5Th World Workshop on Oral Health and Disease in AIDS

5 th World Workshop on Oral Health and Disease in AIDS .

ABSTRACTS Plenary Lectures

Global and Regional In Latin American and the Caribbean, National HIV P1 Epidemiology of HIV and Its prevalence has reached or exceeds 1% in 12 countries, all of Implications them in the Caribbean Basin. Sex between men is an important, but neglected, feature of Latin America’s K Ungchusak* ([email protected]) epidemics. Bureau of Epidemiology, Department of Disease Control, HIV prevalence in the Middle East and North Africa region Ministry of Public Health, Thailand is still very low, with the exception of southern Sudan and recent outbreaks among injecting drug users in some HIV/AIDS is an emerging disease since early 1980. It countries. became a major pandemic that spread to all regions and countries. Because of the long incubation which last several In High Income countries, the total number of people living years, assessing the disease magnitude and trend have to be with HIV continues to rise, largely due to widespread access based on estimation based on available prevalence and to anti retroviral treatment. However, there is more evidence incidence data. of increasing rates of other sexually transmitted infections which reflected the possibility of new increases in HIV Estimates and ranges produced by UNAIDS and WHO incidence, particularly among marginalized groups. showed that by December 2003 the global HIV/AIDS epidemic killed more than 3 million people and an estimated Currently there is no drug to cure the diseases but new ante- of 5 millions acquired new HIV infection bringing to 40 retroviral therapies (ART) have shown its effectiveness to millions the number of people living with the virus around prolong life, reduce suffering from getting other the world. opportunistic infection. But only small proportion of patients is access to ARV. The World Health Organization Table 1. Burden of HIV/AIDS in different regions as has aimed to provide ART for 3 millions population by estimated by UNAIDS and WHO at the end of 2005. It is still a long waiting year before ART is accessible 2003. Newly to all or vaccine are available. People living infect Deaths due with ed to AIDS HIV epidemic has caused suffering to individual, family, Region HIV/AIDS with HIV (x million) society and national as a whole. These sufferings include the (x million) (x million) illness that affected the physical and the discrimination that Sub-Saharan 25 - 28 3 - 3.4 2.2 - 2.4 people living with HIV/AIDS has to face. Although Africa Asia & Pacific 5.3 - 9.5 0.7 - 1.3 0.36 - 0.65 HIV/AIDS bring many sad stories but one of the beautiful Latin America thing is to see good people from different disciplines 1.6 - 2.5 0.16 - 0.26 0.008 - 0.120 & Caribbean working together with the strong determination to serve Eastern Europe 1.2 - 1.8 0.18 - 0.28 0.023 - 0.037 their community, care the patients, prevent and control the & Central Asia North Africa & spread of the disease. With good will and good science, 0.4 - 0.7 0.043 - 0.067 0.035 - 0.050 Middle East there is no doubt that the pandemic of HIV/AIDS can be put High Income 1.3 - 1.9 0.066 - 0.095 0.014 - 0.021 under control as shown in many communities and countries. Countries1 Total 34 - 46 4.2 - 5.8 2.5 - 3.5

1 , include Western Europe, North America, Australia & HIV/AIDS Status and Trends in Asia and New Zealand. P2 the Pacific Region In Sub-Saharan Africa, Southern Africa area which has less S Thanprasertsuk*,1, YR Lo2 than 2% of world population is home to about 30% of people living with HIV/AIDS worldwide. High levels of 1Bureau of AIDS, TB and STIs, Department of Disease new HIV infections are continuing and are now matched by Control, Ministry of Public Health, Thailand, 2WHO South high levels of AIDS mortality. East Asia Regional Office, New Delhi, India The epidemic in Asia and the Pacific is spreading into areas The WHO South-East Asia and the Western Pacific Region and countries when, until recently there was little or no HIV include close to 60 percents of the total world population. present-including China, Indonesia and Vietnam. In older Thus, even low HIV infection rates in this region will epidemic countries such as those in Cambodia and Thailand, contribute to millions of additional people living with there is now significant HIV spread from people with HIV/AIDS (PLWHA) and deaths to the already staggering higher-risk behavior to their sexual partners. global toll of AIDS. The presentation will give an overview of the HIV/AIDS pandemic followed by a description of the The AIDS epidemic in Eastern Europe and Central Asia general patterns and prevalence of HIV risk behaviours and shows no signs of declining. HIV prevalence continues to HIV prevalence trends in this Region, and in selected rise in the Baltic States, Russian Federation and Ukraine. In individual countries in Asia. Central Asia, the epidemic is expanding rapidly. As of 1 December 2003, around the world 40 million people were living with HIV/AIDS. The Sub-Saharan region was

