Neutralizing Antibodies Inhibit Axonal Spread of Herpes Simplex Virus Type 1 to Epidermal Cells In Vitro

Mikloška, Zorka; Sanna, Pietro Paolo; Cunningham, Anthony L.

doi:10.1128/jvi.73.7.5934-5944.1999

Cited by 65 publications

(19 citation statements)

References 49 publications

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“…Antibodies inhibiting neuronal spread via cell-to-cell transmission may significantly reduce the frequency of reactivations and thus have a sustainable impact on the emergence of HSK [ 56 ]. Although the exact mechanism of viral DNA transport or release from the axons is still unknown, several observations also suggest that antibodies could directly interfere with the axonal HSV-1 spread in vitro and in vivo [ 57 , 58 ]. In the present study we demonstrated that mAb 2c and its humanized counterpart both are capable to interfere with the cell-to-cell transmission between epithelial cells and neurons.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Herpes Simplex Virus Induced Stromal Keratitis by a Glycoprotein B-Specific Monoclonal Antibody

et al. 2015

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The increasing incidence of acyclovir (ACV) and multidrug-resistant strains in patients with corneal HSV-1 infections leading to Herpetic Stromal Keratitis (HSK) is a major health problem in industrialized countries and often results in blindness. To overcome this obstacle, we have previously developed an HSV-gB-specific monoclonal antibody (mAb 2c) that proved to be highly protective in immunodeficient NOD/SCID-mice towards genital infections. In the present study, we examined the effectivity of mAb 2c in preventing the immunopathological disease HSK in the HSK BALB/c mouse model. Therefore, mice were inoculated with HSV-1 strain KOS on the scarified cornea to induce HSK and subsequently either systemically or topically treated with mAb 2c. Systemic treatment was performed by intravenous administration of mAb 2c 24 h prior to infection (pre-exposure prophylaxis) or 24, 40, and 56 hours after infection (post-exposure immunotherapy). Topical treatment was performed by periodical inoculations (5 times per day) of antibody-containing eye drops as control, starting at 24 h post infection. Systemic antibody treatment markedly reduced viral loads at the site of infection and completely protected mice from developing HSK. The administration of the antiviral antibody prior or post infection was equally effective. Topical treatment had no improving effect on the severity of HSK. In conclusion, our data demonstrate that mAb 2c proved to be an excellent drug for the treatment of corneal HSV-infections and for prevention of HSK and blindness. Moreover, the humanized counterpart (mAb hu2c) was equally effective in protecting mice from HSV-induced HSK when compared to the parental mouse antibody. These results warrant the future development of this antibody as a novel approach for the treatment of corneal HSV-infections in humans.

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Section: Discussionmentioning

confidence: 99%

Prevention of Herpes Simplex Virus Induced Stromal Keratitis by a Glycoprotein B-Specific Monoclonal Antibody

et al. 2015

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“…It has been shown that re-infection of ganglia is extremely difficult to achieve in previously infected animals due in part to the presence of pre-existing HSV-specific antibody [48] , [49] . Locally-produced antibody in neural tissues may limit virus access to neurons, limit spread and acute replication of virus within the ganglia, and, upon reactivation from latency, interfere with virus spread from infected nerve ending to epithelial cells [50] – [52] . Plasma cells are also a source of cytokine production in inflamed tissues and B cell-derived cytokines such as IL-6, IL-12, TGF-β, and IL-10 that may play a role in regulating the inflammatory response in sites chronically infected with HSV-2.…”

Section: Discussionmentioning

confidence: 99%

Virus-Specific Immune Memory at Peripheral Sites of Herpes Simplex Virus Type 2 (HSV-2) Infection in Guinea Pigs

