Abstract
President's message (Amy Patick)
I am once again very pleased to address the Society following a successful 22nd International Conference on Antiviral Research (ICAR) meeting, held 3–7 May in Miami Beach, FL, USA.
The meeting this year was attended by approximately 300 delegates. While we missed some of our colleagues who could not make the meeting because of various challenges associated with the emergence of the influenza A H1N1 outbreak, we thank all of you who were able to travel and join us.
The scientific program, provided by the Program Chair, Bob Buckheit, was very well received by those at the meeting. We continued to make innovations to the scientific program, which this year included a drug discovery and development session on Sunday afternoon. This featured talks by Chris Lipinski, on medicinal chemistry and lead product discovery, and Shayne Gad, on product development and the path to an investigational new drug (IND). The talks were followed by an interactive panel discussion on antiviral drug development ‘successes and failures’. As well as the mini-symposium on development of novel therapies for hepatitis C, we included an additional special session on ‘topical microbicides’, an area that has not been emphasized at previous ICARs. During the Conference, I was honoured to present the major ISAR awards to two remarkable scientists who have made significant contributions to antiviral research: the Gertrude Elion Memorial Lecture Award to Karen Biron and the William Prusoff Young Investigator Lecture Award to Mark Prichard.
There are many others who worked tirelessly to make this meeting happen whom I acknowledge with special thanks: my fellow officers (Joe Colacino, Chris McGuigan, Susan Cox and Dale Barnard); our Committee Chairs including Chris McGuigan (Conference), Phil Furman and Roger Ptak (Finance), Johan Neyts (Membership), Joe Colacino (Career Breakfasts), Jack Secrist (Nominations), Hugh Field (Publications), Susan Cox (Travel Awards), Rich Whitley (Scientific Excellence Awards), Mark Prichard (Poster Awards) and Andrea Brancale (Web Manager); Anthony Vere Hodge for his excellent scientific summary of the meeting and for assembling this newsletter; John Odom for his invaluable audiovisual services at ICAR; and John Drach for his sage advice and access to his photo archive. I also congratulate Susan Cox on her election to the position of Secretary of ISAR, and Mike Bray and Mark Prichard on their elections to the ISAR Board.
We again conducted an electronic survey following the conference, which provided valuable feedback from approximately 65 attendees. Overall, greater than 87% of attendees were satisfied or very satisfied with the meeting. The award lectures as well as the two mini-symposa were well attended and identified as high points by many delegates. Many of you asked for a social forum specific for students and young investigators to provide a greater opportunity to network. Your comments also highlighted a unique strength of ICAR: its chemistry and biology perspectives on a broad range of topics covering antiviral drugs against different viruses at all stages of discovery and development. As this broad approach appeals to many of you, we will continue to adopt these principles while varying each year the areas for special focus. The cost of attending the meeting was also highlighted and is an area to which ISAR will give greater attention in the future.
Finally, it was pleasure to see many returning ICAR delegates and to welcome new faces into the society. I wish all of you every success in your research and professional activities in the coming year, and we look forward to your abstract submission and attendance at the 23rd ICAR (25–28th April 2010, Hyatt Regency Hotel, San Francisco, CA, USA).
Corporate sponsors: Elsevier, ImQuest BioSciences, Inc., The International Partnership for Microbicides, Genelabs Technolgies, Inc., NIH, Pfizer, Inc, Idenix Pharmaceuticals, PTC Therapeutics, Boehringer Ingelheim (Canada), Abbott Laboratories, Chimerix, Southern Research Institute, Gilead Sciences, GlaxoSmithKline, Pharmasset, Inc, Microbiotix, Avexa Ltd., Tibotec, Debiopharm, JCR Pharmaceutical Co., Ltd., Toyoma Chemical Co., Ltd., Roche Palo Alto, Romark, Vertex, Biota Holdings
22nd ICAR highlights (Anthony Vere Hodge)
Introduction
This review of the 22nd ICAR provides an overview of the conference highlights. As this is a research conference, any references to clinical results should not be taken as a recommendation for clinical use. I wish to thank all those authors who have kindly provided me with copies of their presentations.
