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Marla J Keller

Publications and source records attributed to Marla J Keller.

14 recordsLinked to original sources
PubMed2006

Human alpha- and beta-defensins block multiple steps in herpes simplex virus infection.

This study examined the ability of nine human defensins (HD) to protect against herpes simplex virus infection. Noncytotoxic concentrations of all six alpha-defensins (HNP1-4, HD5, and HD6) and human beta-defensin (hBD) 3 inhibited HSV infection. Two other beta-defensins, hBD1 and 2, lacked this protective activity. Synchronized assays revealed that HNP-4, HD6, and hBD3 acted primarily by preventing binding and entry, whereas HNP1-3 and HD5 also inhibited postentry events. Even when added several hours after entry, substantial reduction in viral gene expression ensued. Human cervical epithelial cells incubated with HNP-1 or HD5 accumulated the peptides intracellularly. Surface plasmon resonance studies revealed that HNPs 1, 2, 3, and HD5 bound HSV glycoprotein B (gB) with high affinity, but showed minimal binding to heparan sulfate, the receptor for attachment. In contrast, HNP-4 and HD6 bound heparan sulfate, but not gB. HBD3 bound both gB and heparan sulfate, but hBD1 and hBD2 bound neither. Admixture of HD5 with hydroxyethylcellulose significantly protected mice from a viral challenge lethal to controls receiving an inactive peptide or hydroxyethylcellulose alone. These findings demonstrate that HDs act at multiple steps in the HSV life cycle and support the development of defensins or defensin-like peptides as microbicides.

Animals↗
PubMed2006

ACIDFORM inactivates herpes simplex virus and prevents genital herpes in a mouse model: optimal candidate for microbicide combinations.

The acidic vaginal milieu is presumed to inactivate pathogens but is neutralized by semen. This notion fostered the development of acid-buffering products, such as ACIDFORM (developed by Program for Topical Prevention of Conception and Disease, Rush University, and licensed by Instead), as microbicides. However, the extent and mechanism of protective activity provided by buffering gels is not known. Exposure of herpes simplex virus (HSV) to pH 4.5 or lower irreversibly inactivated HSV and reduced HSV yields by at least 90%; exposure to pH 5.0 had little or no effect. Pretreatment of HSV-2 with pH 3.5-4.5 triggered proteolysis, disrupting the HSV particle and resulting in a reduction in binding and invasion. ACIDFORM protected 21 (81%) of 26 mice from genital herpes, compared with 3 (12%) of 25 mice who received a placebo gel. ACIDFORM retained significant activity if mice were challenged with HSV delivered in seminal fluid. These findings suggest that ACIDFORM offers considerable protection against HSV and may be an optimal candidate for developing combination microbicides.

Animals↗
PubMed2006

Prioritizing prevention of HIV and sexually transmitted infections: first-generation vaginal microbicides.

PURPOSE OF REVIEW: As the HIV/AIDS pandemic continues unabated, novel control measures for the spread of HIV and other sexually transmitted infections are urgently needed. Topical microbicides are designed to prevent transmission of sexually transmitted infections when applied vaginally. The microbicides discussed in this review may provide a new opportunity for decreasing the spread of HIV and other sexually transmitted infections. RECENT FINDINGS: Epidemiological studies suggest a synergistic relationship between HIV and sexually transmitted infections, particularly between HIV and genital herpes infection. Compounds have been developed to block transmission of HIV-1 and herpes simplex virus, as well as Neisseria gonorrhoea and Chlamydia trachomatis. Several of these compounds have advanced to clinical trials as candidate microbicides. Candidate compounds fall into the following categories: detergents or surfactants that inactivate viral particles, anionic polymers that block attachment of virus to target cells, vaginal acid-buffering agents that maintain a protective vaginal pH, and antiretroviral drugs specific for HIV. Evaluation of the safety of topical microbicides remains problematic. Clinical experiences indicate that current models to assess safety in vitro and in vivo may be insufficient to assess the safety of vaginal microbicides. A critical direction of future studies is to identify which assay(s) provide surrogate laboratory markers of safety that correlate with clinical outcomes. SUMMARY: The spread of HIV, and its increasing burden of disease in women, necessitates the development of novel prophylactic strategies. Topical microbicides offer women an empowering preventative option but require vigorous testing for safety and effectiveness.

Administration, Intravaginal↗
PubMed2005

PRO 2000 gel inhibits HIV and herpes simplex virus infection following vaginal application: a double-blind placebo-controlled trial.

