The oral effects of systemic disease are by no means limited only to the periodontium. All of the tissues in the oral cavity are fair game for a variety of insults, either directly from infection, or indirectly as part of the systemic disease process. There is perhaps no better illustration of the involvement of oral tissues in systemic disease than the oral manifestations of AIDS.

Since the acquired immune deficiency syndrome was first recognized in the United States in 1981, the mouth has provided a remarkable laboratory for the study of this emerging infectious disease that targets the immune system for destruction. The first clinical reports of this syndrome indicated that lesions in the oral cavity were common and often occurred early in the course of the disease. Oral health scientists initiated not only clinical studies to define the oral signs and symptoms, but also a basic research strategy to understand the molecular virology and immunology of AIDS.

Studies of the natural history and epidemiology of HIV/AIDS documented that the fungal disease oral candidiasis is the most common opportunistic infection seen in HIV-infected patients, followed by a second oral lesion termed hairy leukoplakia. A whitish lesion frequently seen on the side of the tongue, hairy leukoplakia is strongly associated with the Epstein-Barr virus and is a reliable predictor of AIDS.

A comparison of HIV-positive patients with similar CD4 counts (a measure of the body's immune response) revealed that those with oral candidiasis or hairy leukoplakia tend to develop major opportunistic infections or progress to AIDS more rapidly than patients without these lesions. Also, the odds of developing oral candidiasis increase as the CD4 counts of infection-fighting T cells decrease. In parts of the world where diagnostic blood tests for HIV are not available, the presence of these oral lesions in otherwise asymptomatic adults can be used as an indicator of HIV infection.

A number of studies are examining candidal species to determine the mechanisms involved in the conversion of this harmless fungus commonly found in the mouth to an aggressive infectious pathogen. NIDCR-supported research to characterize the entire genome of Candida albicans will accelerate this process. Other studies are focusing on drug resistant candida and the potential use of gene therapy to bolster levels of histatin, a potent anti-fungal agent normally found in the saliva. Clinical trials are also under way to determine if scrupulous oral hygiene, the use of antimicrobial mouthrinses, and regular dental care can prevent or reduce oral complications in HIV patients with severely compromised immune systems.

Despite the presence of HIV-associated lesions in the mouth and their implications for escalating disease, studies by NIDCR and other NIH-supported scientists suggest that HIV is not spread through casual contact with saliva. Research has shown that HIV is easily cultured from the blood and spinal fluid of AIDS patients, but not from the saliva of HIV/AIDS patients with oral lesions. Of particular interest is the finding that human saliva demonstrates anti-HIV activity.

The intense search for protective constituents in saliva led NIDCR investigators to a relatively small protein called secretory leukocyte protease inhibitor, or SLPI, which attaches to the surface of monocytes and T cells and blocks infection by HIV. SLPI may help explain why AIDS does not appear to be spread by saliva, but much about its possible protective effect remains unknown. The next steps are to determine the protein binding sites on monocytes and T cells, the role SLPI plays in HIV entry into host cells, and its potential as a protective agent against HIV transmission.

Future NIDCR directions in HIV/AIDS research include expanding both our knowledge of the natural history and epidemiology of oral transmission and manifestations of HIV in various populations (including women, children, adolescents and minorities), and our understanding of opportunistic infections and mucosal immunity. The search for therapeutic interventions, synthetic drugs and vaccines, and innovative delivery systems will also be an important part of the NIDCR research portfolio.

Essential to progress in this area is a better understanding of just what happens at the HIV/monocyte and HIV/lymphocyte interface. One of the long-standing challenges in AIDS research has been figuring out exactly how gp120, the large protein on the surface of HIV, latches onto the CD4 target receptor on T cells in the first step in HIV infection. Studies spearheaded by NIDCR scientists have now identified that binding site, called C4, and determined how it recognizes its target receptor. These findings open the door not only for the design of new drugs and vaccines to fight HIV infection, but also for the development of interventions to block the initial interaction between HIV and cells and thereby inhibit infection.

Studies continue on the cellular and molecular mechanisms underlying immune dysfunction in HIV/AIDS, as well as on the pathogenesis of AIDS-related opportunistic infections. A new finding in this area underscores the importance of controlling opportunistic infections in AIDS patients.

It has been known for some time that CD4 T cells are the primary target of HIV infection and that their destruction leads to a weakened immune system and susceptibility to opportunistic microorganisms. As HIV infection progresses toward AIDS, the CD4 T cells are the chief source of new virus, creating a cycle of escalating virus production and T cell death. The paradox has been how the levels of HIV continue to increase over the course of AIDS, at the same time the T cell population dramatically decreases.

Investigators have now identified tissue macrophages as an unexpected source of new virus and point to opportunistic infections as a trigger that sets off a wave of HIV production. Examination of lymph nodes from AIDS patients with a variety of common opportunistic infections revealed from 5 to over 100 times the number of virus-producing macrophages than were found in the nodes of HIV patients free of such infections. The individual macrophages also demonstrated a much higher level of virus production.

Although the actual mechanism that switches macrophages from HIV carriers to producers is not yet known, the research has important implications. Preventing or eliminating opportunistic infections is not only essential to the immediate well-being of the patient, but can also slow the cycle of virus production that leads to further immune system damage.

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