ACIDFORM Inactivates Herpes Simplex Virus and Prevents Genital Herpes in a Mouse Model: Optimal Candidate for Microbicide Combinations

Tuyama, Ana C.; Cheshenko, Natalia; Carlucci, María Josefina; Li, Jin Hua; Goldberg, Cindy L.; Waller, Donald P.; Anderson, Robert A.; Profy, Albert T.; Klotman, Mary E.; Keller, Maria J.; Herold, Betsy C.

doi:10.1086/506948

Cited by 49 publications

(27 citation statements)

References 30 publications

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“…Short exposures of HSV to mildly acidic pH result in irreversible and partial inactivation of infectivity (2,9,10,20,22,23). Virtually complete, irreversible inactivation of HSV requires hours of pretreatment with mildly acidic pH (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mildly Acidic pH Triggers an Irreversible Conformational Change in the Fusion Domain of Herpes Simplex Virus 1 Glycoprotein B and Inactivation of Viral Entry

Weed

Pritchard

Gonzalez

et al. 2017

J Virol

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Herpes simplex virus (HSV) entry into a subset of cells requires endocytosis and endosomal low pH. Preexposure of isolated virions to mildly acidic pH of 5 to 6 partially inactivates HSV infectivity in an irreversible manner. Acid inactivation is a hallmark of viruses that enter via low-pH pathways; this occurs by pretriggering conformational changes essential for fusion. The target and mechanism(s) of low-pH inactivation of HSV are unclear. Here, low-pH-treated HSV-1 was defective in fusion activity and yet retained normal levels of attachment to cell surface heparan sulfate and binding to nectin-1 receptor. Low-pH-triggered conformational changes in gB reported to date are reversible, despite irreversible low-pH inactivation. gB conformational changes and their reversibility were measured by antigenic analysis with a panel of monoclonal antibodies and by detecting changes in oligomeric conformation. Three-hour treatment of HSV-1 virions with pH 5 or multiple sequential treatments at pH 5 followed by neutral pH caused an irreversible Ͼ2.5 log infectivity reduction. While changes in several gB antigenic sites were reversible, alteration of the H126 epitope was irreversible. gB oligomeric conformational change remained reversible under all conditions tested. Altogether, our results reveal that oligomeric alterations and fusion domain changes represent distinct conformational changes in gB, and the latter correlates with irreversible low-pH inactivation of HSV. We propose that conformational change in the gB fusion domain is important for activation of membrane fusion during viral entry and that in the absence of a host target membrane, this change results in irreversible inactivation of virions.IMPORTANCE HSV-1 is an important pathogen with a high seroprevalence throughout the human population. HSV infects cells via multiple pathways, including a low-pH route into epithelial cells, the primary portal into the host. HSV is inactivated by low-pH preexposure, and gB, a class III fusion protein, undergoes reversible conformational changes in response to low-pH exposure. Here, we show that low-pH inactivation of HSV is irreversible and due to a defect in virion fusion activity. We identified an irreversible change in the fusion domain of gB following multiple sequential low-pH exposures or following prolonged low-pH treatment. This change appears to be separable from the alteration in gB quaternary structure. Together, the results are consistent with a model by which low pH can have an activating or inactivating effect on HSV depending on the presence of a target membrane.KEYWORDS conformational changes, glycoprotein B, herpes simplex viruses, herpesviruses, inactivation, low pH, membrane fusion

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Section: Discussionmentioning

confidence: 99%

Mildly Acidic pH Triggers an Irreversible Conformational Change in the Fusion Domain of Herpes Simplex Virus 1 Glycoprotein B and Inactivation of Viral Entry

Weed

Pritchard

Gonzalez

et al. 2017

J Virol

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“…Because it is important to maintain the acidic environment of the vagina as a natural protective mechanism (1,26) and in order to determine whether efficacy could be improved by the use of an acid-stable AP, the acid stability of several APs was examined, and a more acid-stable AP was evaluated. This acid-stable AP, a 40mer polycytidine amphipathic DNA poly- Z29 † Ͼ100 2.9 Ϯ 1.1 4.1 ---a *, Determined by plaque reduction assay (mean of three independent experiments or the results of one experiment when no standard deviation value is given is given); †, determined by CPE assay (the mean of two independent experiments or the results of one experiment when no standard deviation value is given); †, determined by DNA hybridization assay (the mean of two independent experiments or the results of one experiment when no standard deviation value is given).…”

