Oral viral infections and the therapeutic use of antiviral agents in dentistry

This paper reviews the current concepts of viral classification, infection and replication. The clinical presentation of common oral viral infections encountered in the dental practice are discussed, including: herpes simplex virus types 1 and 2; Epstein-Barr virus; varicella-zoster virus; Coxsackie virus; human papilloma virus; and human immunodeficiency virus. The diagnosis, principles of management and pharmacological agents available for the treatment of oral viral infections are also discussed.

Using cohort studies to estimate mortality among injecting drug users that is not attributable to AIDS

Background: Injecting drug use (IDU) and associated mortality appear to be increasing in many parts of the world. IDU is an important factor in HIV transmission. In estimating AIDS mortality attributable to IDU, it is important to take account of premature mortality rates from other causes to ensure that AIDS related mortality among injecting drug users (IDUs) is not overestimated. The current review provides estimates of the excess non-AIDS mortality among IDUs. Method: Searches were conducted with Medline, PsycINFO, and the Web of Science. The authors also searched reference lists of identified papers and an earlier literature review by English et al (1995). Crude. mortality rates (CMRs) were derived from data on the number of deaths, period of follow UP, and number of participants. In estimating the all-cause mortality, two rates were calculated: one that included all cohort studies identified in the search, and one that only included studies that reported on AIDS deaths in their cohort. This provided lower and upper mortality rates, respectively. Results: The current paper derived weighted mortality rates based upon cohort studies that included 179 885 participants, 1 219 422 person-years of observation, and 16 593 deaths. The weighted crude AIDS mortality rate from studies that reported AIDS deaths was approximately 0.78% per annum. The median estimated non-AIDS mortality rate was 1.08% per annum. Conclusions: Illicit drug users have a greatly increased risk of premature death and mortality due to AIDS forms a significant part of that increased risk; it is, however, only part of that risk. Future work needs to examine mortality rates among IDUs in developing countries, and collect data on the relation between HIV and increased mortality due to all causes among this group.

Will diverse Tat interactions lead to novel antiretroviral drug targets?

More than fifteen years following the description of Tat as a critical HIV gene expression regulatory protein, additional roles for Tat in HIV replication have been described, including reverse transcription. Tat achieves function through direct interaction with viral proteins, including reverse transcriptase, and numerous cellular proteins including cyclin T1, RNA polymerase 11, protein kinase R (PKR), p300/CBP, and P/CAF. Despite our advanced knowledge of how Tat operates, this has not yet resulted in the discovery of effective agents capable of targeting various Tat functions. Nevertheless, Tat remains an attractive, virus-specific molecule and detailed understanding of specific protein interaction holds promise for future drug discovery.

theta-defensins prevent HIV-1 Env-mediated fusion by binding gp41 and blocking 6-helix bundle formation

Retrocyclin-1, a 0-defensin, protects target cells from human immunodeficiency virus, type 1 (HIV-1) by preventing viral entry. To delineate its mechanism, we conducted fusion assays between susceptible target cells and effector cells that expressed HIV-1 Env. Retrocyclin-1 (4 mu M) completely blocked fusion mediated by HIV-1 Envs that used CXCR4 or CCR5 but had little effect on cell fusion mediated by HIV-2 and simian immunodeficiency virus Envs. Retrocyclin-1 inhibited HIV-1 Env-mediated fusion without impairing the lateral mobility of CD4, and it inhibited the fusion of CD4-deficient cells with cells bearing CD4-independent HIV-1 Env. Thus, it could act without cross-linking membrane proteins or inhibiting gp120-CD4 interactions. Retrocyclin-1 acted late in the HIV-1 Env fusion cascade but prior to 6-helix bundle formation. Surface plasmon resonance experiments revealed that retrocyclin bound the ectodomain of gp41 with high affinity in a glycan-independent manner and that it bound selectively to the gp41 C-terminal heptad repeat. Native-PAGE, enzyme-linked immunosorbent assay, and CD spectroscopic analyses all revealed that retrocyclin-1 prevented 6-helix bundle formation. This mode of action, although novel for an innate effector molecule, resembles the mechanism of peptidic entry inhibitors based on portions of the gp41 sequence.