______27 5 th World Workshop on Oral Health and Disease in AIDS . accountable for 26.6 million people infected. An estimated susceptible to HIV no matter of which HIV-1 subtypes are 7.4 million people were living with HIV/AIDS in the Asia predominant in the population. Once infected, Asians have and the Pacific Region. It was estimated globally that 5 similar rate of clinical progression as Caucasians. Pruritic million people became newly infected in 2002. Of them, papular eruption is a common non-AIDS defining skin more than 1 million are in the Asia-Pacific region. In most condition in South East Asia. Tuberculosis, cryptococcal countries in Asia, the epidemic tends to be concentrated in meningitis and pneumocystis pneumonia are the 3 most risk populations, mostly injecting drug users with additional common opportunisitic infections (OI) found in AIDS spread resulting from sex work. Most alarming is the recent patients in South East Asia. Disseminated penicilliosis is increase of HIV prevalence among injecting drug users and common in Northern Thailand and the surrounding Golden sex workers in Indonesia and Nepal after a prolonged period Triangle. of low prevalence. Only Cambodia, Myanmar and Thailand and six states in India have an estimated HIV prevalence of Healthcare personnel in most Asian countries lack proper over 1% among adults. The course of the epidemics in two and updated knowledge in AIDS care. They are concerned of the most populous countries of the world – China and about occupational exposure to HIV and tuberculosis. In India – will have a decisive influence on the course of the many countries, applicants for medical, dental and nursing global pandemic. As of 2003, it was estimated that 840,000 schools drop because the fear of HIV. In order to cope with people in China were living with HIV infection, the rapid increase of HIV patients in Asia, large-scale corresponding to 0.12% of the total adult population aged training of HIV Medicine to all levels of healthcare workers 15–49 years. About 70% of these infections are thought to (HCW) is urgently needed. Knowledge may not guarantee have resulted from injecting drug use or faulty plasma- good attitude in caring for HIV patients. Allowing HCW to collection procedures, and over 80% of all cases are men. have some exposure to HIV-infected patients and to see the Official estimates in India for 2003 put the number of dramatic improvement from care which includes people infected with HIV at 3.8–4.6 million, with antiretrovirals is one useful approach to improve attitude of considerable variation between the states. Current data have HCW. indicated a modest increase in recent years (WHO HIV infection can be considered as a golden opportunity to WRPO/SEARO. AIDS in Asia Report 2003, available at improve various aspects of healthcare delivery system such http://whosearo.org). as counseling, laboratory strengthening, instituting principle In conclusion, it is evident that HIV/AIDS has emerged and of universal precaution and manufacturing of generic drugs become a serious health and developmental problem in Asia in observance of patent rights. Counseling of a patient with and the Pacific. There is an urgent need to closely moniter any diseases before any diagnostic procedures or before any the situation of HIV/AIDS in countries in this region. therapeutic interventions has the same principle as HIV Effective interventions to interrupt HIV transmission are counseling and testing. This improved communication skill critically important to immediately slow down the spread of will certainly reduce number of cases brought to courts. HIV. As there are now increasing number of HIV infection Therefore, training of all levels of HCW in HIV counseling and AIDS, a continuum and comprehensive program on and testing is as important as training in HIV Medicine. treatment and care for PLWHA and for those who are Once trained counselors are available, facility has to be set affected must be developed and implemented to mitigate the up to encourage people at risk to come forward for problem and let them live normally in the society. voluntary counseling and testing (VCT). VCT is proved to be able to modify individuals’ risk taking behaviors and is the entry point for primary and secondary HIV prevention as well as for care and treatment. Impact and Management of HIV in P3 Thailand and South East Asia Laboratory preparedness is the next issue to be addressed. Algorithm for anti-HIV testing needs to be defined. Other P Phanuphak* ([email protected]) related tests need to be developed such as CD4 cell count, viral load assay and resistance assay. We strongly advise Faculty of Medicine, Chulalongkorn University and the that any patients with known HIV infection should regularly Thai Red Cross AIDS Research Centre, Bangkok, Thailand follow their CD4 cells in order to get the maximal benefit HIV/AIDS has great impact on many things at many levels. from being seropositive. With known CD4 cell count, OI Health impact on infected individuals is obvious, followed can be prevented and antiretrovirals (ARV) can be started by psychosocial and economical impacts on individuals and on time. This is of particular importance with global trend affected families, particularly stigma and discrimination. for access to all for ARV. ARV will make HIV diseases and Economical impact at the national level depends on disease AIDS-related deaths preventable. burden and on national resource. HIV has been considered A spectrum of care is needed for HIV patients, ranging from by many countries and by United Nations as a psychosocial care to medical care. Treatment and prevention developmental issue and security threat. Although impact is of HIV-related OIs is the national policy of almost all great but can be minimized if handled properly and countries in Asia. However, it is just for “cheap OIs” such precipitously. One thing that countries with low prevalence as tuberculosis, cryptococcal meningitis and pneumocystis can do is to prevent the widespread of the epidemic by pneumonia. In spite of this, many patients in Thailand have targeted intervention such as condom promotion campaign to discontinue these medications because of various in sex industry and harm reduction programs for drug government restrictions such as the location of the hospital injectors. that a patient must register for free medical treatment. Medical impacts of HIV/AIDS can be divided into those on Prevention of mother-to-child transmission (PMTCT) of infected individuals, those on healthcare professionals and HIV through chemoprophylaxis is another national policy those on the healthcare delivery system. Asians are equally being implemented by many countries in Asia. However,

