| 1. |
- Eriksson, Kristina, 1962, et al.
(författare)
-
CD4(+) T-cell responses to herpes simplex virus type 2 (HSV-2) glycoprotein G are type specific and differ in symptomatic and asymptomatic HSV-2-infected individuals
- 2004
-
Ingår i: J Gen Virol. - 0022-1317. ; 85:Pt 8, s. 2139-47
-
Tidskriftsartikel (refereegranskat)abstract
- T-cell recognition of the secreted and membrane-bound portions of the herpes simplex virus type 2 (HSV-2) glycoprotein G (sgG-2 and mgG-2, respectively) was compared in symptomatic and asymptomatic HSV-2-infected individuals and in HSV-2-seronegative controls and the responses with HSV-1 glycoproteins C and E (gC-1 and gE-1) were compared. CD4(+) T cells from HSV-2-infected individuals specifically recognized both sgG-2 and mgG-2, whereas HSV-1-infected and HSV-seronegative controls did not respond to these glycoproteins. The responses to gC-1 and gE-1, on the other hand, were not type specific, as blood mononuclear cells from both HSV-1- and HSV-2-infected individuals responded in vitro. There was an association between the status of the infection (symptomatic versus asymptomatic) and the CD4(+) T-cell responsiveness. Symptomatic HSV-2-seropositive individuals responded with significantly lower Th1 cytokine production to sgG-2 and mgG-2 than did asymptomatic HSV-2-infected carriers, especially within the HSV-1-negative cohort. No differences in T-cell proliferation were observed between asymptomatic and symptomatic individuals. The results have implications for studies of HSV-2-specific CD4(+) T-cell reactivity in general and for analysis of immunological differences between asymptomatic and symptomatic individuals in particular.
|
|
| 2. |
- Görander, Staffan, 1952, et al.
(författare)
-
A truncated glycoprotein G vaccine formulated with Advax-CpG adjuvant provides protection of mice against genital herpes simplex virus 2 infection
- 2021
-
Ingår i: Vaccine. - : Elsevier BV. - 0264-410X. ; 39:40, s. 5866-5875
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted disease that affects approximately 500 million individuals globally. There is currently no approved vaccine to prevent HSV-2 infection. EXCT4 is a truncated form of the mature glycoprotein G-2 (mgG-2) that unlike full mature form is secreted by expressing cells enabling it to be rapidly scaled up for production. The current study examined whether EXCT4 immunity in mice could be further enhanced through use of adjuvants. EXCT4 formulated with Advax-CpG adjuvant induced a strong Th1-type immune response characterized by interferon gamma (IFN-gamma) and protected animals against a lethal genital challenge with HSV-2. This response was associated with reduced viral load in vaginal washes, spinal cord, and dorsal root ganglia. Together the results provide proof of concept that EXCT4 formulated with Advax-CpG adjuvant is a promising HSV-2 vaccine candidate warranting further investigation. (C) 2021 Elsevier Ltd. All rights reserved.
|
|
| 3. |
- Görander, Staffan, 1952, et al.
(författare)
-
Anti-Glycoprotein G Antibodies of Herpes Simplex Virus 2 Contribute to Complete Protection after Vaccination in Mice and Induce Antibody-Dependent Cellular Cytotoxicity and Complement-Mediated Cytolysis
- 2014
-
Ingår i: Viruses-Basel. - : MDPI AG. - 1999-4915. ; 6:11, s. 4358-4372
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated the role of antibodies against the mature portion of glycoprotein G (mgG-2) of herpes simplex virus 2 (HSV-2) in protective immunity after vaccination. Mice were immunized intramuscularly with mgG-2 and oligodeoxynucleotides containing two CpG motifs plus alum as adjuvant. All C57BL/6 mice survived and presented no genital or systemic disease. High levels of immunoglobulin G subclass 1 (IgG1) and IgG2 antibodies were detected and re-stimulated splenic CD4(+) T cells proliferated and produced IFN-gamma. None of the sera from immunized mice exhibited neutralization, while all sera exerted antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytolysis (ACMC) activity. Passive transfer of anti-mgG-2 monoclonal antibodies, or immune serum, to naive C57BL/6 mice did not limit disease progression. Immunized B-cell KO mice presented lower survival rate and higher vaginal viral titers, as compared with vaccinated B-cell KO mice after passive transfer of immune serum and vaccinated C57BL/6 mice. Sera from mice that were vaccinated subcutaneously and intranasally with mgG-2 presented significantly lower titers of IgG antibodies and lower ADCC and ACMC activity. We conclude that anti-mgG-2 antibodies were of importance to limit genital HSV-2 infection. ADCC and ACMC activity are potentially important mechanisms in protective immunity, and could tentatively be evaluated in future animal vaccine studies and in clinical trials.
