1. Immune Reconstitution and Oral Manifestations of HIV/AIDS. Presentation made to TRAC CHUK 7 th May 2010 Dr. Moses Isyagi. BDS. MMed (Pathology) Senior Lecturer, Department of Dentistry Kigali Health Institute. Clinical Coordinator Kigali Health Institute Dental Consultancy Centre..

2. Introduction: The oral environment. The oral mucosa is rich with immunologically functional cells, including dendritic cells, lymphocytes, monocytes, macrophages and neutrophils. The surface of the mucosa is covered by salivary carbohydrates, lipids and proteins, directly interacts with the oral environment, containing bacteria, fungi, viruses, food, tobacco products, alcohol, etc. produces or is bathed by cytokines, chemokines, antibodies and innate host factors in saliva. The exposure of the oral mucosa to multifactorial factors makes it susceptible to opportunistic infections by HHV-8, CMV, EBV, HPV and Candida The oral mucosa is apparently resistant to HIV infection and replication.

3. Introdution: The Oral Environment and HIV The oral mucosal tissue has been shown to be a potential route of entry in both humans and primates. HIV RNA and proteins can be detected directly in the oral mucosa and saliva from infected subjects. infectious HIV virions are rarely found in the saliva, suggest that the oral mucosa is not permissive for efficient HIV replication. The structural and environmental protective factors that make the oral mucosa more resistant to HIV replication than other mucosal sites are currently being studied.

4. Intriduction: The Oral Environment and HIV The ability of the oral cavity to resist HIV infection and replication provides a unique opportunity study the differential patterns of host defenses, the mechanisms utilized by oral pathogens to evade the immune response To uncover the mechanisms involved in reactivation of latent oral viral pathogens to cause disease. Poly microbial interaction plays a role in the pathogenesis of the viral complications associated with HIV/AIDS via virus-virus, virus-bacteria or virus-fungal interaction.

5. HAART and Immune reconstituition.… Immune reconstitution is the increase in functional CD4 cells which guide the immune response against pathogens such as HIV, resulting in the suppression of viral load and other beneficial outcomes. It is mostly seen in profoundly Immunosuppressed patients with CD4 T-cell counts of less than 100 cells/μl with concurrent sub clinical infection, who rapidly achieve an undetectable plasma viral load and increase in CD4 T cells soon after initiating therapy. This may trigger an inflammatory reaction soon after Anti Retroviral therapy is began and signs of immunological improvement are evident-known as immune reconstitution syndrome (IRS) or immune reconstitution inflammatory syndrome (IRIS). Presents with either active opportunistic infections, recurrence of previous infections or non specific generalized inflammatory response. Symptoms often resembles an AIDS-defining illness or other condition seen in people with HIV/immunosuppression. Symptoms of IRIS may be severe or mistaken for true disease progression and resolve after a few weeks Sources. Brigitte Autran The 9th Conference on Retroviruses and Opportunistic Infections Nicholas Cheonis San Francisco AIDS Foundation Winter 2004/2005 A Pires et al.. J Immune Based Ther Vaccines. 2005; 3: 7.

6. HAART and Immune reconstituition mechanism of action Immune reconstitution syndrome remains poorly understood. In acute infection, replicating HIV activates CD4 cells specific for HIV antigens inducing an initial cytotoxic T-Lymphocyte response mediated by CD8 cells. Activated CD4 cells become a prime target for HIV infection, rapidly causing their death. With the loss of HIV-specific CD4 helper cells, maintenance of effective HIV-specific cytotoxic T Lymphocyte activity is not possible.

7. HAART and Immune reconstituition mechanism of action After initiation of ART, HIV replication drops, decreasing the amount of HIV antigens necessary to reconstitute HIV-specific CD4 responses that support the cytotoxic T-lymphocyte responses (CTL) of CD8 cells When suppressive ART is used, viral replication and antigen load disappears, and CTL can no longer target the latently infected CD4 cells that harbour replication-competent pro viral DNA.

8. HAART and Immune reconstituition mechanism of action Development of IRIS appears to be linked to increases in CD4 cell levels and higher CD8 cell counts induced by HAART. An elevated CD8 cell count has been suggested as a prime contributing factor in worsening of both herpes zoster and hepatitis B or C symptoms after the initiation of anti-HIV therapy

9. I HAART and Immune reconstituition The incidence (rate of new cases) of IRIS varies depending on the study, the population under investigation, and the associated pathogens involved. 3 studies have show incidence ranges from 18 to 63 % In one cohort of 52 subjects with previously diagnosed CMV retinitis, 19 of 30 (63%) who responded to HAART developed symptomatic IRV, compared with no cases in those who did not respond to therapy. In a different cohort of 33 similar subjects with CMV retinitis, only six (18%) developed symptomatic IRU In a case control study of 200 ethnically diverse subjects at King's College Hospital in London, 42 (21%) experienced an IRIS event a median of 12 weeks after starting HAART.

10. Conditions Associated With Inflammatory Reactions associated with a variety of latent or sub clinical infections commonly seen in people with very low CD4 cell counts. E.g. Castleman disease,Cryptococcus neoformans, cytomegalovirus (CMV), eosinophilic folliculitis, Graves' disease Hansen's disease (leprosy), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), herpes zoster (shingles), Histoplasma capsulatum, human papilloma virus (HPV), Kaposi's sarcoma (KS), Mycobacterium avium complex (MAC), myopathy, non-Hodgkin's lymphoma (NHL) Pneumocystis carinii (P. jiroveci) pneumonia (PCP), progressive multifocal leukoencephalopathy, sarcoidosis, systemic lupus erythematosus, tuberculosis

11. Immune Reconstitution and Oral manifestations of HIV. Oral manifestations of HIV infection component of disease progression occur in approximately 30 to 80 percent of the affected patient population. Predisposed by CD4 counts less than 200 cells/mm3, viral load greater than 3000 copies/mL, xerostomia, poor oral hygiene and smoking. Oral lesions seen are: Fungal Infections, viral Infections bacterial infections Neoplasms such as Kaposi’s sarcoma Non-specific presentations  aphthous ulcerations  salivary gland disease.

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13. Immune Reconstitution and Oral manifestations of HIV. Oral manifestations of HIV-1 infection have changed with the advent of HAART Studies have noted: significant reduction in oral hairy leukoplakia necrotizing ulcerative periodontitis. No significant change in incidence of oral candidiasis, oral ulcers Kaposi’s sarcoma Increased incidence of salivary gland enlargement Oral warts. (David A. Reznik, D.D.S.,Christine O’Daniels WWW.HIVDENT.ORG )

14. Immune Reconstitution and Oral manifestations of HIV. incidence of HIV-1–related salivary gland enlargement presumably as a manifestation of lympho-proliferative reactivation due to therapy-induced immune reconstitution. Bilateral parotid gland enlargement also may be encountered more frequently Patients with HIV-related salivary gland disease present with signs and symptoms similar to those of patients with Sjögren's syndrome characterized by lymphocytic infiltration of the salivary glands and lympho-epithelial cysts of the major salivary glands. Occasionally lymphomas may develop within the salivary glands. inconclusive.. Marked increase in incidence of oral warts (3 to six fold) possibly due to immune reconstitution of patients. Sources: David A. Reznik, D.D.S.,Christine O’Daniels. WWW.HIVDENT.ORG EVANGELOS RIZOS et al. MAYO CLIN PROC. 2003;78:1561-1563 K Shetty. 5th World Workshop on Oral Health and Disease in AIDS

15. Reference articles of interest

16. Immune Reconstitution and Oral manifestations of HIV.