______28 5 th World Workshop on Oral Health and Disease in AIDS . most countries use single dose nevirapine regimen which is Every year, millions of adolescents and adults needlessly cheap but with lower efficacy. With current lower-price suffer from illnesses that could be prevented or treated with ARV, most of these countries should be able to provide simple interventions. The World Health Organization more efficacious ARV regimens to their pregnant women. (WHO) has called for international action to meet the "3 by The current Thai Red Cross PMTCT donation program is 5" target, delivering anti-retroviral therapy to three million providing triple therapy to all pregnant women irrespective people by the end of 2005. Also, a new cross-cutting of the CD4 count. The program is being extended into activity in WHO, the Integrated Management of Adolescent MTCT-Plus program by providing life-long highly active and Adult Illness provides a strategy to improve the quality antiretroviral therapy (HAART) to women after delivery of health care for these disadvantaged populations living in and their family members, a project also known as “Treat low-resource settings. This initiative includes the Global the Parents, Prevent the Orphans”. Oral Health Programme since the oral health sector can make important contributions to the early diagnosis, Many countries and territories in Asia, usually those with prevention and treatment of HIV/AIDS. Such activities sizable number of HIV-infected patients such as Singapore, focus on the identification of the most indicative oral Hong Kong, and Japan have national policy to provide manifestations of HIV/AIDS, involvement of oral health HAART to all patients if needed. However, stigma makes personnel in documentation of the disease, training of other many people untreated or come to Thailand for lower-price health professionals on how to screen for oral lesions, and generic drugs. Thailand is the only country in Asia which provision of systematic approaches to implementation of has a national policy to treat tens of thousands of HIV- epidemiological studies for surveillance of oral conditions infected patients with HAART. As a result of generic drug related to HIV infection. Finally, the WHO Global Oral manufacturing within the country, a fixed dose combination Health Programme has implemented strategies related to of stavudine, lamivudine and nevirapine costs only US$1 a HIV/AIDS prevention as part of the WHO Global School day. This allows the Thai government to increase the Health Initiative. coverage of free ARV from 12,000 patients in 2003 to 50,000 patients in 2004 in conjunction with the 2004 International AIDS Conference in Bangkok. Many challenges still lie ahead of this national ARV access HIV Pathogenesis: Knowledge Gained program. Examples are how to train adequate number of P4 after Two Decades of Research knowledgeable prescribers, what cost-effective laboratory JA Levy* ([email protected]) tools to monitor treatment outcome and to detect early resistance as well as what regimens to be used after failing University of California, San Francisco, USA the first-line regimen. A great deal of progress has been made since the initial In conclusion, impact of HIV infection is great but can be discovery of HIV twenty years ago. Its recognition as a minimized. We should turn this tragedy into opportunity by lentivirus and its ability to infect CD4 lymphocytes and a improving our healthcare infrastructure. Lessons learned wide variety of other cells in the body has become should be used to maximize the effort in different settings. appreciated as well as its role in immunologic, gastrointestinal and central nervous system disorders. The P3A mechanism for HIV infection of cells was initially linked to the CD4 molecule and later determined to involve other HIV Care and Counselling in India coreceptors particularly the chemokine receptors, CXCR4 and CCR5. The role of the various virus-associated genes has uncovered unique pathways that can be observed as well Action Programme Towards Control in normal cells. The unusual role of Rev in preventing the P3B of HIV/AIDS: the Role of the WHO splicing of message so that large message can be transported Global Oral Health Programme, Geneva, Switzerland to the cytoplasm for expression and subsequent viral assembly. The multi-potential role of Nef as well as the PE Peterson* ([email protected]) transactivation of Tat which uncovered its role in the elongation of message. The interactions of Vif, Vpu, and Oral Health Programme, World Health Organization, Vpr in transactivation, apoptosis and cell surface protein Geneva, Switzerland expression are also uncovering novel approaches for At the beginning of the 21st century, HIV/AIDS is the combating HIV besides those that attack its three major number one cause of death in Africa and is number four enzymes: reverse transcriptase, integration, and protease. globally. Just twenty years ago, when HIV/AIDS first Most recently, the discovery of natural cellular resistance appeared, few would have predicted the current state of the factors such as APOBEC-3G and TRIM.5 offer avenues to pandemic, particularly in sub-Saharan Africa. In seven sub- pursue for novel antiviral therapies. Saharan African countries at least one out of five adults is The existence of long-term survivors (or long-term living with HIV/AIDS and in addition, in five sub-Saharan nonprogressors) has provided insight into adaptive and African countries one out of ten adults is HIV positive. innate immune responses that can control HIV and in some Meanwhile, Thailand, Senegal and Uganda have achieved cases prevent virus infection. Neutralizing antibodies and promising results in their campaign. In Thailand and CD8+ cell cytotoxic responses have been evaluated using a Uganda concerted efforts at all levels of civil society have variety of conventional and novel techniques. In addition, notably decreased the HIV prevalence rates and in Senegal, several innate pathways are being appreciated such as the programmes put into place early in the epidemic kept HIV function of plasmacytoid dendritic cells, the major type 1 prevalence rates low. interferon-producing cells. And, CD8+ cell noncytotoxic responses (CNAR) mediated by the CD8+ cell antiviral

______29 5 th World Workshop on Oral Health and Disease in AIDS . factor (CAF) are providing important directions for enlisting antibodies. This strategy was used in vaginal immunization host immune responses without depending on the potent but of macaques with CCR5 peptides in addition to HIV env toxic antiviral drugs. and SIV gag antigens, all which were linked to the 70kD heat shock protein (HSP70). Immunization with this vaccine Vaccine studies have indicated how conventional elicited serum and vaginal IgG and IgA antibodies, IFN approaches do not work with a virus that is an intracellular and IL-2 producing cells, and increased concentrations of parasite becoming part of the genetic make-up of the CCL-3 and CCL-4. Vaginal challenge with SHIV 89.6 infected cell. Induction of both innate and adaptive immune showed significant clearance of SHIV in the immunized responses must be achieved. While HIV is the most studied macaques. This platform strategy will now be developed to and most understood virus that has affected humankind, the activate the costimulatory pathways with the aim of nature of its replicative cycle and its pathologic effect on the enhancing the primary allogeneic and CCR5 directed immune response and on other tissues has made it a difficult responses which are involved in natural protection to HIV microbe to control and to prevent its infection. The past 20 infection. years have offered important information on the cause of AIDS and on viral-host interactions, which promises to lead to effective long-term therapy and an effective antiviral vaccine. P7