|
|
| 4. |
- Görander, Staffan, 1952
(författare)
-
Functions of glycoprotein G of herpes simplex virus type 2
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted infection with more than 500 million individuals infected world-wide. A major global health problem is that HSV-2 infection facilitates the spread of HIV. This epidemiological situation warrants the development of a vaccine to reduce the spread of HSV-2. As HSV-2 often is transmitted without symptoms type specific serology is valuable in diagnosis of the infection. The envelope glycoprotein G (gG-2) of HSV-2 is cleaved intracellularly into a membrane bound portion (mgG-2) and a secreted portion (sgG-2). Although the function of mgG-2 is unknown the protein induces a type specific antibody response. This feature is utilized in several serological HSV-2 type specific assays. A general problem is that assays which are reliable in Western world country populations show lower performance for sera from African countries. Aims: To evaluate sgG-2 as type specific antigen in ELISA for detection of HSV-2 infection in a Swedish cohort and define the performance for both sgG-2 and mgG-2 in ELISA for high HSV-2 prevalence cohorts in Tanzania (paper I and II). To elucidate the function of mgG-2, using HSV-2 mutants, in a genital mouse model (paper III) and to evaluate mgG-2 as a vaccine candidate against genital HSV-2 infection in mice (paper IV). Methods: Natively produced sgG-2 and mgG-2 proteins were purified by immunosorbent columns from HSV-2 infected cell cultures. For the vaccine studies mgG-2 was purified using Helix pomatia lectin affinity chromatography. A frame shift HSV-2 mutant devoid of mgG-2 and an emerald green fluorescent protein labelled sgG-2 and mgG-2 negative HSV-2 were used for functional studies in C57BL/6 mice. Viral load was estimated by virus isolation and by real time PCR. C57BL/6 mice were immunized with mgG-2 and CpG as adjuvant and challenged genitally with wild type HSV-2. Results: We showed that sgG-2 is a novel antigen that can be used for type specific serological diagnosis of HSV-2 infection and that an ELISA based on mgG-2 can improve the detection of HSV-2 infected individuals from Africa. Both mgG-2 deficient HSV-2 mutants were severely attenuated and all mice survived a genital infection. The viral mutants infected the genital mucosa but did not induce genital disease and were not propagated to the sensory ganglia or to the CNS. Finally, mice immunized with mgG-2 and adjuvant were highly protected against a lethal dose of wild type HSV-2. Protection was associated with an enhanced Th1 response and IFN-γ production in re-stimulated CD4+ T cells. Conclusion: Native sgG-2 and mgG-2 proteins induce type specific antibody responses and perform well in ELISA in low as well as in high HSV-2 prevalence populations. The mgG-2 protein has an important function in the ability of HSV-2 to infect nervous tissue. As vaccination with mgG-2 protects mice from lethal disease mgG-2 constitutes a promising vaccine candidate against HSV-2 infection. In human trials detection of anti-sgG-2 antibodies may be a valuable tool to discriminate between vaccine induced immunity and natural HSV-2 infections.
|
|
| 5. |
- Görander, Staffan, 1952, et al.
(författare)
-
Glycoprotein G of Herpes Simplex Virus 2 as a Novel Vaccine Antigen for Immunity to Genital and Neurological Disease
- 2012
-
Ingår i: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 86:14, s. 7544-7553
-
Tidskriftsartikel (refereegranskat)abstract
- The envelope glycoproteins of herpes simplex virus 1 (HSV-1) and HSV-2, with the exception of glycoprotein G, elicit cross-reactive B- and T-cell responses. Human vaccine trials, using the cross-reactive glycoproteins B and D, have shown no protection against genital HSV-2 infection or disease. In this study, the mature form of glycoprotein G (mgG-2) of HSV-2 was used for immunization of mice, either alone or in combination with adjuvant CpG, followed by an intravaginal challenge with a lethal dose of a fully virulent HSV-2 strain. Mice immunized with mgG-2 plus CpG showed low disease scores and a significantly higher survival rate (73%) than mice immunized with mgG-2 alone (20%) or controls (0%). Accordingly, limited numbers of infectious HSV-2 particles were detected in the spinal cord of mice immunized with mgG-2 plus CpG. The observed protection was associated with a gamma interferon (IFN-gamma) response by splenic CD4(+) T cells upon antigen restimulation in vitro and in vaginal washes 1 day postinfection. The majority of sera collected from mice immunized with mgG-2 plus CpG showed macrophage-mediated antibody-dependent cellular cytotoxicity and antibody-dependent complement-mediated cytolysis, while no neutralization activity was observed. In conclusion, we have shown that immunization with the type-specific mgG-2 protein in combination with CpG could elicit protective immunity against an otherwise lethal vaginal HSV-2 challenge. The mgG-2 protein may therefore constitute a promising HSV-2 vaccine antigen to be considered for future human trials.
|
|
| 6. |
- Görander, Staffan, 1952, et al.
