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Emerging and Re-emerging
Research and Issues on Oral
Aspects of HIV/AIDS
Isaac R. Rodriguez-Chavez, Ph.D., M.S., M.H.S.
Director, AIDS and Immunosuppression Program, NIDCR, USA
Emerging and Re-emerging Issues on
Oral Aspects of HIV/AIDS
Overview
1. The biology of HIV transmission
2. HIV virology and oral viral pathogenesis
3. Pathogenesis of oral opportunistic infections
4. Oral HIV pathogenesis connected with metabolic,
nutritional and body composition change
5. Pathogenesis of AIDS-related oral malignancies
6. Oral pathogenesis of HIV and neurological
manifestations
7. Oral mucosal HIV vaccines
8. HIV diagnostics
Topic 1: The Biology of HIV Transmission
Goal: To determine viral, genetic and immune mechanisms
involved in oral HIV transmission and the establishment and
spread of HIV infection.
• Role of phenotype/genotype/fitness/variants in oral
transmission of HIV
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Mechanisms of virus- and host-encoded genes/products and
their interactions
Role of the oral microbiome, viriome and fugizome in
transmission, establishment, spread, and exacerbation of lesions
Characterize target cell subsets for HIV entry, dissemination and
replication at different stages of replication
Topic 1: The Biology of HIV Transmission
(continued)
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Determine mechanisms by which oral innate and mucosal
immunity interplay with systemic immunity and how they are
influenced by genetic and environmental factors to modulate
HIV replication, transmission, establishment and spread
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Saliva soluble factors, cellular and humoral components
HLA polymorphisms –B*27, B*57
Assess the role of inflammation and its mediators in the oral
cavity, impacting HIV transmission and dissemination
Topic 2: HIV Virology and Oral Viral
Pathogenesis
Goal: To determine viral and host mechanisms in the oral cavity
linked with HIV induced immune dysfunction, abnormal
immune activation, inflammation and disease progression
• Define factors and mechanisms that regulate initial HIV
replication, blocking and/or controlling virus during 1ry
infection, establish viral setpoint and disease progression
• Determine early events of HIV infection in the oral cavity
connected with systemic spread and later clinical course
• Define virologic and host factors in the oral cavity that enable
HIV to establish and maintain persistent infection
• Delineate molecular mechanisms by which virus-encoded
gene products, host cellular factors, and intracellular
compartments regulate HIV replication and influence oral
pathogenesis
Topic 2: HIV Virology and Oral Viral
Pathogenesis (continued)
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Determine the factors that influence the identification and
susceptibility of target cells in the oral cavity to HIV infection
and their ability to support HIV replication
Determine the structures of complexes between viral proteins
and saliva soluble factors involved in the process that block
HIV infection
Define mechanisms underlying HIV induced depletion and
dysfunction of immune cells in the oral cavity
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T, NK, DC, B, MØ loss/impairment, cell death,
nonresponsiveness, dysregulation, altered production of factors,
regeneration and homeostasis of cell populations
Define the role and mechanisms of immune activation and
inflammation (IRIS) in the oral cavity to HIV disease
progression
Topic 2: HIV Virology and Oral Viral
Pathogenesis (continued)
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Evaluate whether and to what extend viral-induced damage to
the oral mucosal immune system can be reversed following
suppression of HIV replication by therapy
Define viral and host markers and develop assays to study
oral innate and mucosal immunity in the context of HIV
Study oral reservoirs (MØs) of HIV that permit persistence in
the setting of therapy and ongoing immune responses
Define the viral and host factors associated with clinical
response/lack of response to oral therapy in infected subjects
Topic 3: Pathogenesis of Oral Opportunistic
Infections
Goal: To elucidate the pathogenic mechanisms and consequences