This report does not follow the chronology of the meeting, but starts with the presentations by the winners of the society's two major awards. These are followed by the keynote address, the three mini-symposia, a plenary lecture and contributed presentations. Occasionally, I have added my own aside.
Gertrude Elion Memorial Lecture Award: Following acyclovir: The quest for a more potent CMV drug by Karen Biron (Pathfinder Pharmaceuticals Inc. Raleigh, NC, USA)
Karen Biron introduced herself as one who had gained much from Trudy Elion's influence. Acyclovir was the first truly selective antiherpetic agent, with good activity against herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), and Epstein–Barr Virus (EBV), but only modest activity against human cytomegalovirus (HCMV). Screening other nucleoside analogues indicated that ganciclovir (GCV) had good activity against HCMV.
Fortuitously, Biron obtained a GCV-resistant double mutant selected by Dr Don Coen. Their two laboratories collaborated in the genetic mapping of GCV resistance to the HCMV UL97 gene. A separate collaboration was initiated with Drs Leroy Townsend and John Drach at the University of Michigan to investigate benzimidazoles as novel inhibitors of HCMV. This collaboration led to the discovery of GW275175X and 1263W94 (maribavir; see Figure 1).
Gertrude Elion Memorial Lecture Award winner: Karen Biron
For GW275175X, the target enzymes are encoded by HCMV UL89 and/or UL56, which cleave the high molecular weight herpes viral DNA as it is packaged into capsids. GW275175X has been evaluated in a Phase I trial: after oral dosing, there was a linear increase in maximum concentration (Cmax) and area under the curve (AUC) over 100–1,200 mg dose range, long plasma half-life (12–15 h) and the compound was well tolerated.
A surprise came with the demonstration that maribavir had yet another novel target: UL97 protein kinase. Maribavir is highly selective for HCMV UL97 kinase, but without activity against 71 human kinases. In a Phase I/II study in HIV-positive patients, although there was only a 1.3 log10 reduction in HCMV DNA by PCR, there was nearly a 4 log10 reduction in semen HCMV infectivity titre.
In conclusion, the quest for more potent inhibitors of HCMV was successful: two drug candidates were identified, each having a novel mode of action. Both compounds were progressed into Phase I trials and were subsequently licensed out.
William Prusoff Young Investigator Lecture Award: Viral kinases as targets for antiviral therapy by Mark Prichard (University of Alabama, Birmingham, AL, USA)
The importance of viral thymidine kinase (TK), for activating anti-herpes compounds, was identified by William (Bill) Prusoff and colleagues in the mid 1970s. It was first shown for acyclovir by Gertrude B Elion in 1977. Later, the protein kinase encoded by HCMV UL97 was shown to activate GCV (see Elion Memorial Lecture Award). This lecture focused on one of many roles of UL97 kinase. But first, a useful measure of synergy between drugs was described. This was developed by the speaker with Charles Shipman, Jr. Free downloads of an Excel spreadsheet, MacSynergy II, are available on the web (http://main.uab.edu/peds/Templates/Inner.aspx?pid=118889).
One aspect of innate immunity is to sequester low complexity (for example, viral) proteins into aggresomes. In HCMV-infected cells, the expected formation of aggresomes is inhibited; however, when treated with maribavir, aggresomes are formed and these contained large quantities of virion proteins. Cotransfection of HCMV genes led to the identification of two genes, pp71 and IE1, which also altered aggresome formation. This was a fortuitous discovery that led to the discovery that pUL97 kinase activity is required for inactivation of the host retinoblastoma (Rb) protein. Rb has a critical role in regulating the cell cycle by repressing E2F, which would otherwise stimulate the host cell into growth and replication. Maribavir, by inhibiting the kinase activity of UL97, prevents Rb inactivation and maintains the repression by E2F.
In summary, UL97 kinase seems to mimic the host cyclin-dependent kinase. Both proteins phosphorylate (inactivate) Rb, thereby releasing the repression of E2F. It is known that viral oncoproteins result in the inactivation of Rb, so could UL97 kinase have oncogenic properties? If so, then maribavir might be useful in the treatment in any HCMV-induced proliferative disorders if these were to be identified.