Section: Discussionmentioning

confidence: 99%

Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo

Bernstein

Goyette

Cardin

et al. 2008

Antimicrob Agents Chemother

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Phosphorothioated oligonucleotides have a sequence-independent antiviral activity as amphipathic polymers (APs). The activity of these agents against herpesvirus infections in vitro and in vivo was investigated. The previously established sequence-independent, phosphorothioation-dependent antiviral activity of APs was confirmed in vitro by showing that a variety of equivalently sized homo-and heteropolymeric AP sequences were similarly active against herpes simplex virus type 1 (HSV-1) infection in vitro compared to the 40mer degenerate parent compound (REP 9), while the absence of phosphorothioation resulted in the loss of antiviral activity. In addition, REP 9 demonstrated in vitro activity against a broad spectrum of other herpesviruses: HSV-2 (50% effective concentration [EC 50 ], 0.02 to 0.06 M), human cytomegalovirus (EC 50 , 0.02 to 0.13 M), varicella zoster virus (EC 50 , <0.02 M), Epstein-Barr virus (EC 50 , 14.7 M) and human herpesvirus types 6A/B (EC 50 , 2.9 to 10.2 M). The murine microbicide model of genital HSV-2 was then used to evaluate in vivo activity. REP 9 (275 mg/ml) protected 75% of animals from disease and infection when provided 5 or 30 min prior to vaginal challenge. When an acid-stable analog (REP 9C) was used, 75% of mice were protected when treated with 240 mg/ml 5 min prior to infection (P < 0.001), while a lower dose (100 mg/ml) protected 100% of the mice (P < 0.001). The acid stable REP 9C formulation also provided protection at 30 min (83%, P < 0.001) and 60 min (50%, P ‫؍‬ 0.07) against disease. These observations suggest that APs may have microbicidal activity and potential as broad-spectrum antiherpetic agents and represent a novel class of agents that should be studied further.Microbicides are intended to prevent the transmission of sexually transmitted infections (STIs) from one sexual partner to another. The ideal microbicide would be completely safe and broadly effective against a variety of STIs (reviewed in reference 9). Despite recent setbacks, including failed trials of nonoxynol 9, Savvy (C31G), and cellulose sulfate (6), there are more than 30 other microbicides being investigated (9). Because genital herpes infections are not only one of the most common STIs but also have recently been shown to have profound effects on the spread of human immunodeficiency virus (HIV), they have been another major target for microbicides (reviewed in references 11 and 8). Thus, several preclinical microbicide evaluations have used animal models of genital herpes for the initial testing (20).Recently, the use of a novel class of compounds, phosphorothioate oligonucleotides (PS-ONs), has been suggested as a promising microbicide approach (17). The presence of sequence-independent antiviral activity with PS-ONs in HSV has been previously described (10,12,13). Recently, this sequenceindependent antiviral activity of PS-ONs was more clearly elucidated in HSV and other viruses (17,22,27) and was shown to be derived from the chemical nature of PS-ONs amphipathic polymers, independent of the ...

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“…The gel was generally well tolerated, however, one study in Brazil reported mild to moderate vulvar irritation when applying Acidform gel followed by sexual intercourse [127]. Another study showed that Acidform inactivates HSV and prevents genital herpes [128]. A phase I safety and acceptability study compared the use of Acidform, BufferGel and KY Jelly in combination with a diaphragm and found no serious adverse events [129].…”

Section: Vaginal Milieu Protectorsmentioning

confidence: 99%

HIV sexual transmission and microbicides

Ariën

Jespers

Vanham

2011

Reviews in Medical Virology

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Pathogens often rely on the contacts between hosts for transmission. Most viruses have adapted their transmission mechanisms to defined behaviours of their host(s) and have learned to exploit these for their own propagation. Some viruses, such as HIV, the human papillomavirus (HPV), HSV-2 and HCV, cause sexually transmitted infections (STIs). Understanding the transmission of particular viral variants and comprehending the early adaptation and evolution is fundamental to eventually inhibiting sexual transmission of HIV. Here, we review the current understanding of the mechanisms of sexual transmission and the biology of the transmitted HIV. Next, we present a timely overview of candidate microbicides, including past, ongoing and future clinical trials of HIV topical microbicides.

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ACIDFORM Inactivates Herpes Simplex Virus and Prevents Genital Herpes in a Mouse Model: Optimal Candidate for Microbicide Combinations

Cited by 49 publications

References 30 publications

Mildly Acidic pH Triggers an Irreversible Conformational Change in the Fusion Domain of Herpes Simplex Virus 1 Glycoprotein B and Inactivation of Viral Entry

Mildly Acidic pH Triggers an Irreversible Conformational Change in the Fusion Domain of Herpes Simplex Virus 1 Glycoprotein B and Inactivation of Viral Entry

Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo

HIV sexual transmission and microbicides

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