BACKGROUND: Microbicides used to prevent the transmission of human immunodeficiency virus (HIV) are advancing to clinical trials on the basis of activity observed in vitro and in animal models. However, no data demonstrate activity of microbicides after application in humans. This study was designed to determine the antiviral activity in cervicovaginal lavage (CVL) samples collected after intravaginal application of 0.5% PRO 2000 gel (Indevus). METHODS: A randomized, double-blind study was conducted to assess the anti-HIV and anti-herpes simplex virus (HSV) activity of PRO 2000 in CVL samples obtained at screening (48 hours before) and 1 hour after application of study or placebo gel. HeLa cells or human macrophages were inoculated with CVL samples spiked with replication-defective HIV containing a luciferase indicator gene and pseudotyped with an R5 envelope. Human cervical epithelial cells were inoculated with CVL samples and challenged with HSV-2(G), and the virus titer was then determined. RESULTS: CVL samples obtained after application of PRO 2000 gel significantly inhibited HIV and HSV infection by at least 1000-fold, compared with CVL samples obtained at screening (P < .001). There were no differences in cytokine levels between the drug and placebo groups. CONCLUSIONS: PRO 2000 gel (0.5%) is sufficiently bioavailable and retains substantial antiviral activity after intravaginal application. This strategy provides a mechanism for testing the efficacy of a microbicide before embarking on large-scale clinical trials.

Administration, Intravaginal↗
PubMed2005

Cervicovaginal secretions contribute to innate resistance to herpes simplex virus infection.

Defining and preserving the innate antiviral activity found in cervicovaginal secretions is critical. Cervicovaginal lavage (CVL) samples were obtained from 20 healthy women and evaluated for anti-herpes simplex virus (HSV) activity. CVL samples reduced HSV-2 yields by 23-fold (median), and the anti-HSV activity of CVL samples correlated with the concentration of human neutrophil peptides (HNP)-1-3. Both CVL samples and HNP-1-3 interacted with virus and prevented entry after binding. Substantially less protective activity was observed in CVL samples obtained from 20 human immunodeficiency virus--infected subjects, but the addition of CVL samples from healthy subjects enhanced the antiviral activity. The significance of the innate activity was further demonstrated by showing that CVL samples prevented murine genital herpes. Fourteen of 15 mice were protected from genital herpes if they were challenged with HSV-2 pretreated with CVL samples from healthy subjects. In contrast, all 15 mice challenged with untreated HSV-2 died. These findings are evidence that cervicovaginal secretions contribute to innate resistance to HSV-2 and identify defensins as contributors to this activity.

Adult↗
PubMed2005

Topical microbicides for the prevention of genital herpes infection.

Genital herpes is one of the most prevalent sexually transmitted infections worldwide and is the most common cause of genital ulcers. Despite increased public awareness and the initiation of efforts to prevent transmission, the prevalence of herpes simplex virus (HSV) type 2 continues to increase. What makes HSV so difficult to control is that most sexual and perinatal transmission occurs during unrecognized or asymptomatic shedding. The impact of genital herpes as a public health threat is amplified because of its epidemiological synergy with HIV/AIDS. Thus, there is an urgent need for novel prophylactic methods, such as topical microbicides designed for genital application, to prevent both HSV and HIV transmission. Several candidate microbicides are being advanced to clinical trials based on in vitro activity and animal studies. These include compounds that inactivate virus directly, those that enhance innate immunity, and drugs that block viral binding and entry. A more vigorous evaluation of the safety of these and other candidate topical microbicides in development should include assessment of the impact of repeated application on innate host defences in the genital tract.

Administration, Intravaginal↗
PubMed2005

Role of mucosal immunity in preventing genital herpes infection.

The female genital tract is immunologically unique because it must be tolerant to spermatozoa, pregnancy, and vaginal flora, but also protect the host from pathogen challenge. The mucosal response to herpes simplex viruses (HSV), a major cause of genital ulcerative disease and critical co-factor in the HIV/AIDS epidemic, is complex and consists of the normally acidic vaginal environment, constitutively secreted and induced antimicrobial peptides, complement, and cellular responses mediated by epithelial and immune cells. This review summarizes our current understanding of the mucosal response to HSV focusing on those factors that may prevent initial infection. Understanding how each of these components contribute to innate immunity, mechanisms of antiviral activity, and whether the virus has evolved strategies to evade their effects may lead to the development of novel vaginal microbicides.

Female↗
PubMed2005

Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action.