Keynote address: Beautiful biology but bad chemistry by Christopher Lipinski (Melior Discovery, Waterford, CT, USA)
Christopher Lipinski gave both the opening presentation of the conference and the keynote address.
As a candidate drug moves from an initial hit in a high-throughput screen (HTS) through to clinical trials, rapidly increasing resources are needed. Therefore, it is important to check the chemistry at an early stage; always re-synthesize compounds to check that it is the stated compound.
William Prusoff Young Investigator Lecture Award winner: Mark Prichard
Of all human proteins, only about 3,000 have a site suitable for drug binding and, of these, perhaps only 100 might be medically useful. A protein might have excellent biology (for example, essential to bacteria but not humans) but poor chemistry (no drug-binding site); therefore, it is not a good target. The author is well known for his ‘rule of five’ (see Box 1), which actually has only four rules! These were devised having considered 7,483 named drugs. If a candidate compound has any one of these undesirable attributes, consider carefully if it should be progressed. If it has more than one of these properties, it is unwise to progress. The fifth rule might be that there are always exceptions, for example, if the compound is a substrate for a natural transporter.
Mini-symposium: Development of novel therapies for hepatitis C virus (HCV)
It is planned to publish this mini-symposium as a review in Antiviral Research; therefore, this report includes only a brief summary of each presentation.
Innate immune responses in HCV infection by Stanley Lemon (University of Texas, Galveston, TX, USA)
The HCV protease, NS3/4A, has a major role in disrupting the host immune response to the viral infection. Therefore, is it possible that an antiviral protease inhibitor might have dual benefits, not only disrupting the viral replication but also restoring the host immune response? The data so far indicate that protease inhibitors are unlikely to have such an additional benefit.
The complexities of HCV entry by Jane McKeating (University of Birmingham, Birmingham, UK)
There are three routes for viral spread: direct entry of the virion into a liver cell, by cell-to-cell contact and via attachment to B-cells. For virion entry, scavenger receptor B1 (SR-B1) seems to be the first point of attachment. Then the tetraspanin (CD81) and the tight junction proteins (claudin-1 [CLDN-1] and clathrin [OCLN]) act during the late stage of the entry process. HCV infection in Huh-7 cells in culture gives discrete areas of infected cells, suggesting the cell-to-cell transfer of virus is a major factor in viral spread. This route seems to be independent of CD81 and OCLN. HCV binds to B-cells, enhancing their adhesion to Huh-7 cells which then become infected. B cells express SR-B1 and CD81, which would explain the initial attachment of the virion to the cell, but the lectins, DC-SIGN and L-SIGN, are important for the transinfection to liver cells.
Box 1. Christopher Lipinski's rule of five for oral bioavailability: Attributes to avoid
Solubility; log P >5
Molecular weight >500
Sum of oxygen and nitrogen atoms >10
Number of hydrogen donors >5
Targeting HCV NS2: An unusual protease with multiple functions by Thomas Pietschmann (TWINCORE-Center, Hanover, Germany)
There are a number of compounds inhibiting the major protease (NS3), but the minor protease (NS2) has been largely neglected. Whereas NS3 cleaves the HCV polyprotein at four positions, NS2 catalyses a cleavage at a single site, the NS2–NS3 boundary. The protein has a C-terminal cytoplasmic domain that is sufficient for catalytic activity. The structure of this domain has been solved. Although the active site has similarities to other proteases, the structure seems to be novel.
Having a fully permissive cell culture infection system for HCV has enabled the multiple roles of NS2 to be investigated. Not only is the cleavage of the HCV polyprotein essential, but NS2 seems to have a vital role in virus assembly and various effects on the host cell. These recent findings should encourage the development of NS2 protease inhibitors.
New methods to identify and analyse HCV helicase inhibitors by David Frick (New York Medical College, New York, NY, USA)
The HCV NS3 gene encodes a protein with two catalytic activities, protease and helicase. The crystal structure of the helicase, with and without RNA, has been solved. The helicase portion of NS3 is a Y-shaped molecule; there is an ATP-binding site and an ssRNA-binding cleft. A second ssRNA strand might bind in the cleft separating the helicase and protease portions of the protein.