et al. 2014

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Despite its importance in modulating HSV-2 pathogenesis, the nature of tissue-resident immune memory to HSV-2 is not completely understood. We used genital HSV-2 infection of guinea pigs to assess the type and location of HSV-specific memory cells at peripheral sites of HSV-2 infection. HSV-specific antibody-secreting cells were readily detected in the spleen, bone marrow, vagina/cervix, lumbosacral sensory ganglia, and spinal cord of previously-infected animals. Memory B cells were detected primarily in the spleen and to a lesser extent in bone marrow but not in the genital tract or neural tissues suggesting that the HSV-specific antibody-secreting cells present at peripheral sites of HSV-2 infection represented persisting populations of plasma cells. The antibody produced by these cells isolated from neural tissues of infected animals was functionally relevant and included antibodies specific for HSV-2 glycoproteins and HSV-2 neutralizing antibodies. A vigorous IFN-γ-secreting T cell response developed in the spleen as well as the sites of HSV-2 infection in the genital tract, lumbosacral ganglia and spinal cord following acute HSV-2 infection. Additionally, populations of HSV-specific tissue-resident memory T cells were maintained at these sites and were readily detected up to 150 days post HSV-2 infection. Unlike the persisting plasma cells, HSV-specific memory T cells were also detected in uterine tissue and cervicothoracic region of the spinal cord and at low levels in the cervicothoracic ganglia. Both HSV-specific CD4+ and CD8+ resident memory cell subsets were maintained long-term in the genital tract and sensory ganglia/spinal cord following HSV-2 infection. Together these data demonstrate the long-term maintenance of both humoral and cellular arms of the adaptive immune response at the sites of HSV-2 latency and virus shedding and highlight the utility of the guinea pig infection model to investigate tissue-resident memory in the setting of HSV-2 latency and spontaneous reactivation.

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“…This result suggests that this FcγR-dependent mechanism is active very early after HSV-2 exposure and is consistent with the detection of FcγR-expressing cells capable of mediating ADCC in the genital tract within the first 2 days after HSV-2 challenge. Ab has been shown to interact with HSV at several sites including the vaginal epithelium, sensory nerve endings, nerve axons, and on the surface of infected neurons in the sensory ganglia (McDermott et al, 1984;Eis Hubinger et al, 1993;Mikloska et al, 1999;Sanna et al, 1999). The detection of populations of granulocytes and monocyte/macrophages in both genital and neuronal sites of HSV infection suggests the FcγR-dependent mechanism may have been active at either or both sites.…”

Section: Discussionmentioning

confidence: 99%

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

Chu

Meador

Young

et al. 2008

Journal of Reproductive Immunology

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The ability of antibody (Ab) to modulate HSV pathogenesis is well recognized but the mechanisms by which HSV-specific IgG antibodies protect against genital HSV-2 disease are not well understood. The requirement for Ab interactions with Fcgamma receptors (FcgammaR) in protection was examined using a murine model of genital HSV-2 infection. IgG antibodies isolated from the serum of HSV-immune mice protected normal mice against HSV-2 disease when administered prior to genital HSV-2 inoculation. However, protection was significantly diminished in recipient mice lacking the gamma chain subunit utilized in FcgammaRI, FcgammaRIII, FcgammaRIV and FcepsilonRI receptors and in normal mice depleted of Gr-1(+) immune cell populations known to express FcgammaR, suggesting protection was largely mediated by an FcgammaR-dependent mechanism. To test whether neutralizing Ab might provide superior protection, a highly neutralizing HSV glycoprotein D (gD)-specific monoclonal antibody (mAb) was utilized. Similar to results with HSV-specific polyclonal IgG, administration of the gD-specific mAb did not prevent initial infection of the genital tract but resulted in lower virus loads in the vaginal epithelium and provided significant protection against disease and acute infection of the sensory ganglia; however, this protection was independent of host FcgammaR expression and was manifest in mice depleted of Gr-1(+) immune cells. Together, these data demonstrate that substantial Ab-mediated protection against genital HSV-2 disease could be achieved by either FcgammaR-dependent or -independent mechanisms. These studies suggest that HSV vaccines might need to elicit multiple, diverse antibody effector mechanisms to achieve optimal protection.

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Neutralizing Antibodies Inhibit Axonal Spread of Herpes Simplex Virus Type 1 to Epidermal Cells In Vitro

Cited by 65 publications

References 49 publications

Prevention of Herpes Simplex Virus Induced Stromal Keratitis by a Glycoprotein B-Specific Monoclonal Antibody

Prevention of Herpes Simplex Virus Induced Stromal Keratitis by a Glycoprotein B-Specific Monoclonal Antibody

Virus-Specific Immune Memory at Peripheral Sites of Herpes Simplex Virus Type 2 (HSV-2) Infection in Guinea Pigs

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

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