Recombinant Kunjin virus replicon vaccines induce protective T-cell immunity against human papillomavirus 16 E7-expressing tumour

The persistence of the E7 oncoprotein in transformed cells in human papillomavirus (HPV)-associated cervical cancer provides a tumour-specific antigen to which immunotherapeutic strategies may be directed. Self-replicating RNA (replicon) vaccine vectors derived from the flavivirus Kunjin (KUN) have recently been reported to induce T-cell immunity. Here, we report that inclusion of a CTL epitope of HPV16 E7 protein into a polyepitope encoded by a KUN vector induced E7-directed T-cell responses and protected mice against challenge with an E7-expressing epithelial tumour. We found replicon RNA packaged into virus-like particles to be more effective than naked replicon RNA or plasmid DNA constructed to allow replicon RNA transcription in vivo. Protective immunity was induced although the E7 CTL epitope was subdominant in the context of other CTL epitopes in the polyepitope. The results demonstrate the efficacy of the KUN replicon vector system for inducing protective immunity directed towards a virally encoded human tumour-specific antigen, and for inducing multi-epitopic CTL responses. (C) 2004 Elsevier Inc. All rights reserved.

West Nile virus vaccines

West Nile virus (WNV) is a mosquito-borne flavivirus that is emerging as a global pathogen. In the last decade, virulent strains of the virus have been associated with significant outbreaks of human and animal disease in Europe, the Middle East and North America. Efforts to develop human and veterinary vaccines have taken both traditional and novel approaches. A formalin-inactivated whole virus vaccine has been approved for use in horses. DNA vaccines coding for the structural WNV proteins have also been assessed for veterinary use and have been found to be protective in mice, horses and birds. Live attenuated yellow fever WNV chimeric vaccines have also been successful in animals and are currently undergoing human trials. Additional studies have shown that immunisation with a relatively benign Australian variant of WNV, the Kunjin virus, also provides protective immunity against the virulent North American strain. Levels of efficacy and safety, as well as logistical, economic and environmental issues, must all be carefully considered before vaccine candidates are approved and selected for large-scale manufacture and distribution.

Papillomavirus virus-like particles activate the PI3-kinase pathway via alpha-6 beta-4 integrin upon binding

We have previously shown that human papillomavirus virus-like particles (VLPs) are able to activate the Ras/MAP kinase pathway. Ras can also elicit an anti-apoptotic signal via PI3-kinase so we investigated this further. Here we show that binding of VLPs from HPV types 6b, 18, 3 1, 35 and BPV1 results in activation of PI3-kinase. Activation was achieved by either L1 or L1/L2 VLPs and was dependent on both VLP-cell interaction and correct conformation of the virus particle. VLP-induced PI3-kinase activity resulted in efficient downstream signaling to Akt and consequent phosphorylation of FKHR and GSK3 beta. We also present evidence that PV signaling is activated via the alpha 6 beta 4 integrin. These data suggest that papillomaviruses use a common receptor that is able to signal through to Ras. Combined activation of the Ras/MAP kinase and PI3-kinase pathways may be beneficial for the virus by increasing cell numbers and producing an environment more conducive to infection. (c) 2006 Elsevier Inc. All rights reserved

Prophylactic HPV vaccines: Underlying mechanisms

Human papillomavirus virus-like particles (HPV VLP) can be generated by the synthesis and self-assembly in vitro of the major virus capsid protein L1. HPV L1 VLPs are morphologically and antigenically almost identical to native virions, and this technology has been exploited to produce HPV L1 VLP subunit vaccines. The vaccines elicit high titres of anti-L I VLP antibodies that persist at levels 10 times that of natural infections for at least 48 months. At present the assumption is that the protection achieved by these vaccines against incident HPV infection and HPV-associated ano-genital pathology is mediated via serum neutralising Immunoglobulin G (IgG). However, since there have been very few vaccine failures thus far, immune correlates of protection have not been established. The available evidence is that the immunodominant neutralising antibodies generated by L1 VLPs are type-specific and are not cross-neutralising, although highly homologous HPV pairs share minor cross-neutralisation epitopes. Important issues remaining to be addressed include the duration of protection and genotype replacement. (c) 2006 Elsevier Ltd. All rights reserved.