The author's research group has devised a successful assay using a fluorescent tag bound to RNA which, because of its sequence, forms hairpins after being released by the helicase activity. A few new classes of inhibitors are being evaluated against a panel of viral and human helicases.
New targets within HCV: NS4B by Jeffrey Glenn (Stanford University, Stanford, CA, USA)
Until recently, NS4B protein was without a known function. HCV genome replication is associated with intracellular membraneous web-like structures, which form in HCV-infected cells. NS4B has been shown to be both necessary and sufficient to induce the formation of these structures. Furthermore, the author's group discovered that NS4B has an RNA-binding site, which was specific for the 3′ terminus of negative-strand HCV RNA. A screen identified clemizole hydrochloride as an inhibitor of NS4B RNA binding. Clemizole was used clinically in the USA in the 1950s and 60s as an antihistamine. It inhibited HCV replication, resistant replicon strains were obtained and sequencing revealed mutations in either NS4B or the 3′-terminus of the negative-strand RNA. Clemizole was found to be highly synergistic when used with the protease inhibitor SCH503034. This combination also delayed the emergence of resistant HCV.
In conclusion, NS4B is now known to have a vital role in the replication of HCV. Furthermore, this work provides an interesting new use for an old compound.
The HCV NS5A protein by Timothy Tellinghuisen (The Scripps Research Institute, Jupiter, FL, USA)
HCV NS5A protein has three domains, designated I, II and III. Previous work had implicated domain I having a role in viral RNA replication. The author's group demonstrated that domain II was also involved, but that domain III was not. However, a deletion in domain III was found to block HCV infectious virus production without any effect on viral RNA replication. Further work showed that a single serine, at position 457 within this deletion, was critical for infectivity. This serine lies in a motif predicted to be a phosphorylation site for casein kinase II (CKII) and it seems to be acting as a phosphorylation switch to move from RNA synthesis to virion packaging.
Clinical symposium: Clinical update on antiviral drugs
Filibuvir, a non-nucleoside reverse transcriptase inhibitor (NNRTI) for HCV by Jennifer Hammond (Pfizer, Groton, CT, USA)
Filibuvir (FBV; formerly PF-00868554) has similar activities against HCV genotypes 1a and 1b, but has limited activities against other genotypes. FBV binds to the HCV RNA polymerase at the site known as Thumb 2. The major resistance mutation is M423T.
A Phase II trial compared FBV (200, 300 and 500 mg twice daily for 4 weeks) in treatment-naive HCV patients (none with HIV). All patients were on standard of care, which was continued during the observation period (to week 12). Combining the FBV groups, 17 of 26 patients had undetectable HCV RNA at week 4. All patients who achieved a rapid virological response had undetectable HCV RNA at week 12. Adverse events were similar to those on standard of care alone.
Tenofovir disoproxil fumarate (Viread®) in the treatment of chronic hepatitis B virus (HBV) by Tomas Cihlar (Gilead Sciences, Foster City, CA, USA)
Tenofovir (TFV, 300 mg once daily) was approved in Europe in April 2008 and in the USA in August 2008. In two registration trials (102 and 103), TFV was compared with adefovir (ADV) in hepatitis Be antigen (HBeAg)-negative and HBeAg-positive patients, respectively. Dosing (300 mg of TFV or 10 mg of ADV once daily) was from week 0 to 48. Then patients were offered open-label TFV to week 240 (∼5 years). This presentation reported the data at 96 weeks. With the longer treatment times, there is a slow but continuing seroconversion, initially with HBeAg and later with hepatitis B surface antigen, the latter being considered a ‘cure’ (1.3% at weeks 48 and 5% at week 96).
At each year-end, every patient with >400 copies/ml HBV DNA is tested for viral resistance. So far, no true resistance has been detected.
Clinical development of CMX001 by Neil Frazer (Chimerix Inc., Durham, NC, USA)
A Phase I trial in healthy patients with CMX001 (hexadecyloxypropyl prodrug of cidofovir) has been started with doses ≤2 mg/kg for a single dose and ≤1 mg/kg for multiple dosing. Because there was concern about the possible gastrointestinal effects, each patient has been followed with a pill-cam (a small camera). No effects were seen. Blood levels of CMX001 were much greater than in mice. Tablets and solution were compared; the time to maximum concentration (Tmax) was delayed by about 1 h with tablets, but AUCs were similar. After a high-fat meal, AUC was reduced by 40%. There was no accumulation of CMX001.
