageenan, and PRO2000 (sulfonated poly-naphthalene), failed to protect women against contraction of HIV when tested as intravaginal virucides in several large clinical trials (10-12). Furthermore, there was an indication that one of these GAG mimetics, i.e., cellulose sulfate, increased the risk of contracting HIV (10). Although it is unclear why these compounds lack protective effects in humans (12, 13), some intrinsic features of the virus-GAG interaction, such as reversibility of the binding, may help to elucidate this issue. Virus binding to ubiquitous cell surface components, such as GAGs or sialic acid, has to be neatly balanced to avoid redundant dead-end interactions resulting in trapping of viral particles. Some...

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“…Passive transfer of a panel of mouse monoclonal antibodies against HSV-2 glycoproteins with no HSV-2 neutralizing activity partially protected mice from HSV-2 footpad infection, and the effect correlated with ADCC activity of the monoclonal antibodies (49). An HSV-2 gG vaccine which induced low levels of serum neutralizing antibody but induced both ADCC and complement-mediated cytotoxicity partially protected mice from HSV-2 intravaginal challenge (50). More recently, vaccination of mice with a replication-defective HSV-2 gD deletion mutant protected animals from i.vag.…”

Section: Discussionmentioning

confidence: 99%

A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

Wang

Goodman

et al. 2016

J Virol

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G enital herpes simplex is one of the most prevalent sexually transmitted diseases. In 2012, more than 417 million persons worldwide were reported to be infected with herpes simplex virus 2 (HSV-2), with more than 19.2 million new persons infected in that year alone (1). While HSV-2 disease is mild in most cases, infection can be severe and life threatening in immunocompromised patients and neonates. In addition, genital herpes increases the risk of acquisition of HIV infection 3-fold (2). While HSV-2 traditionally has been the principal cause of genital herpes, more recent studies have shown that HSV-1 may be replacing HSV-2 as the most frequent cause of genital herpes in the United States (3, 4). While both HSV-1 and HSV-2 cause primary and recurrent genital herpes, genital recurrences are much more frequent with HSV-2 than with HSV-1 (5).HSV-2 infects epithelial cells in the vaginal mucosa, replicates in the cells, and enters the nerve endings innervating the mucosa. Viral capsids travel retrograde in axons to the cell body in sensory ganglia, where HSV establishes a latent infection in the nuclei of neurons. Latent HSV can be reactivated by multiple stimuli, such as stress, fever, and exposure to UV light. Viral capsids travel anterograde from the ganglion down the axons to the mucosa, where the virus replicates and is shed in the presence or absence of symptomatic genital lesions. This allows the virus to spread to unin- Citation Wang K, Goodman KN, Li DY, Raffeld M, Chavez M, Cohen JI. 2016. A herpes simplex virus 2 (HSV-2) gD mutant impaired for neural tropism is superior to an HSV-2 gD subunit vaccine to protect animals from challenge with HSV-2.

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Glycoprotein G of Herpes Simplex Virus 2 as a Novel Vaccine Antigen for Immunity to Genital and Neurological Disease

Cited by 27 publications

References 55 publications

Immunization with HSV-2 gB-CCL19 Fusion Constructs Protects Mice against Lethal Vaginal Challenge

Immunization with HSV-2 gB-CCL19 Fusion Constructs Protects Mice against Lethal Vaginal Challenge

The Cholestanol-Conjugated Sulfated Oligosaccharide PG545 Disrupts the Lipid Envelope of Herpes Simplex Virus Particles

A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

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