P5 Therapeutic Management of HIV Oral Lesions of HIV/AIDS in P8 Industrialized Countries Innate and Adaptive Mucosal D Greenspan* ([email protected]) and J P6 Immunity in Protection Against Greenspan HIV Infection University of California San Francisco, CA, USA T Lehner* ([email protected]) Mucosal Immunology Unit, Guy’s, King’s & St. Thomas’ Knowledge concerning the varied nature, clinical and Medical and Dental School, Kings College London, London biological significance, and management of the oral disease SE1 9RT, England found in those with HIV infection has grown in concert with the huge and expanding body of work published on the The HIV epidemic in developing countries is out of control AIDS epidemic. Oral candidiasis, Kaposi's sarcoma and and an effective vaccine has not been developed. The lymphoma were among the earliest described lesions of prevalent DNA prime-viral boost strategy aims largely to AIDS seen in homosexual and bisexual men. In the elicit cytotoxic lymphocytes (CTL) against HIV and this subsequent 23 years, a growing body of investigation, approach is subject to rapid mutation of HIV which may publications and clinical experience have reinforced, escape CTL control. An alternative strategy is to focus on to confirmed and built upon those initial observations. Most of four somewhat neglected areas of vaccination. (1) Innate this aspect of AIDS science has been conducted in the immunity with its rapid protective response to infection that industrially developed parts of the world, although is independent of memory. (2) Targeting the genital and increasing attention is being paid to exploration of these rectal mucosa, with the associated lymph nodes, in order to lesions in those countries where the pandemic is elicit an immune response at the site of transmission of concentrated. Clinicians with a wide range of professional HIV. (3) Stimulating a broadly based adaptive immune training can easily examine the mouth and pharynx. Oral response that induces maturation of dendritic cells, results in lesions are often clearly visible and several can be Th1 polarized immunity and enhances the memory CD4+ diagnosed accurately on clinical features alone. Thus, in and CD8+ T cells and B cells. (4) Taking advantage of two cases where HIV status is unknown and where HIV testing “experiments of nature” in homozygous 32 CCR5 is difficult, certain oral lesions provide strong indication of individuals and in alloimmunity with a defined protection the presence of HIV infection. Hairy leukoplakia, oral and against HIV infection. Alloimmunity has been found to be pharyngeal candidiasis, and the presence of both of these protective in vertical transmission from infected mothers to oral lesions are indicators of progression to AIDS. They can their babies, in alloimmunization of women with their parallel the decline in CD4 cell counts but may also be partners’ mononuclear cells and in monkeys immunized independent indicators of prognosis. It is therefore not with SIV grown in human T cells. Furthermore, significant surprising that certain oropharyngeal lesions, notably oral increase in the alloimmune response to the male partners’ candidiasis and hairy leukoplakia, feature in all lymphoid cells, compared with unrelated cells, was found in classification, staging and prognosis, systems currently in women practicing unprotected sexual intercourse with a use. These observations emphasize the high importance of a regular partner. CD4+ T cells from these women thorough oral examination at every stage in the diagnosis demonstrated a dose-dependent inhibition of HIV infection, and management of all HIV-positive patients, as well as compared with those practicing protected sex. Thus, vaginal those thought to be infected or at risk, and explain the mucosal immunization resulted in in vitro protection against weight given to these lesions in HIV prevention and HIV transmission and this was confirmed in macaques. The intervention programs. It is also important to note that the second type of native protection is found in persons with the presence and development of oral lesions are used as entry homozygous 32 CCR5 mutation, with a lack of cell criteria and end points for prophylaxis, therapy and vaccine surface expression of CCR5, which is associated with an trials. Indeed, the intriguing possibility exists that some oral increase in CC chemokines and the development of CCR5 lesions, notably herpes simplex and the Epstein-Barr virus

______30 5 th World Workshop on Oral Health and Disease in AIDS . infection of hairy leukoplakia, may act as risk modifiers or even co-factors that actively modulate the progress of HIV infection. In recent years, it has become clear that the presence of prevalent oral lesions and their incident development are related to HIV viral load. Furthermore, they are reduced in frequency as highly active anti-retroviral therapy (HAART) becomes effective. They recur or may develop anew as HAART fails and viral resistance occurs. Public Health Implications of Oral The type and distribution of oral lesions seem to change in P10 Disease in HIV/AIDS people on HAART, with multiple oral warts becoming more PG Robinson* ( [email protected] ) frequent, along with salivary gland disease. These apparently paradoxical observations may relate to Dental Public Health, School of Clinical Dentistry, incomplete reconstitution of the immune system as HAART University of Sheffiled, UK plays its role and HIV viral load falls, although other Dental Public Health is the science and practice of explanations cannot be excluded. The treatment needs for preventing oral diseases, promoting oral health and the huge population of HIV-infected persons relate to improving the quality of life through the organised efforts of mucosal lesions, caries and periodontal disease, while society. Its concern with population health means that action separating out those needs that are related to HIV-infection, is focused at the level of the community rather than the from the background disease load in the population presents individual. Dental public health practitioners may therefore practical problems. These problems have considerable act on the determinants of health as well as commissioning policy implications. group oral care programmes. This presentation approaches implications of HIV- associated oral diseases in three ways. First, oral diseases Oral Lesions and Conditions may have a value in indicating the health of people with Associated with Human P9 HIV. Immunodeficiency Virus Infection in 1700 South Indian Patients Secondly, there is a large body of evidence that oral candidiasis, ulcerative periodontal diseases, Kaposi’s K Ranganathan* ([email protected]), N Kumarasamy, sarcoma and oral ulceration constitute a dental public health S Solomon, NW Johnson problem. Furthermore, oral diseases that are not associated Ragas Dental College and Hospital, Uthandi, Chennai 600 with the HIV are a public health problem in people with 119, India infection. Whilst there are limited data on the effectiveness of healthcare interventions to treat or prevent these diseases, Background: Human Immunodeficiency Virus (HIV) less is known of their appropriateness, accessibility, infection is a major global health problem. Significantly, acceptability, efficiency or equity. This paper will consider 90% of HIV infected persons live in the developing the configuration of oral health services for people with countries. It is estimated that the number of people living HIV infection. with HIV infection in India could be 4-5 million (NACO, 2002) and this number is rapidly increasing. Given these Finally, the presentation will consider broader approaches to figures management of HIV infection has become one of the health promotion with respect to HIV-associated oral priority health issues in India. diseases. Objective: To identify and report oral lesions in HIV seropositive patients. Molecular Mechanism of Salivary Setting and Method: 1700 HIV seropositive patients P11 Gland Disease (SGD) presenting at YRG CARE and Ragas Dental College - non- governmental organizations, Chennai, India over a period of C McArthur1* ([email protected]), Y Wang1, D Ntongsi, 6 years (1998-2003) were examined by qualified physicians P Achu2 and Dental surgeons. Oral lesions were diagnosed on 1University of Missouri-School of Dentistry, Kansas City, clinical appearance, using the EC-classification (1993). MO, USA and 2Mezam Polyclinic Research Center, Results: Of the 1700 patients 95% had acquired the Cameroons infection through heterosexual contact. There were 1251 Objectives: The goal of our laboratory is to elucidate the males and 449 females, aged from 7 months to 72 years. mechanism of salivary gland disease (SGD) in HIV/AIDS Forty-three percent of the patients were in the age group 21- and Sjögren’s Syndrome (SS) and develop therapeutic 30 years. CD4 cell counts were ascertained for 790 patients, approaches such as immunomodulation and gene therapy. 339 (42.9%) had CD4 counts  200. A total of 1412 (83%) Our working hypothesis is that glandular acinar cell of the 1700 patients had some oral lesions when examined. destruction is cytokine-mediated and that apoptosis and Gingivitis (69%), and pseudo-membranous candidiasis adhesion molecules play a key role via TNF-α and (13.2%) were the most common oral lesions. The other oral Metalloproteinases (MMPs), under the regulation of lesions seen were oral mucosal pigmentation (24.6%), Nuclear transcription factor β (NF β). erythematous candidiasis (2.8%), periodontitis (28.5%), қ қ angular cheilitis (7.7%), oral ulcers (3%), oral hairy Background: Salivary gland disease is a global oral health leukoplakia (2%), hyperplastic candidiasis (1%). There were problem which occurs in HIV/AIDS as a result of the 12 cases of oral submucous fibrosis and 17 cases of oral destruction of the salivary glands. Forty million people leukoplakia. globally, 80% of whom live in the Sub-Sahara, have

