Genital Herpesvirus hominis Infection in Mice. II. Treatment with Phosphonoacetic Acid, Adenine Arabinoside, and Adenine Arabinoside 5'-Monophosphate

Kern, Earl R.; Richards, James T.; Overall, James C.; Glasgow, Lowell A.

doi:10.1093/infdis/135.4.557

Cited by 44 publications

(30 citation statements)

References 23 publications

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“…The mouse model of genital HSV-2 infection has been used to evaluate therapies since 1977 (1,24). In this model, virus first replicates in the vaginal epithelium and then ascends to the dorsal root ganglia, spinal cord, and brain (33).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In most studies, local administration of chemotherapeutic drugs has been much more effective than systemic treatment against intravaginal HSV-2 infections in mice (2,11). Thus, experiments were carried out to determine whether local administration of the immunomodulator pyran would produce an enhanced antiviral effect (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…The inhibitory effects of pyran were similar to those reported for phosphonoacetic acid against orofacial (14) or intradermal (25) HSV-1 infections. Phosphonoacetic acid, however, must be administered locally beginning within hours after Virus infection to be protective (11,14,19,25). In contrast, local or systemic administration of pyran is equally effective, but the drug must be administered prophylactically to be effective (15).…”

Section: Resultsmentioning

confidence: 99%

“…Prophylaxis with pyran appears to reduce virus replication very early and prevent viral entry into the central nervous system; we have previously established that the mechanism involves the nonspecific action of activated macrophages (5,15). If the HSV-2 infection reaches the central nervous system, it evidently does not stop at the ganglionic level but progresses to the cerebellum to cause encephalitis and death (5,11,16). Immunization, on the other hand, may act at a stage in viral pathogenesis later than does pyran, reducing sufficiently the number ofganglionic cells infected, so that infection can be stopped at the ganglionic level, with subsequent survival of an animal that is latently infected with virus (20,22,23).…”

Section: Resultsmentioning

confidence: 99%

“…Included are compounds with direct antiviral properties (1,2,11,18,19) and compounds with immunomodulatory activity (3-5, 8, 12, 17). In addition, various herpes simplex virus vaccines are being tested (10,13).…”

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confidence: 99%

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Effect of Pyran on Latency After Herpes Simplex Virus Infections

Morahan

Cline

Breinig

et al. 1979

Antimicrob Agents Chemother

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The immunomodulator pyran protected mice against both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections. In infections of the lip with HSV-1, prophylactic administration of pyran reduced the severity of the herpetic lesions and enhanced their resolution, but did not decrease the high incidence of development of latent HSV-1 infection of the trigeminal ganglia. In vaginal infections with HSV-2, prophylactic administration of pyran either systemically or locally reduced mortality, reduced the incidence of mice with vaginal HSV-2 infection, and did not alter the low incidence of latent infection of the spinal dorsal root ganglia. Pyran treatinent before systemic herpetic infection after intravenous inoculation of HSV-2 also reduced mortality and virus replication, as evidenced by a decreased antibody response in the survivors, and it either reduced latent infection in the spinal dorsal root ganglia or did not predispose mice to latent infection. Treatment with the immunomodulator appeared to inhibit or reduce HSV infection early in viral pathogenesis in all three model systems, producing protection from clinical disease and resulting in less virus to induce a systemic antibody response, with either a reduction in latent virus infection or no enhancement of development of latency. In all of the HSV models, the development of latent herpetic infection was closely correlated with sufficient virus replication early in the infection to induce a systemic neutralizing-antibody response.

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Chemotherapy of Viral Infections

Jones¹

1982

Handbook of Experimental Pharmacology

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Genital Herpesvirus hominis Infection in Mice. II. Treatment with Phosphonoacetic Acid, Adenine Arabinoside, and Adenine Arabinoside 5'-Monophosphate

Cited by 44 publications

References 23 publications

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

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

Effect of Pyran on Latency After Herpes Simplex Virus Infections

Chemotherapy of Viral Infections

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