The main approaches that have been taken to chemically modify polymer surfaces are introduced and reviewed. These are wet chemical oxidation, plasma treatment, classical organic chemistry, and attachment of polymer chains. The extent to which each of these approaches can produce the specific modifications desired is discussed, and any unwanted effects that commonly occur are cited. Finally, the need for using several methods of surface analysis in concert to obtain adequate surface characterization is described.
Antibodies in sera of HIV-1 infected individuals against the HIV-1 core protein (p24), HIV-1 envelope glycoprotein (gp120) and reverse transcriptase (RT) are characterized by a skewed light chain isotype expression. The kappa/lambda ratios of antibodies to p24 and gp120 in infected individuals were found to be unique in each individual, but constant over several years independently from disease progression. The oligoclonal nature of the anti-HIV-1 antibodies suggested by skewed kappa/lambda expression was confirmed with isoelectric focusing of affinity purified antibodies to p24 and gp120. Analysis of the utilization of V gene families in purified anti-p24 and anti-gp120 antibodies revealed a restricted and biased VH gene family usage. In contrast, the utilization of VK gene families appeared to be random. The finding of stable and restricted antibody responses in infected individuals could be one of the causes for the failure to produce antibodies to HIV-1 that are effective against escape virus variants.
The efficacy of topical nitric oxide-releasing therapeutics to inhibit viral replication was demonstrated in vitro and in vivo. NVN1000 or NVN4000 drug substance, dissolved in phosphate buffered saline, was applied 1 hour/day for 6 days to organotypic cultures of primary human keratinocytes containing HPV-18 genomic replicons. Preliminary results indicate a dose responsive reduction of viral DNA copy number to less than 20% of the untreated cultures. At the highest concentrations applied (1.5 mg or 2 mg/ml), no cytotoxicity was detected, as judged from hematoxylin and eosin staining of normal or HPV-18 containing raft cultures. The NVN1000 drug substance was formulated into SB206 gel and the ability of a daily topical drug product (5 doses/week for 8 weeks) to inhibit papilloma growth in vivo was assessed in the Cottontail Rabbit Papillomavirus (CRPV) model. Dosing of SB206 gel was initiated two weeks after inoculation of CRPV viral DNA into the scarified skin sites. Topical SB206 treatment inhibited papilloma formation in a dose dependent fashion with the highest dose, 10% SB206 gel, achieving 82% inhibition compared to the Vehicle control group. Blinded histological analysis of biopsies from 10% SB206-treated animals exhibited mild hyperplasias, with an absence of viral infection as evidenced by a lack of intra-nuclear basophilic inclusions. Qualitative assessment of inflammation and quantitative cytokine gene expression was similar across all dose groups, suggesting immune activation did not account for the efficacy observed in the CRPV model and supports a direct anti-viral effect of Novan's nitric oxide releasing therapeutic agents. SB206 Gel is currently being evaluated as a topical therapy for external genital warts in a Phase 2 clinical trial.
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