(författare)
-
Mature glycoprotein g presents high performance in diagnosing herpes simplex virus type 2 infection in sera of different tanzanian cohorts.
- 2006
-
Ingår i: Clinical and vaccine immunology : CVI. - 1556-6811. ; 13:6, s. 633-9
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted infection in sub-Saharan Africa. Glycoprotein G (gG) of HSV-2 elicits a type-specific antibody response and is widely used for serodiagnosis. gG is cleaved into a secreted portion (sgG-2) and a highly O-glycosylated mature portion (mgG-2). The performances of these two native immunosorbent purified antigens were compared in an enzyme-linked immunosorbent assay (ELISA) format with a commercially available assay (FOCUS2) using sera from blood donors (n = 194) and individuals (n = 198) with genital ulcer disease (GUD) from Tanzania. Discordant results were resolved by Western blotting. The HSV-2 seroprevalence for blood donors was estimated as 42%, and that for the GUD cohort was estimated as 78%. The prevalence increased significantly with age for both cohorts and was higher among human immunodeficiency virus (HIV)-positive individuals than among HIV-negative subjects. In the GUD cohort with a high HSV-2 prevalence, all three assays showed statistically similar performances, with sensitivities between 97% and 99% and specificities in the range of 86% to 91%. In contrast, among blood donors with a lower seroprevalence, the mgG-2-based ELISA presented significantly higher specificity (97%) than the sgG-2 ELISA (89%) and FOCUS2 (74%). Overall, the mgG-2 ELISA gave a high performance, with negative and positive predictive values of 96% for blood donors and a negative predictive value of 95% and a positive predictive value of 97% for the GUD cohort. We conclude that native purified mgG-2 showed the highest accuracy for detection of HSV-2 in patient sera from Tanzania and is therefore suitable for seroprevalence studies as well as in clinical settings.
|
|
| 7. |
- Görander, Staffan, 1952, et al.
(författare)
-
Multiphasic encephalomyelitis in a patient with recurrent herpes simplex type 2 meningitis.
- 2006
-
Ingår i: Scandinavian journal of infectious diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 38:10, s. 942-5
-
Tidskriftsartikel (refereegranskat)abstract
- We here describe a patient with a history of recurrent HSV-2 meningitis who had been free from symptoms for almost 20 y when he developed an acute encephalomyelitis. The clinical course laboratory and radiological findings support an acute multiphasic disseminated encephalomyelitis induced by a recurrent HSV-2 infection.
|
|
| 8. |
- Görander, Staffan, 1952, et al.
(författare)
-
Secreted portion of glycoprotein g of herpes simplex virus type 2 is a novel antigen for type-discriminating serology.
- 2003
-
Ingår i: Journal of clinical microbiology. - 0095-1137. ; 41:8, s. 3681-6
-
Tidskriftsartikel (refereegranskat)abstract
- The secreted portion of glycoprotein G (sgG-2) of herpes simplex virus type 2 (HSV-2) was evaluated as a novel antigen in an enzyme-linked immunosorbent assay (ELISA) format for detection of type-specific immunoglobulin G (IgG) antibodies in HSV-2-infected patients. The results were compared with those obtained by a commercially available assay, the HerpeSelect 2 ELISA (the FOCUS2 assay). Five different panels of sera were analyzed: panel A consisted of 109 serum samples from patients with a culture-proven HSV-1 infection that were Western blotting (WB) negative for HSV-2; panel B consisted of 106 serum samples from patients with a culture-proven recurrent HSV-2 infection that were WB positive for HSV-2; panel C consisted of 100 serum samples with no detectable IgG antibodies against HSV-1 and HSV-2; panel D consisted of 70 HSV-2 negative "tricky" serum samples containing antinuclear IgG antibodies or IgM antibodies against other viruses or bacteria; and panel E consisted of consecutive serum samples from 21 patients presenting with a first episode of HSV-2-induced lesions. When sera in panels A to C were analyzed, the sgG-2 ELISA and the FOCUS2 assay both showed sensitivities and specificities of >or=98%. In total, among the samples in panel D, 13 serum samples (19%) were false positive by the FOCUS2 assay and 1 serum sample (1.4%) was false positive by the sgG-2 ELISA. When the sera in panel E were analyzed, the sgG-2 ELISA detected seroconversion somewhat later than WB or the FOCUS2 assay did. We conclude that sgG-2 induces an HSV-2 type-specific antibody response and can be used for type-discriminating serology.
|
|
| 9. |
- Görander, Staffan, 1952, et al.