of opportunistic infections (OIs) and co-infections in HIVinfected individuals and the factors that regulate susceptibility
to OIs that may be targeted for prevention
• Conduct studies on oral pathogens and their interactions with
the host
• Determine genetic and environmental risk factors associated
with susceptibility to, the development of, and the progression
of oral OIs in HIV infected individuals
• Study the effects of oral OIs and co-infections on immune
dysfunction, impact on nutritional status and progression
• Define mucosal immune responses to oral OIs and determine
how they may be altered by HIV infection/ART
Topic 3: Pathogenesis of Oral Opportunistic
Infections (continued)
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Study how HIV infection changes the pathogenesis of coinfecting oral pathogens
Elucidate mechanisms of immune function that mediate
protection against oral OIs
Study the effects of HIV therapy-associated immune
reconstitution on the clinical course and manifestation of oral
OIs and co-infections
Use of metagenomics analyses to characterize oral
microbiome, viriome and fungizome and their alterations due
to oral OIs, impacting HIV infection and progression
Determine biomarkers and factors associated with clinical
response and lack of response to oral therapy against OIs and
co-infections in HIV infected subjects
Topic 4: Oral HIV Pathogenesis Connected
with Metabolic, Nutritional and Body
Composition Change
Goal: To define the etiology, oral pathophysiology, consequences of
HIV infection and treatment-related metabolic disorders, body
composition changes, nutritional status, endocrine dysfunction,
oral health status and cardiovascular disease in HIV infected
subjects
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Define mechanisms underlying alterations in metabolism, body
composition, nutritional status, endocrine function, growth and
development, and the risks of developing oral manifestations in HIV
infected subjects
Study the impact of HIV on aging populations, including implications
of HIV infection for oral disease.
Use novel therapies that suppress HIV infection to explore the
pathogenic mechanisms underlying alterations in metabolism, body
composition, nutritional status, growth, development and oral disease
Define factors tied with clinical response (or lack of) to oral therapy
linking metabolic, nutritional and body composition change with oral
health and/or disease
Topic 5: Pathogenesis of AIDS-related Oral
Malignancies
Goal: To elucidate the etiologic factors, co-factors, pathogenesis, and
consequences of HIV-related oral malignancies
• Elucidate the immune defects and host factors in HIV infection that
predispose to the development of oral malignancies
• Elucidate the mechanisms by which HIV infection and its treatment
enhance the development of oral malignancies
• Identify the mechanisms by which immune dysfunction, oncogenes,
suppressor genes, carcinogens and non-HIV viral and other
microbial genes and proteins contribute to oral malignancies
• Conduct studies on the biology of pathogens causing oral
malignancies and their interaction with the oral cavity –
mechanisms
• Investigate the contribution of HIV-associated or opportunisticpathogen-associated inflammatory pathways and immune
dysregulation to oral cancers
• Determine the impact of AIDS-associated oral malignancies on the
immune response to HIV
Topic 6: Oral Pathogenesis of HIV and
Neurological Manifestations
Goal: To elucidate the mechanisms of HIV-associated neurological
disease and neurobehavioral dysfunction linked with oral health
status
• Determine the impact and relationship between poor oral health
status and the development of CNS manifestations, including
neuropathies and dementia in the context of HIV infection
• Define if oral viral reservoirs (MØs) play a role in the
neuropathogenesis of HIV/AIDS – mechanisms
• Define mechanisms of immunologic control of HIV, oral OIs and
co-infections in the CNS
• Define mechanisms of immune reconstitution syndrome in the
CNS in the setting of oral OIs and co-infections
• Determine the role of oral OIs, co-infections, and therapy in
neurologic and neurobehavioral complications of AIDS
Topic 7: Oral Mucosal HIV Vaccines