Poly(styrene 4-sulfonate), cellulose sulfate, polymethylenehydroquinone, and PRO 2000 are sulfated or sulfonated polymers (SPs) under development as topical microbicides. They are presumed to work through similar mechanisms of action, although to date there has been no extensive comparison of their anti-human immunodeficiency virus activities. To determine whether any of these candidate microbicides offers a potential advantage, their in vitro activities, mechanisms of action, stabilities in biological secretions, and toxicities were compared. All four compounds were found to be active against X4, R5, and dualtropic primary isolates and against X4 and R5 laboratory-adapted strains in CD4+ T cells, macrophages, and single-coreceptor cell lines. Our single-cycle experiments using pseudotyped virus suggest that all four SPs function at the binding and entry stages of the viral life cycle but differ in degree of postentry effect. Surface plasmon resonance analyses demonstrate that SPs bind to X4 and R5 monomeric glycoprotein 120 with similar high binding affinities. When mixed with cervicovaginal lavage fluid, SPs maintain inhibitory activity at concentrations achievable in formulations.

Administration, Topical↗
PubMed2004

Solid organ transplantation in HIV-infected recipients.

HIV is generally regarded as an acceptable reason to exclude a potential recipient from consideration for transplantation. Most of the data in the literature regarding transplantation of HIV sero-positive individuals pertains to the time prior to the administration of Highly Active Anti-Retroviral Therapy (pre-HAART). This data, therefore, provides little guidance for the management of HIV-positive individuals in the current era. The development of HAART has resulted in a decreased mortality. With prolonged survival more HIV-infected individual are developing end stage organ disease from co-existing conditions such as HCV and HBV, and diseases common in the general population such as diabetes mellitus and hypertension. This has lead to clinicians, researchers and patients to actively investigate the role of solid organ transplantation in HIV-infected individuals. In this article We review the literature to date in liver and renal transplantation, including more recent data in patients receiving HAART.

AIDS-Associated Nephropathy↗
PubMed2004

Candidate topical microbicides bind herpes simplex virus glycoprotein B and prevent viral entry and cell-to-cell spread.

Topical microbicides designed to prevent acquisition of sexually transmitted infections are urgently needed. Nonoxynol-9, the only commercially available spermicide, damages epithelium and may enhance human immunodeficiency virus transmission. The observation that herpes simplex virus (HSV) and human immunodeficiency virus bind heparan sulfate provided the rationale for the development of sulfated or sulfonated polymers as topical agents. Although several of the polymers have advanced to clinical trials, the spectrum and mechanism of anti-HSV activity and the effects on soluble mediators of inflammation have not been evaluated. The present studies address these gaps. The results indicate that PRO 2000, polystyrene sulfonate, cellulose sulfate, and polymethylenehydroquinone sulfonate inhibit HSV infection 10,000-fold and are active against clinical isolates, including an acyclovir-resistant variant. The compounds formed stable complexes with glycoprotein B and inhibit viral binding, entry, and cell-to-cell spread. The effects may be long lasting due to the high affinity and stability of the sulfated compound-virus complex, as evidenced by surface plasmon resonance studies. The candidate microbicides retained their antiviral activities in the presence of cervical secretions and over a broad pH range. There was little reduction in cell viability following repeated exposure of human endocervical cells to these compounds, although a reduction in secretory leukocyte protease inhibitor levels was observed. These studies support further development and rigorous evaluation of these candidate microbicides.

Anti-Infective Agents, Local↗
PubMed2002

Male sexual dysfunction associated with antiretroviral therapy.

To determine whether treatment with protease inhibitors (PIs) is associated with male sexual dysfunction, we conducted a retrospective, cohort study of 254 adult male PI recipients who received care from the staff-model division of a large managed care organization in New England between 1993 and 1998. After a median of 5.0 years of observation, 80 incident cases of sexual dysfunction were observed. Relative to unexposed individuals, the rate of sexual dysfunction adjusted for confounding was most elevated with use of ritonavir (hazard ratio [HR], 2.83; 95% confidence interval [CI], 1.34-5.97; p =.006) followed by indinavir (HR, 1.69; 95% CI, 0.84-3.37; p =.14), nelfinavir (HR, 1.53; 95% CI, 0.66-3.54; p =.32) and saquinavir (HR, 1.25; 95% CI, 0.53-2.96; p =.60). We conclude that PIs, especially ritonavir, appear to increase the risk of sexual dysfunction.

Adolescent↗
PubMedDate not supplied

Impact of microbicides and sexually transmitted infections on mucosal immunity in the female genital tract.

Human immunodeficiency virus, genital herpes, and other sexually transmitted infections are a critical national and global health priority requiring the rapid development of safe and effective control methods. Topical microbicides, self-administered agents designed for vaginal use, that block transmission at the mucosal surface may provide a realistic method of intervention that could be distributed worldwide. An optimal microbicide should protect against infection but must also be safe, without adversely affecting the mucosal environment, including mediators of host defense. Thus, a critical component in microbicides development is to identify optimal assays that could serve as surrogate markers to predict safety of microbicides prior to embarking on large-scale clinical trials. This will require a greater understanding of the mediators of mucosal immunity in the female genital tract.

Animals↗