(författare)
-
Seroprevalences of herpes simplex virus type 2, five oncogenic human papillomaviruses, and Chlamydia trachomatis in Katowice, Poland.
- 2008
-
Ingår i: Clinical and vaccine immunology : CVI. - 1556-679X. ; 15:4, s. 675-80
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus type 2 (HSV-2), human papillomaviruses (HPVs), and Chlamydia trachomatis are the most common pathogens causing sexually transmitted infections (STIs). There is limited information about the prevalences of these STIs in Poland. Here, we estimated the occurrence of immunoglobulin G (IgG) antibodies against HSV-2, HPV, and C. trachomatis in 199 blood donors and 110 patients of both genders attending an STI clinic in Katowice in southern Poland. The seroprevalences of HSV-2 were 5% for blood donors and 14% in the STI cohort. The seroprevalences of the five potentially oncogenic HPV types 16, 18, 31, 35, and 51 were 15%, 7%, 5%, 5%, and 17%, respectively, in blood donors and 37%, 8%, 12%, 5%, and 21%, respectively, in the STI cohort. The majority of HPV-infected individuals showed antibodies against more than one type, i.e., had been infected with multiple HPV types. Anti-C. trachomatis IgG antibodies were detected in 6% of blood donors and 13% of individuals attending the STI clinic. The relatively high prevalence of HPV-51 may have implications for future vaccine programs, as the newly introduced HPV vaccines are based on the potentially oncogenic HPV types 16 and 18.
|
|
| 10. |
- Liljeqvist, Jan-Åke, 1954, et al.
(författare)
-
Human Antibodies against Herpes Simplex Virus 2 Glycoprotein G Do Not Neutralize but Mediate Antibody-Dependent Cellular Cytotoxicity
- 2024
-
Ingår i: ANTIBODIES. - 2073-4468. ; 13:2
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus 2 (HSV-2) is a sexually transmitted infection affecting 491 million individuals globally. Consequently, there is a great need for both prophylactic and therapeutic vaccines. Unfortunately, several vaccine clinical trials, primarily employing the glycoprotein D of HSV-2 (gD-2), have failed. The immune protection conferred by human anti-HSV-2 antibodies in genital infection and disease remains elusive. It is well-known that gD-2 elicits cross-reactive neutralizing antibodies, i.e., anti-gD-2 antibodies recognize gD in HSV-1 (gD-1). In contrast, anti-glycoprotein G in HSV-2 (mgG-2) antibodies are exclusively type-specific for HSV-2. In this study, truncated versions of gD-2 and mgG-2 were recombinantly produced in mammalian cells and used for the purification of anti-gD-2 and anti-mgG-2 antibodies from the serum of five HSV-2-infected subjects, creating a pool of purified antibodies. These antibody pools were utilized as standards together with purified mgG-2 and gD-2 antigens in ELISA to quantitatively estimate and compare the levels of cross-reactive anti-gD-1 and anti-gD-2 antibodies, as well as anti-mgG-2 antibodies in sera from HSV-1+2-, HSV-2-, and HSV-1-infected subjects. The median concentration of anti-mgG-2 antibodies was five times lower in HSV-1+2-infected subjects as compared with cross-reactive anti-gD-1 and anti-gD-2 antibodies, and three times lower in HSV-2 infected subjects as compared with anti-gD-2 antibodies. The pool of purified anti-gD-2 antibodies presented neutralization activity at low concentrations, while the pool of purified anti-mgG-2 antibodies did not. Instead, these anti-mgG-2 antibodies mediated antibody-dependent cellular cytotoxicity (ADCC) by human granulocytes, monocytes, and NK-cells, but displayed no complement-dependent cytotoxicity. These findings indicate that antibodies to mgG-2 in HSV-2-infected subjects are present at low concentrations but mediate the killing of infected cells via ADCC rather than by neutralizing free viral particles. We, and others, speculate that Fc-receptor mediated antibody functions such as ADCC following HSV-2 vaccination may serve as a better marker of protection correlate instead of neutralizing activity. In an mgG-2 therapeutic vaccine, our findings of low levels of anti-mgG-2 antibodies in HSV-2-infected subjects may suggest an opportunity to enhance the immune responses against mgG-2. In a prophylactic HSV-2 mgG-2 vaccine, a possible interference in cross-reactive immune responses in already infected HSV-1 subjects can be circumvented.
|
|