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HIV/AIDS. Most Africans with HIV in Cameroon have and that apoptosis and adhesion molecules have a role in salivary gland disease as well as 80% of HIV/AIDS patients pathogenesis. This collection of differences in HIV and SS in the US. A similar histological and clinical picture to that suggests the mechanisms are different. in HIV/AIDS also occurs in SS although the T-cell phenotypes differ suggesting different mechanisms. To elucidate these mechanisms we have developed in vitro models using ductal (HSG) and acinar cells (NS-SV-AC) with and without transfection by HIV-1 tat. Dendritic Cells and HIV Infection Methods: Patients: Minor salivary gland biopsies (3-5) and P12 saliva (10 ml) were obtained from 100 patients with M Pope* ([email protected]) HIV/AIDS and 60 HIV negative controls who were recruited following IRB approval in Cameroon, West Center for Biomedical Research, Population Council, New Africa. Thirty HIV/AIDS patients and 30 healthy controls in York, USA the US also provided saliva and received a labial salivary gland biopsy. Biopsies were embedded in paraffin, 5 μm Dendritic cells (DCs) positioned within and just beneath the sections were cut and stained by routine hemotoxylin and epithelia are one of the first leukocytes that encounter HIV eosin followed by histologic grading as previously and likely contribute to the efficient dissemination of virus described (McArthur et al 2000, 2003). Active to neighboring lymphocytes/macrophages that then rapidly metalloproteinases and TIMP inhibitors (MMP-2, MMP-9 amplify the incoming viruses. In addition, virus-carrying TIMP-1 and TIMP-2) were quantified in saliva using a DCs can migrate to the draining lymphoid tissues to further competitive binding ELISA assay and protein confirmed by exacerbate HIV dissemination. Infection of target cells Western Blot analysis as described (McArthur et al 2002). within the mucosa is largely dependent on CCR5, but virus Apoptosis was determined in biopsies by detection of capture (most adeptly by DCs) is independent of CCRs, nuclear staining and DNA fragmentation using TUNEL involving CLRs, with some contribution from CD4 and assays. Apoptosis was evaluated in in vitro models of other receptors. Newly produced virus as well as that salivary gland disease using TNF-α and activation of entrapped by cells is efficiently transmitted to T cells Procaspase to Caspase 3 was evaluated by Western Blot driving virus spread. Coincident with these events however, analysis. Total cellular RNA was isolated as previously DCs should be presenting antigenic determinants to the described (McArthur et al 2001) and gene expression in the immune system to induce anti-viral immune responses. TNF-α-stimulated model was determined by transcriptional Learning how to boost the ability of virus-bearing DCs to profiling using low density Gene Expression Arrays (GE elicit potent immunity against HIV (while lessening virus Superarray). Transcriptional validation of GE Arrays was spread) is critical. Increasing evidence underscores how achieved using RT-PCR. HIV especially exploits immature DCs to facilitate infection in the face of poor immunity. Therefore, identifying ways to Results: High grades of SGD in activate DCs in vivo and/or target antigens to mature DCs HIV was associated with a 6 fold represent more promising approaches to effect potent increase in MMP-9 (31ng/ml) immunity for improved therapies or vaccines. A whole P13 inactivated virus (AT-2 virus, that mimics live virus while compared with controls (6 ng/ml) in African patients who had not received ARV therapy but not in US HIV patients also providing a wealth of antigenic determinants) is readily (6 ng/ml) or healthy controls (5.4 ng/ml). All HIV patients captured by DCs and at least some of the antigens are had received ARVs. Increase in TIMP 1 and 2 paralleled presented to virus-specific T cells. Plasmacytoid DCs are these findings. Apoptosis occurred in HIV/AIDS and SS but also activated by AT-2 virus and DC function can be further it was markedly increased in SS. The apoptotic pattern was enhanced by immunostimulatory agents (e.g., ISS-ODNs, periductal in SS and perivascular in HIV/AIDS. In our in CD40L) to boost antigen presentation. Specifically, CpG-C vitro ductal cell model, Procaspase was activated and ISS-ODNs augment IL-12 and IFN- release (to favor DC cleaved to Caspase 3 during apoptosis and Fodrin was activation) and up-regulate CD80/CD86 expression, cleaved to yield α-fodrin demonstrated by Western blot. together encouraging stronger T (and B) cell responses. Western blot analysis of saliva from HIV and SS patients Studies continue to explore ways to target activated mucosal using monospecific antibodies, showed α-fodrin was present DCs with potent vaccine antigens like AT-2 virus to in saliva from SS patients but not in saliva from HIV improve oral/nasal mucosal vaccine approaches to thwart patients. Gene expression in HSG cells stimulated with HIV spread. TNF-α, showed up-regulation of ICAM-1 and MMP-9 consistent with in vivo observations. Acinar cells, which appear more susceptible to destruction in vivo in both Epithelial Cells in HIV Infection diseases, were more resistant to apoptosis in vitro than HSG cells. HSG cells showed up-regulated ICAM-I, V-CAM-1 and other integrins but not MMP-9. N Baumgarth* ([email protected]) Conclusions: Apoptosis occurs in SGD in HIV but it is Center for Comparative Medicine, University of California, unlikely that this is the major mechanism of salivary Davis and Dept. Stomatology, University of destruction. In this study, apoptosis was vigorous in SS California, San Francisco, USA suggesting it does play a major role. Cleavage of Fodrin Epithelial cells on mucosal surfaces such as the oral cavity and increased adhesion molecules in HSG cells stimulated are regarded as a barrier to HIV entry. While infection of in vitro to yield α-fodrin, and the presence of α-fodrin in CD4-negative epithelial cells with HIV can occur even in saliva in vivo, further suggests this is a marker of disease the absence of HIV-envelope glycoproteins in vitro, this

