Antibody-mediated protection against genital herpes simplex virus type 2 disease in mice by Fc gamma receptor-dependent and -independent mechanisms

Chu, Chin-Fun; Meador, Michael G.; Young, Christal G.; Strasser, Jane E.; Bourne, Nigel; Milligan, Gregg N.

doi:10.1016/j.jri.2007.08.004

Cited by 31 publications

(24 citation statements)

References 43 publications

(53 reference statements)

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“…Research investigating antibody-mediated protection in a mouse vaginal HSV-2 infection model demonstrated that polyclonal HSVspecific IgG antibodies largely rely on FcγR-dependent mechanisms (30). By using T-cell, B-cell, and natural killer cell function deficient NOD/SCID mice in the present study we could show that the protective mechanism conferred by mAb hu2c is entirely independent from FcγR-mediated effector functions.…”

Section: Prophylactic and Therapeutic Treatment With Mab Hu2c Protectsmentioning

confidence: 57%

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

Krawczyk

Arndt

Grosse‐Hovest

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

105

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Despite the availability of antiviral chemotherapy, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections remain a severe global health problem. Of particular concern is the growing incidence of drug resistance in immunocompromised patients, which stresses the urgency to develop new effective treatment alternatives. We have developed a humanized monoclonal antibody (mAb hu2c) that completely abrogates viral cell-to-cell spread, a key mechanism by which HSV-1/2 escapes humoral immune surveillance. Moreover, mAb hu2c neutralized HSV fully independent of complement and/or immune effector cell recruitment in a highly efficient manner. Prophylactic and therapeutic administration of mAb hu2c completely prevented infection-related mortality of severely immunodeficient mice being challenged with a lethal dose of HSV-1. The high neutralization capacity of mAb hu2c was fully maintained toward clinical HSV isolates being multiresistant to standard antiviral drugs, and infection was fully resolved in 7/8 nonobese diabetic/SCID mice being infected with a multidrug resistant HSV-1 patient isolate. Immunohistochemical studies revealed no significant cross-reactivity of the antibody toward human tissues. These features warrant further clinical development of mAb hu2c as an immunotherapeutic compound for the management of severe and particularly drugresistant HSV infections.acyclovir resistance | immunocompromised mice | stem cell transplantation

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Section: Prophylactic and Therapeutic Treatment With Mab Hu2c Protectsmentioning

confidence: 57%

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

Krawczyk

Arndt

Grosse‐Hovest

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

105

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“…It is wellknown that the mouse IgG2 subclass binds to Fc␥RI more efficiently than IgG1 (50). Protection induced by passive transfer of anti-HSV MAbs or immune sera in mice was shown to correlate with Fc␥-dependent mechanisms, such as ADCC (2,11,25). As a single mgG-2 MAb was earlier shown to present low ADCC activity (2), four of our own produced anti-mgG-2 MAbs (34) were tested.…”

Section: Discussionmentioning

confidence: 99%

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

Görander

Harandi

Lindqvist

et al. 2012

J Virol

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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-␥) 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 macrophagemediated 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.

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“…The effectiveness of vaccines can be improved with potent adjuvants, and there is a recent boom in the interest in adjuvants (19,28,44). The ability to induce a T-cell response may be especially important for a herpesvirus vaccine (7,9,23,27,30,31). The mechanism of action of adjuvants is complex and incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

“…Studies from animal models of HSV infection and human studies indicate that high levels of neutralizing antibodies, innate immunity natural killer (NK) cells, interferon (IFN), and macrophages contribute to protection from HSV infection, but the major determinants of HSV protection are both CD8 ϩ and especially CD4 ϩ T cells (7,9,23,27,30,31). Clearance of virus from recurrent lesions is also more closely correlated to T-cell immunity.…”

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confidence: 99%

Potent Adjuvant Activity of Cationic Liposome-DNA Complexes for Genital Herpes Vaccines

Bernstein

Cardin

Bravo

et al. 2009

Clin Vaccine Immunol

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Development of a herpes simplex virus (HSV) vaccine is a priority because these infections are common. It appears that potent adjuvants will be required to augment the immune response to subunit HSV vaccines. Therefore, we evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant in a mouse model of genital herpes. Using a whole-virus vaccine (HVAC), we showed that the addition of CLDC improved antibody responses compared to vaccine alone. Most important, CLDC increased survival, reduced symptoms, and decreased vaginal virus replication compared to vaccine alone or vaccine administered with monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) following intravaginal challenge of mice. When CLDC was added to an HSV gD2 vaccine, it increased the amount of gamma interferon that was produced from splenocytes stimulated with gD2 compared to the amount produced with gD2 alone or with MPL-alum. The addition of CLDC to the gD2 vaccine also improved the outcome following vaginal HSV type 2 challenge compared to vaccine alone and was equivalent to vaccination with an MPL-alum adjuvant. CLDC appears to be a potent adjuvant for HSV vaccines and should be evaluated further.Herpes simplex virus type 1 (HSV-1) and HSV-2 are two members of the HSV family of alphaherpesviruses, which establish lifelong latent infection in sensory neurons and lead to chronic herpes disease. HSV-1 infection causes facial/ocular disease, while HSV-2 is the leading cause of genital herpes, although both viruses can be found at oral and genital sites. Indeed, the incidence of HSV-1 genital disease is increasing and approximates that of HSV-2 in certain countries (17). Approximately 45 million people in the United States (20 to 30%) have genital herpes infection, and new infections occur at a rate of 1 million per year (17,29). One of the most serious complications of genital herpes occurs when the virus is transmitted from mother to neonate. Infection of the neonate causes significant morbidity and mortality, even with proper antiviral therapy (25). Genital herpes infection also increases the risk of acquiring human immunodeficiency virus (HIV) infection and increases shedding of HIV in genital lesions (5, 40).HSV-2 infection induces both humoral and T-cell-mediated immunity; however, the mechanisms that contribute to longterm control of genital herpes are not understood and could be different from those that will protect against primary infection or disease. Studies from animal models of HSV infection and human studies indicate that high levels of neutralizing antibodies, innate immunity natural killer (NK) cells, interferon (IFN), and macrophages contribute to protection from HSV infection, but the major determinants of HSV protection are both CD8 ϩ and especially CD4 ϩ T cells (7,9,23,27,30,31). Clearance of virus from recurrent lesions is also more closely correlated to T-cell immunity. Thus, when a recurrent lesion occurs, mononuclear cells, primarily CD4 ϩ T cells, infiltrate the lesion as early as 2 days after formation and ...

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Antibody-mediated protection against genital herpes simplex virus type 2 disease in mice by Fc gamma receptor-dependent and -independent mechanisms

Cited by 31 publications

References 43 publications

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

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

Potent Adjuvant Activity of Cationic Liposome-DNA Complexes for Genital Herpes Vaccines

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