Goal: To develop prophylactic oral mucosal HIV vaccines to
help boost local and systemic immunity against HIV
infection
 Determine the mechanisms linking oral mucosal and
innate immunity with systemic adaptive immunity
 Develop HIV vaccine antigens in oral expression vectors
that are stable in the oral cavity and have the ability to
trigger anti-HIV protective immunity
 Define the role of oral DC and NK cell subset changes
during disease progression or upon oral mucosal HIV
vaccination
 Determine DC-NK cross-talk in the oral cavity and
relationship to systemic adaptive immunity upon oral
mucosal HIV vaccination
Topic 7: Oral Mucosal HIV Vaccines
(continued)
 Determine similarities and differences between DC-NK
cross-talk in the oral mucosal site compared with other
mucosal sites
 Characterize soluble defense molecules produced in oral
secretions upon oral mucosa HIV vaccination
 Develop oral mucosal vaccine strategies that will induce
sustained high levels of broadly reactive neutralizing
antibodies to primary isolates at oral as well as other
mucosal sites of infection such as the rectum and vagina
 Define methodologies to increase or mobilize antigen
presenting cells (e.g., immature DCs) to oral mucosal
vaccination sites
Topic 7: Oral Mucosal HIV Vaccines
(continued)
 Understand the mechanisms involved in maintaining the
balance between inductive vaccine responses and tolerance
to facilitate the development of oral mucosal vaccines against
HIV
 Develop approaches to enhance and characterize HIV
vaccine-induced immunologic memory and long term
protection to oral mucosal vaccination
 Harness innate immunity and regulatory T cell responses
together for development of an oral mucosal vaccine
 Develop and validate adjuvants (TLR ligands, fusogens,
cytokines, etc) that will improve the immunogenicity of oral
mucosal vaccines
 Elucidate approaches to enhance and characterize HIV
vaccine-induced immunologic memory and long term
protection to oral mucosal vaccination
Why might mucosal immunity be important
for HIV vaccines?
 HIV acquisition: Most HIV infections sexually transmitted.
Mucosal immunity could protect against acquisition.
 HIV disease progression: CD4+ CCR5+ effector memory T
cells destroyed early in HIV infection. Clinic course may be
ameliorated by protecting these cells at mucosal surfaces
(e.g. gut mucosal T cells).
 HIV transmission: HIV viral load predicts transmission to
new partners. Local effects at genital, rectal and oral
mucosa may lower VL in semen, vagina, gut and the oral
cavity and reduce onward transmission.
Type I and II mucosae: different tissue
architecture of potential vaccination sites
Immune responses can occur at distal sites
due to lymphocyte homing
Holmgren & Czerkinsky, Nature Med 2005
Nasal immunization: systemic and mucosal
immunity comes with safety concerns
 Advantage
 Strong responses in blood, large bowel, cervix/vaginaa
 Safety concerns
 Retrograde axonal transport of virus in olfactory nerve or
CNS in mice.b,c
 Cholera toxin (CT) and CTB given intranasally found in
olfactory nerve/ bulb in mice. Tetanus toxoid found in
olfactory nerve when given with CT.d
 NALT is not found in humans
aNeutra
and Kozlowski. Nat Rev Imm. 2006 b Kuo et al, Brain Research 1995
cLemiale et al. JV 2003 dGinkel et al, J Immunol 2000
Lymphatic tissue of Waldeyer’s ring, a
potential vaccination site
Putative scheme for B cell homing from
tonsils
NALT
Waldeyer’s Ring
Upper airways
Lacrimal and
Salivary glands
Systemic
Immune
System
Peripheral blood
circulation
Uterine
Cervix
Mucosa
GALT
Peyer’s Patches
Large
Bowel
Mucosa
Small
Bowel
Mucosa
Topic 8: HIV Diagnostics
Goal: To develop novel assays for HIV diagnostics with
multiple uses, including: screening and confirmatory tests;
central clinical/research/back up/diagnostic labs; and field
applications
• EIAs –antigen and antibody combination
• Rapid tests
• Point of care devices
• NAT and high throughput screening – multiplex assays,
microarrays, deep sequencing methods
Lateral Flow Assay Format
Microfluidic Chip Development
Question?
•
Where would you contribute to help solve the
emerging and re-emerging issues on oral
aspects of HIV/AIDS?
Acknowledgement
• NIH, OD, OAR – Etiology and Pathogenesis
• Drs. Ann Duerr and Daniel Malamud
• NIDCR