A Phase II trial, for the prevention of HCMV, is open for enrolment in kidney or stem cell transplant patients.
Apricitabine: An NRTI with a unique barrier to HIV resistance by Susan Cox (Avexa, Richmond, VIC, Australia)
Clinical study AVX 201 investigated apricitabine (ATC, AVX 754 or (−)dOTC) in HIV patients failing lamivudine (3TC)/emtricitabine (FTC) therapies, all with the M184V mutation. Until day 21, twice-daily dosing was with ATC (800 or 600 mg) or 3TC (150 mg). Treatment was effectively monotherapy until day 21 when the background therapy was optimized. After week 24, all patients were put on open-label ATC. The key results from this trial were that the M184V strain remained in most patients and, with a few patients now reaching 96 weeks, no HIV resistance to ATC has been detected.
Development of a pharmacokinetic enhancer without anti-HIV activity by Anita Mathias (Gilead Sciences, Foster City, CA, USA)
The HIV integrase inhibitor elvitegravir (EVG) is in Phase III trials with ritonavir to improve EVG bioavailability. There was a concern that the low dose of ritonavir might give rise to HIV protease mutations, so a pharmacokinetic (PK) enhancer, without HIV activity, was sought. This led to the development of GS-9350.
The aim is to have a ‘quad’ tablet with EVG (150 mg), FTC (200 mg), TDF (300 mg) and GS-9350 (50, 100 or 150 mg). The 150 mg dose of GS-9350 was chosen for progression. With 14-day dosing to date, there have been no safety issues. The quad tablet gave the expected bioavailabilities of each component and it is in a Phase III trial versus Atripla®. The primary endpoint is the proportion of patients achieving <50 copies/ml HIV RNA.
The safety and pharmacokinetics of FV-100 by Amy Morris (Inhibitex Inc., Alpharetta, GA, USA)
This presentation reported two Phase I trials of FV-100 (oral prodrug for Cf-1743): the first in healthy patients aged 18–55 years old and the second in older patients (≥65 years old).
In the first trial, ascending doses (100, 200, 400 and 800 mg) once daily and 400 mg twice daily of FV-100 were given orally for 7 days. For safety evaluation, patients were followed to day 22. All adverse events were comparable to placebo. The PK profiles of Cf-1743 confirmed that there was rapid conversion from FV-100 to Cf-1743. For Cf-1743, Cmax and AUC increased by more than proportional to dose over the dose range studied. There appeared to be a modest accumulation (<twofold) with multiple dosing. Concentrations of Cf-1743 remained above the EC50 value (170 pg/ml) for 24 h with all doses studied.
In the study with elderly patients, FV-100 (400 mg) was given as a single dose or once daily for 7 days. Generally, the results were similar in the two trials; however, the elderly tended to report less adverse events.
Mini-symposium: Perspectives and challenges in the development of topical microbicides
A microbicide perspective by Sharon Hillier (University of Pittsburgh, Pittsburgh, PA, USA)
In stark contrast to expectations, Nonoxynol-9 increased the risk for HIV. This experience emphasized the need for testing ‘obvious’ treatments in proper clinical trials. After several failed trials with various agents, the first positive result was with 0.5% PRO2000. The lessons are that in vitro studies overestimate efficacy of candidate agents and that mouse HSV-2 models are not good predictors for microbicides.
Microbicide product development by Jim Turpin (NIH/NIAID/DAIDS, Bethesda, MD, USA)
In 2001, NIAID proposed a screening algorithm for testing microbicides. This was updated, published in Antiviral Agents and Chemotherapy (2008;
Formulation of compounds for vaginal and rectal delivery by Patrick Kiser (University of Utah, Salt Lake City, UT, USA)
As adherence is a major problem, vaginal rings, currently with 30-day duration, are being evaluated. These rings can have several segments, so that the formulation can be optimized for each compound. Formulation for vaginal delivery might be difficult, but rectal delivery has many more problems, both scientific and political. However, rectal delivery needs to be considered because a survey among heterosexual couples indicated that rectal sex was not uncommon.