______32 5 th World Workshop on Oral Health and Disease in AIDS . type of infection is inefficient and in vivo might occur only lesions presented in HIV-infected patients can be diagnosed rarely, if at all. However, systemic HIV infection does easily and treated promptly. Therefore, knowledge of strongly affect the ability of mucosal surfaces to combat common skin diseases found in HIV-infected individuals is infections with obligate and opportunistic pathogens. In the certainly necessary for any practicing health care worker in oral cavity this is seen in particular in the increased the HIV field. occurrence of lesions caused by Epstein-Barr virus, Human Papilloma virus and Candida albicans. The reasons for this increased susceptibility are only partially understood. It is Prevention and Treatment of possible that epithelial cells, while not directly infected, are Opportunistic Infections Associated with functionally altered by the HIV-mediated alterations of the HIV in Thailand immune system. To investigate this possibility, we aimed to determine the effects of systemic HIV infection and highly- P16 C. Ploenchan* ([email protected]) antiretroviral therapy (HAART) on oral epithelium. We performed laser-dissection microscopy-assisted gene Division of Infectious Diseases and Tropical Medicine, expression studies on punch-biopsies from normal buccal Faculty of Medicine, Khon Kaen University, Khon Kaen, mucosa of HIV-negative and HIV-infected patients Thailand with/without HAART, who were oral lesion free at the time Opportunistic infections (OI) are the major clinical of biopsy. Biopsy materials from HPV32-induced oral warts presentations on HIV-infected patients in Thailand. were also studied. Gene expression measurements were Mycobacterium tuberculosis is the most common infection done using both a newly developed multiplex real-time RT- followed by fungal infection, Pneumocystis carinii PCR approach, as well as comprehensive microarray pneumonia and cryptococcosis. Another fungal infection analyses. Immunohistochemistry was performed on the that has exhibited marked geographic variation is same biopsies to assess the composition of the leukocytic disseminated Penicillium marneffei infection which infiltrate in the epithelium. The results of these studies point prevalence in the North. to subtle but distinct HIV/HAART-induced changes in the stratum spinosum of the oral mucosa. The most striking There are two major differences of primary prophylaxes of finding was the strong induction of genes associated with OI in Thailand from other guidelines for tuberculosis and the Type I IFN system, potentially affecting both antigen- cryptococcosis. The primary prophylaxis is not routinely presentation as well as antiviral defenses. Furthermore, recommended due to the concerning of drug resistance and HIV/HAART was associated with the induction of various the difficulty in performing of tuberculin skin test. Primary innate effector molecules, including multiple alpha- and prophylaxis of cryptococcosis is generally offered in beta-defensins. In contrast, the leucocytic infiltrate and patients with CD4 cell counts < 100 cells/mm3 with low other measurements related to the adaptive arm of the dose fluconazole (400 mg weekly). The recommendation is immune system seemed little if at all affected. It is tempting based on the high prevalence of the disease and the to speculate that these and other functional changes in tendency of survival benefit. Itraconazole 200 mg daily is an steady-state innate immune defenses of the oral epithelium alternative choice in endemic area of penicilliosis since it fundamentally alter the susceptibility of mucosal surfaces to can prevent both penicilliosis and cryptococcosis. insult and infection with pathogens. These studies provide a Mycobacterium avium complex (MAC) infection in basis from which specific mechanisms affecting host- Thailand is difficult to make diagnosis and treatment. Acid pathogen interactions can now be evaluated. This work was fast staining cannot differentiate between M. tuberculosis supported by the NIH/NIDCR grant DE-PO1-07496 and MAC. The mycobacterial culture is not widely obtainable. The unavailable of medications is not only the obstacle for the treatment of MAC but also for CMV Expression of HIV-1 Receptors, Co- infection. Management of CMV retinitis is markedly diverse P14 receptors and Alpha-defensins in Thailand. Few patients receive standard treatment and secondary prophylaxis, some get only local treatment, and most of them get no treatment. The use of highly active P14A antiretroviral therapy (HAART) is the great benefit in HIV Current Status of Oral Mucosal Immunity in HIV infected patients especially for CMV infected patients. With HAART therapy, most of patients can be discontinuation of secondary prophylaxis successfully. P15 Proper prevention and treatment of OIs is importance in the Skin Lesions: Mirror Images of Oral Lesion Infections care of HIV-infected patients in Thailand. N Phanuphak* ([email protected]) P17 The Thai Red Cross AIDS Research Centre, Thailand, [email protected] Candida Host Interactions in HIV Skin diseases are very common in HIV-infected individuals. Not only can skin lesions be among the first presenting P Fidel* ([email protected]) signs of HIV infection, they can frequently be the only visible signs of systemic infections or diseases. Like oral Department of Microbiology, Immunology, and lesions, skin lesions can harm HIV-infected patients both Parasitology, Center of Excellence in Oral and Craniofacial physically and mentally since they are so obvious and easily Biology, Louisiana State University Health Sciences Center, recognized by public as HIV stigma. Fortunately, most skin New Orleans, LA, USA

