AIDS and Oral Manifestations of Immunosuppression Program
Infectious Diseases and Immunity Branch
Division of Basic and Translational Sciences
Objective: This Concept Clearance is for research utilizing a proteomic approach to characterize the protein profiles and protein-protein interactions in oral mucosal tissues in conjunction with HIV infection. The research is expected to provide significant insights into the cellular and molecular mechanisms underlying the pathogenesis of the oral disorders associated with AIDS and the impact of highly active antiretroviral therapy (HAART). It is anticipated that this initiative will identify novel strategies for prevention and management of oral manifestations of AIDS.
Background: Proteomic approaches, or protein profiling of protein-protein interactions are increasingly being used to identify the pathogenic basis of disease. Examples of these approaches include studies of HIV replication that identified viral and cellular protein interactions; studies that advanced our knowledge of the efficient mechanisms evolved by hepatitis C virus to evade the immune response; and studies of molecular communications of signal transduction pathways in cancer research. Some of these specific protein-protein interactions could be targeted for development of novel therapeutic interventions.
The immunosuppression associated with HIV infection makes patients vulnerable to several oral complications, including oral tumors, oral candidiasis, oral viral infections, HIV related salivary gland disorders, and oral ulcerations of diverse etiologies. The majority of infections associated with HIV disease are initiated at mucosal surfaces, occurring as a result of the adherence to and passage of the pathogens across mucosal membranes. The oral mucosa however, is more resistant to HIV infection than other mucosal sites in the body. The reasons for this resistance are poorly understood, and the factors underlying such resistance may be the basis for novel prevention strategies against HIV/AIDS and HIV-associated opportunistic infections. Although the oral mucosa is relatively resistant to HIV, it serves as a portal of entry to other types of viruses such as Epstein-Barr virus or human papilloma virus. The reasons for the differential susceptibility to infection are undetermined and require further research.
The oral mucosa is rich in immune cells, such as CD4+ and CD8+ T cells and their Th1/Th2 subpopulations, Langerhans cells and dendritic cells. The cascade of events triggered by HIV and HIV-associated oral pathogens in the oral mucosa may affect local and systemic innate and adaptive host immune responses. Elucidating the sequence of events, and the immunological and virological factors involved, are likely to shed light on how HIV and the associated oral viral pathogens evade the host immune response. Despite the wide interest in this area of research, many questions remain unanswered. A proteomic approach to determine the patterns of protein expression and their interaction with one another or with host immune networks will be crucial to understand the oral mucosal milieu that facilitates either immune protection against and/or immune evasion by HIV and the opportunistic infections associated with AIDS.
Although the incidence of some of the oral lesions associated with HIV infections has been reduced after the introduction of HAART, some did not change and others increased. For example, while there was a reduction in the incidence of oral candidiasis and oral Kaposi’s sarcoma over time, there was no change in the incidence of aphthous ulcers and an increase in the incidence of salivary gland disease and oral warts. An increasing problem among patients receiving HAART is the development and spread of drug resistant strains, which in turn leads to failure of therapy, disease progression and rebound of oral complications. The effects of HAART can not be completely explained by immune reconstitution and the reduction in the viral load. Examining the effects of HAART on the mucosal proteome will elucidate the conditions that appears conducive or protective to these lesions.
Current Portfolio Overview: Although some of the research areas outlined in this initiative are currently being studied, none has incorporated a global proteomic approach in addressing the oral complications in their research of HIV/AIDS. Current studies generally examine the effect of environmental factor(s) within the oral cavity on the expression of one or more proteins. The availability and advent of bioinformatics and state-of-the-art high throughput technologies and procedures such as laser capture microdissection that allow the procurement of specific pure subpopulations of cells from diseased and/or healthy tissues makes the conduct of such studies timely and feasible.
Recommendations From Workshops: Proteomic approaches for studying the protein profiles in oral mucosal tissues in conjunction with HIV infection were recommended at the “Oral Health and Disease in AIDS: 5th World Workshop, July 6-10, 2004, Phuket, Thailand” and the NIDCR sponsored Workshop “HIV/AIDS Associated Oral Viral Infections: Pathogenesis and Transmission” held in April 2004 in Bethesda, MD.
Collaborative Activities: None
Funding Mechanisms: This initiative will utilize the R01 and R21 mechanisms