Development of microbicides with broad-based anti-infective action by Betsy Herold (Albert Einstein College of Medicine, Bronx, NY, USA)
HSV-2 seropositivity is associated with increased risk (two to fivefold) of acquiring HIV, so suppressive therapy with acyclovir should help; however, two trials showed no effect. In a trial testing PRO2000 (see above), gel samples were taken from patients 1–2 h after administration to determine the remaining anti-HSV activity. There was some anti-HSV activity remaining when adding HSV in phosphate-buffered saline, but little activity when adding HSV in semen. The situation is further complicated with compound PK properties being changed by coitus. The search for a broad-acting microbicide remains challenging.
The microbicide pipeline: Development success and failure by Joseph Romano (International Partnership for Microbicides, Wayne, PA, USA)
The next stage in the search for effective microbicides will be to investigate known anti-HIV compounds formulated in vaginal rings. Tenofovir, a nucleotide reverse transcriptase inhibitor, and dapivirine, an NNRTI, are currently in clinical trials. The aim is to get high drug concentrations (>1,000×EC50) in vaginal tissues, but low levels in plasma. The International Partnership for Microbicides is seeking to license compounds with differing modes of action. Recently, Pfizer has licensed maraviroc for topical administration. In clinical trials, with drugs in combination, patients will be monitored closely for HIV infection and, when transmission has occurred, the patient will be treated promptly.
However, I wonder what would happen in general use when there would be no close monitoring of HIV infection?
Plenary lecture
A strong dominant negative mutation in the HIV-1 Gag protein defines a new drug target by Ronald Swanstrom (University of North Carolina, Chapel Hill, NC, USA)
As the HIV virion buds from a cell, it is in an immature, non-infectious form. The protease cleaves Gag so that a dense cone-shaped structure is formed within the virion. A series of mutants (Y132I, L363I, M377I, N432I and F448I) were constructed to prevent cleavage at each of these five sites. Interestingly, the loss of infectivity was not proportional to the proportion of mutant: there was a 50% loss of infectivity with just 4% of Y132I in the Gag population and essentially a total loss of infectivity with 20% mutant. The sensitivity of infectivity to loss of the cleavage site is explained by many Gag molecules having to be cleaved to form the proper cone structure in the virion.
Interesting new compounds
Effects of anti-human papillomavirus (HPV) disease agents on HPV episome levels by Terri Edwards and James Baskin (NanoVir, Kalamazoo, MI, USA)
There were two presentations reporting on the evaluation of polyamides to reduce HPV DNA episomes in cell cultures. Polyamides (PAs) can be synthesized to target particular DNA sequences by binding to the minor groove. NV1028 and NV1036 target the HPV DNA origin of replication. Their EC50s were about 100 and 30 nM, respectively. When W12 cells are grown as raft cultures, a single dose of NV1028 (10–100 μM) showed a dose-dependent reduction of viral DNA.
Viral resistance
Drug resistance mutations in HSV-1 UL5 selected using a helicase–primase inhibitor: Frequency and effects on virus growth and pathogenicity by Hugh Field (University of Cambridge, Cambridge, UK)
HSV helicase (UL5) forms a complex with HSV primase (UL52) and an ancillary protein (UL8). In UL5, G352V/R and K356N resulted in high levels of resistance (400-fold, 3,000-fold and 5,000-fold, respectively) to BAY 57-1293, but variable virulence in mice (high, low and high, respectively). From two recent clinical isolates, highly resistant mutants, including K356N, were obtained at high frequencies. Mismatched primers, designed to detect these resistant mutants, will be used to investigate the proportion of clinical isolates with pre-existing resistant mutations.
A role for compounds targeting host proteins for antiviral therapy
Nitazoxanide in combination with other anti-HCV agents by Brent Korba (Georgetown University Medical Center, Washington, DC, USA)
Nitazoxanide (NTZ) is already in clinical use for cryptosporidium infections and is in development for HCV. The active metabolite of NTZ is tizoxanide (TIZ). Combinations of TIZ and other anti-HCV drugs, particularly HCV-796 (NNRTI) and VX-950 (PI), are synergistic. Importantly, TIZ retains activity against clinically relevant resistant viruses.