Oropharygeal candidiasis (OPC) caused by the commensal growth conditions. At least three of the several oxylipin- organism, Candida albicans, is the most common oral and lipoxin-like metabolites produced by C. albicans have infection in HIV disease. Although cell-mediated immunity been characterized by tandem mass spectrometry. One of (CMI) by Th1-type CD4+ T cells is considered the these, 3R18 dihydroxytetraenoidic acid (HETE) has been predominant host defense mechanism against OPC, local shown to be a potent biologically active compound which immune mechanisms are critical when blood CD4+ T cells affects the host innate immune system through such are reduced below a protective threshold. For example, the activities as the inhibition of host neutrophil migration Th cytokine profile in saliva may influence resistance or (Deva, et al., 2002). We believe that these genomic susceptibility to OPC. In OPC lesions, CD8+ T cells become comparisons have led us to uncover a lipid-mediated accumulated at the lamina propria-epithelium interface dialogue between host and pathogen which is composed of a suggesting some role for CD8+ T cells against OPC. large and diverse repertoire of biologically active lipid However, the absence of CD8+ T cells in close proximity metabolites. Many of these metabolites have counterparts in with Candida at the outer epithelium indicate that both plants and evolutionarily distant vertebrates such as susceptibility to OPC involves a dysfunction in the CD8+ T amphibians and fish. With the publication of an increasing cells or in the microenvironment. Further evaluation of the number of genome sequences from both pathogenic and buccal mucosa lesion showed that CD8 T cell-associated nonpathogenic fungi and microbes, we are examining the cytokine and chemokine mRNA is increased compared to potential association of these lipid-associated activities and buccal mucosa from lesion negative matched controls. The pathogenesis. majority of CD8+ T cells present possess the  T cell receptor and 47 homing receptor. While several adhesion + - molecules are similar in OPC vs. OPC persons, E-cadherin Viruses in the Oral Cavity in HIV + is reduced in tissue of OPC persons. These results support Disease: an overview + P19 evidence for a role for CD8 T cells against OPC, but that a putative dysfunction in mucosal T cell trafficking may be CG Teo* ([email protected]) associated with susceptibility to infection. Similar levels of Sexually Transmitted and Blood Borne Viruses Laboratory, Candida-specific antibodies in those with and without OPC Health Protection Agency Colindale, London, UK confirmed a limited role for humoral immunity. Finally, oral epithelial cells inhibit the growth of Candida in vitro in a Herpesviruses and papillomaviruses that are tropic for static rather than cidal manner. Clinically, oral epithelial cell tissues in the mouth may influence oral HIV replication. anti-Candida activity is reduced in HIV+ persons with OPC Mechanisms that contribute include heterologous compared to controls. The mechanism of action includes a transactivation, increased expression of HIV receptors and strict requirement for cell contact by an acid-labile moiety co-receptors, the release of cytokines and chemokines and on intact, but not necessarily live, epithelial cells with no the production of superantigens. In addition, diseases that role for soluble factors. Taken together, host defense against are common in the HIV co-infected host, particularly those OPC involves several levels of activity. The status and that are inflammatory and that arise following antiretroviral efficiency of local host defenses when blood CD4+ T cells therapy, also contribute. The extent to which oral HIV are not available appear to play a role in protection against transmission may be heightened following co-infection with or susceptibility to OPC. these viruses remains controversial. HIV (both oral and systemic) and the immune suppression that results from its infection can, in turn, promote the replicative and oncogenic Lipid-Mediated Dialogues between Host activity of oral viruses. In sub-Saharan Africa, both the P18 and Pathogen endemic and epidemic forms of Kaposi's sarcoma remain N Agabian* ([email protected]) and S Nigam significant causes of morbidity and mortality. In the West, the prevalence of oral warts in the HIV-coinfected is rising; Genomic comparisons how such rise may relate to the development of HPV- between the opportunistic associated head and neck squamous cell carcinoma is pathogen Candida albicans unknown. and the non-pathogenic P20 P21yeast Saccharomyces cerevisiae identified approximately 200 genes of known function which are either absent in Expression and Oral Manifestation of EBV and HHV8 Saccharomyces, or for which their closest homologue is found in more evolutionarily distant eukaryotic organisms. More than 60% of these "Candida-specific" genes are in lipid and fatty acid metabolism, oxidative metabolism and respiratory functions (Scherer, et al., Proc. Natl. Acad. in Biology of HPV in HIV Infection press). We have pursued this observation in an effort to understand what the role of lipids might be in Candida J Palefsky* ([email protected]) pathogenesis. Our studies suggest that Candida albicans, University of California, San Francisco, USA while typically grown fermentatively, is equally and perhaps preferentially, able to grow oxidatively, utilizing long chain Objectives: To describe the epidemiology and pathogenesis fatty acids and lipids as sole carbon source and to grow to of human papillomavirus (HPV) infection in HIV-positive cell densities equal to or better than those achieved in men and women. fermentable carbons sources such as glucose. Moreover, mono-, di- and tri-hydroxy derivatives of C18, C20 and C22 Background: HIV-positive men and women are at polyunsaturated fatty acids (PUFAs) are made under these increased risk of anogenital and oral HPV infection. The