In vitro anti-HCV activities and resistance profile of Debio 025 by Lotte Coelmont (Rega Institute for Medical Research, Leuven, Belgium)
Currently, Debio 025 is in Phase II trials. The notable feature of Debio 025 is that it is able to clear HCV RNA from replicon cells within two to three passages. There appears to be no cross resistance with other anti-HCV drugs.
Recruitment of the TSG101/ESCART-1 machinery in host cells by influenza virus by Leyla Diaz (Functional Genetics, Inc., Gaithersburg, MD, USA)
TSG101 is a host protein that is part of the cellular system which regulates transport within the cell. Importantly, TSG101 is normally found only in the cytoplasm of uninfected cells. Influenza viral proteins bind to TSG101 and it becomes localized on the cell surface. TSG101 antibodies reduced the release of influenza virus from infected cells. As TSG101 is normally resident inside the cell, it is anticipated that TSG101 antibody would be safe to use. Furthermore, TSG101 antibody might be effective against other viruses (HIV, RSV, HSV-1 and 2, Ebola, and parainfluenza).
New concepts – new targets
Pradimicin-S is a highly soluble, non-peptidic, small-size, carbohydrate-binding antibiotic that might qualify as a potential drug lead for HIV treatment by Jan Balzarini (Rega Institute for Medical Research, Leuven, Belgium)
Jan Balzarini, as the 2008 Gertrude Elion Memorial Lecture awardee, summarized his work on Pradimicin-A (PRM-A). Pradimicin-S (PRM-S) is a water-soluble form of PRM-A. Its activity against HIV was about two to threefold less active than PRM-A in various cell culture assays.
Further evaluation of these compounds is being delayed by their very limited supply. However, a talk about a potential microbicide illustrated the added value that ICAR can generate. Alamelu Mahalingam (University of Utah, Salt Lake City, UT, USA) described the use of a synthetic ‘lectin’, a boronic acid polymer. These polymers can be synthesized easily in large quantities.
Awards winners in 2009 (Mark Prichard)
Each year, two major awards are given by the Society: the Gertrude Elion Memorial Lecture Award and the William Prusoff Young Investigator Lecture Award.
The Gertrude Elion Memorial Lecture Award recognizes pre-eminent investigators who have made outstanding contributions to the field of antiviral research and have a sterling international reputation for scientific integrity. A genuine love of science and willingness to guide young scientists are among the important qualities used to help select those who merit the highest award given by the Society. This year's award winner was Karen Biron, who worked closely with Gertrude Elion at Burroughs Wellcome. Her accomplishments include groundbreaking work with acyclovir and VZV, and her lifelong dedication to the development of new therapies for HCMV infections that resulted in the discovery of maribavir. This specific inhibitor of the HCMV UL97 protein kinase represents an innovative strategy to the treatment of viral infections.
The William Prusoff Young Investigator Lecture Award acknowledges outstanding young scientists who have demonstrated dedication and excellence in the field of antiviral research and future potential for contribution to the field and the society. This year the award was given to Mark Prichard at the University of Alabama at Birmingham. He presented his work characterizing the function of the HCMV UL97 kinase. Using maribavir, which inhibits UL97 kinase specifically, Mark has been able to investigate the many roles of this kinase in HCMV replication both directly and indirectly via altering various host cell responses. In this presentation, Mark focussed on his work that led to the discovery that UL97 kinase seems to mimic the host cyclin-dependent kinase, including its role to inactivate the Rb tumour suppressor.
Poster awards are selected from presentations at the ICAR meeting. Two winners are selected in the categories of Graduate Student, Postdoctoral Fellow and Young Investigator, with $1,000 and $500 cash awards for first and second place recipients, respectively. This year the Poster Award Committee noted that the posters were of very high quality and presented work that was innovative and had the potential to advance significantly the field of antiviral research. Tilmann Schulz won first prize in the Graduate Student category and Meike Chevillotte was awarded second prize. In the Postdoctoral category, Sophie Duraffour and Brian Gentry were awarded first and second prize, respectively. Young investigator Dirk Daelemans was awarded first prize and Janette Ward was selected to receive second prize. Abstracts for all award winners can be viewed on the ISAR website and in the May 2009 issue of Antiviral Research.
Business meeting (Susan Cox)
The Society Meeting was held on Wednesday 6 May. The ISAR President, Treasurer, Secretary, and the Chairs of the Conference Poster Awards, Placement and Program Committees all presented reports.
The President reported on the elections, which were held electronically via e-mail this year, with a 28% turnout. Dr Susan Cox was elected as Secretary and Drs Mike Bray and Mark Prichard to the ISAR Board; all were warmly congratulated.
Chris McGuigan presented the locations of future ICARs: 2010 in San Francisco and 2011 in Sofia, Bulgaria. Several locations for the 2012 conference were suggested, and members were asked to provide their feedback via the conference survey after the conference. Chris noted the importance of attendees staying at the conference hotel because the conference rooms and poster rooms were free of charge providing a sufficient number of attendees stay at the hotel. If ICAR were to pay for the meeting space, this would result in increased registration fees.
Dale Barnard, Treasurer, presented the finances of the society for fiscal year-end 2008. Total income was US$525,858, with corporate support and ICAR registrations forming a large part. Total expenses were US$340,162. Corresponding figures at 29 April 2009 were US$192,393 and US$59,338. Figures for the 22nd ICAR were not yet finalized, but indicated a possible small shortfall – emphasizing Chris McGuigan's earlier comments regarding the cost of running the ICAR.
Susan Cox presented a report on society membership. We are a diverse society, with members from many countries; however, the US still has the highest membership and many countries have only a few members, despite being active in antiviral research. Members were encouraged to tell their colleagues about ISAR. The membership is fairly evenly divided between those working in academia, industry and government/hospitals/other locations.
Each year, the society awards grants to help members defray the costs of attending ICAR. This year, 34 applications were received and 25 awards made, both up on last year. The majority was to PhD students, but around a quarter were to post-docs and half went to European members. However, disappointingly, a few awardees were not able to obtain a visa for USA and some applications were received too late or incomplete. For travel awards for San Francisco next year, the deadline is the end of December.
Joe Colacino, President-Elect and Chair of the Placement Committee, reported on the Career Breakfasts. This event has become popular at ICAR, demonstrated by the number of members attending the 6:45am meetings. The meetings provide a forum for discussions on career paths and choices, and help students connect with established members and hear about their career experiences. Joe thanked Thomas Cihlar, who will be taking over next year.
ISAR awards prizes for excellence in the posters presented at the conference. Mark Prichard described the process, categories and eligibility. Presenters were encouraged to be by their poster to answer questions. Posters were scored by the members of the Poster Award Committee. Judging was in full progress and awards were to be made at the banquet that evening.
Finally, Bob Buckheit, Chair of the Program Committee, described their work in striving to ensure that the conference presents the highest quality of relevant and exciting science, to inform and stimulate. Bob described features of the program, such as the keynote address, drug discovery and development session, clinical symposium and shotgun poster sessions, all of which present high quality science and provide young researches with opportunities to learn and present their data. All members were encouraged to provide feedback on the content of the conference and put forward relevant topics and speakers they would like to see featured on the program next year.
International Society for Antiviral Research Financial Statement for 2008
The President closed by thanking all members and reminding them that there are many opportunities to get involved in the work of the Society; new volunteers are always warmly welcomed.
Visit the ISAR web site…
Visit the ISAR Web site at http://www.isar-icar.com to discover more about the 23rd ICAR. Information on the conference will be posted on the ICAR website by August 2009. If you have any questions please do not hesitate to contact the ISAR/ICAR Office at 202-973-8690 or by e-mail at
ISAR News is a publication of the International Society for Antiviral Research prepared by the ISAR Publication Committee: Hugh Field (Chair), Masanori Baba, Erik De Clercq, Brian Gowen, Colleen B Jonsson, Justin Julander, Luis Schang, Ashoke Sharon, Bart Tarbet, Simon Tucker and Anthony Vere Hodge.