______34 5 th World Workshop on Oral Health and Disease in AIDS . risk of HPV-associated condyloma and high-grade instability, genetic changes and HPV integration increases, intraepithelial neoplasia (IN) are also increased. However, with the most common genetic change being amplification the risk of HPV-associated cancer varies by mucosal site of chromosome 3q. with the relative risk among HIV-positive individuals being highest for anal cancer. Conclusions: Current data support a model in which immune suppression plays a more prominent role in the Methods: Prospective cohort studies anogenital and oral earlier stages of disease up to an including incident high- HPV infection and associated lesions in HIV-positive men grade IN. Persistent high-grade IN and development of and women; AIDS and cancer registry matches; array-based cancer are more strongly related to the cumulative effect of comparative genomic hybridization and single nucleotide HPV-associated genetic instability and the resulting host polymorphisms analysis of HPV-associated lesions chromosomal changes. HPV integration is associated with genetic changes and multiple genes on chromosome 3q may Results: There is an increased prevalence and incidence of be important in progression to cancer. oral, anal and cervical HPV infection in HIV-positive individuals with the risk increasing with progressively lower CD4+ levels. The risk of incident high-grade IN also increases with lower CD4+ level. Highly active antiretroviral therapy has a modest effect on reversing high- grade IN or no effect at all. In contrast to IN, development of cancer is not as clearly related to lower CD4+ level. With increasing grade of IN, the proportion with genetic

ABSTRACT Plenary Workshop

W1W4 Scientific Opportunities and Mechanisms from the Collaborative Research and Funding Mechanisms NIDCR/NIH P Phanuphak* ([email protected]) M Nokta* ([email protected]) Faculty of Medicine, Chulaongkorn University and the Thai National Institute of Dental and Craniofacial, NIH, Red Cross AIDS Research Centre, Bangkok, Thailand Bethesda, MD, USA HIV/AIDS has taught us many things about research. The mission of the National Institute of Dental and Discoveries in the laboratory have to be rapidly developed Craniofacial Research is to improve and promote into clinical products because of the urgent need. AIDS craniofacial, oral and dental health through encouraging and drugs are examples of such accelerated development. An supporting research. In doing so, the NIDCR seek the best average of 2-3 new AIDS drugs will be licensed each year. science, including global research findings and promotes In order to obtain such fast results, multicenter and and encourages collaborations between United States and multinational trials are needed. AIDS Clinical Trials foreign Research Institutions. The oral complications Groups (ACTG) are examples of such collaborative associated with HIV/AIDS, is a major worldwide public research. Initially, it was limited to sites within USA but is health problem. Recognizing the magnitude of the problem, now being extended to many other sites both in developed the NIDCR currently supports research in this general area, and developing countries. Standard operating procedures for through a number of programs and mechanisms. The good clinical practice (GCP) and good laboratory practice NIDCR supports research that will increase our (GLP) have been formulated and made popularized within understanding of the pathogenesis of the oral complications the last 2 decades as a result of large-scale collaborative associated with HIV/AIDS; determine the Interaction of clinical trials. It is aimed to ensure that all data are reliable HIV and /or other chronic viral or fungal oral pathogens and standardized. Protecting the rights of the volunteers and with innate and adaptive immune networks; and identify research ethics are highlighted in HIV research. In addition, novel strategies for prevention and treatment of the oral social scientists and biomedical scientists are working closer manifestations of AIDS and other immunosuppressive than ever in HIV research since prevention and control of conditions. In addition the NIDCR supports training HIV/AIDS requires a multidisciplinary approach. programs as well as epidemiological and translational research. An overview of current funding opportunities and Multicenter and multidisciplinary collaboration may be mechanisms will be presented. within the country or between countries. The collaborating centers can be universities, hospitals, or research institutions. In some countries such as USA and Australia, HIV clinical trials sites can be private clinics. The HIV W2 Netherlands Australia Thailand Research Collaboration Research and Training Opportunities from the (HIV-NAT) is the example of such multi-continent NIDCR/NIH collaboration in HIV clinical research. It is Asia’s first HIV W3 clinical trials center established since 1996. HIV-NAT is internationally known through its published study results which benefit AIDS patients worldwide. Role of the WHO Research fund may come from local university or local government. However, large fund usually comes from abroad, either from foreign governments or foreign universities or from internationally-based pharmaceutical industry. Research funding creates the status of donors and recipients. In fact, both donors and recipients will benefit from the results of the research. Therefore, both donors and recipients should have equal respects, equal rights and equal shares of the responsibilities and of the benefits coming out from the research in order to make a healthy donor-recipient relationship.

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