Crosstalk
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Research Plan

The Crosstalk Program is organized into four project groups which are all supported by the clinical and biostatistical cores.

Project 1
Project 2
Project 3
Project 4
Clinical Core
Biostatistical Core

Project 1

Drs. Haiteng Deng and David Fenyö
Comparative Proteomic analysis of saliva from HIV-, HIV+/HAART na´ve, and HIV+ post-HAART samples.

Saliva is an important determinant of oral health and contains a large number of proteins and peptides that maintain the oral cavity in good health. A feature of saliva is its potent antimicrobial activity against a wide array of invading pathogens. These include viruses such as HIV-1, the fungus Candida albicans, and bacteria associated with oral and systemic diseases. However, little is known regarding the overall protein species present in saliva and their changing pattern during the course of HIV-1 infection. The uniqueness of our approach is the integration of mass spectrophotometric technologies to determine differences in salivary protein profiles in HIV-negative and HIV-positive individuals before and after high actively antiretroviral therapy (HAART). This strategy can simultaneously compare protein expression profiles from multiple samples within days at the sensitivity of femtogram level, thereby offering a comprehensive overview with the great sensitivity to identity the changes in quantity of proteins in saliva samples in normal and disease settings. We believe that results from this project will contribute significantly towards our understanding of the salivary response to HIV-1 infection and facilitate identification of novel antiretroviral factors for use as novel diagnostic, oral microbicides or therapeutics against HIV-1 infection.

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Project 2

Drs. Yihong Li and Deepak Saxena
Defining the oral microbiota in HIV- vs. HIV+ saliva samples, and HIV+ before and after HAART.

HIV/AIDS, killed 2.8 million persons in 2005, continues to be a major public health problem throughout the world. In the U.S. alone, approximately 40,000 persons become infected with HIV each year. Highly active antiretroviral combination therapy (HAART) has significantly reduced the number of AIDS deaths by 70% since 1996, and has changed the clinical profile of HIV infection from a sub-acute lethal to a chronic ambulatory disease. However, HIV-infected patients experience more mucosal opportunistic infections, more dental caries, and severe periodontal diseases, even after HAART, suggesting that compromised oral micro-environment within the oral cavity is a consequence of the viral infection. The objectives of the proposed study are to define the difference in oral microbiota between HIV-infected and non-infected individuals and to determine the effect of subsequent HAART on the dynamic changes of the microbial community in the oral cavity. Our central hypothesis is that HIV infection decreases the level of overall microbial colonization and diversity in the oral cavity and that HAART alters the compromised microbiota. A related question is that the changes in microbial diversity in HIV+ individuals results in an increase in cariogenic and periodontal bacteria, with a comensurate increase in caries and periodontal disease. We will measure the colonization of (a) total cultivable microbes; (b) total Candida spp.; (c) total streptococci; and (d) total lactobacilli in saliva of HIV infected and noninfected subjects; examine the microbial diversity using the 16S rDNA-based approach; , and determine the association among specific salivary proteins of known involvement in HIV infection, specific cariogenic and periodontopathogenic bacterial colonization, and oral health assessments. The findings of this study will provide new insight into whether HIV infection causes changes in oral microbiota and salivary protein profiles favoring the development of caries and periodontal diseases and may the development of specific antibiotic therapy to prevent the adverse change in the microbiota and to decrease susceptibility to other infections

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Project 3

Drs. Michael Poles and Zhiheng Pei
Gastrointestinal tract study focusing on innate immune mediators and microbes.

Protective immunity requires interaction between the acquired and the innate immune systems. While great advances have been made towards understanding the critical role of the acquired immune system in the defense against HIV infection, our knowledge of the role of innate immunity is rather limited. The GI mucosal immune system plays a vital role in protection against infection by HIV and opportunistic pathogens, in part through mucosal secretions, containing a rich variety of soluble innate immune mediators. We hypothesize 1) that differences identified in the susceptibility of mucosal infection by HIV orally compared to the rectum or vagina are a result of differences in the types and concentrations of soluble innate immune mediators in their secretions, 2) that the increased risk of development of GI opportunistic infections with immunosupression are a result of decreased secretion of innate immune mediators by the mucosa, 3) that immunosuppression is also associated with wholesale changes in the mucosal microbiota, 4) that alterations in the local microbiota contribute to alteration in the secretion of soluble mediators of innate immunity, and 5) that increased mucosal colonization by proinflammatory bacterial species will result in secretion of mediators that stimulate mucosal HIV replication. This project will explore the changes associated with HIV infection in the GI mucosa. Factors considered are depressed mucosal secretion of soluble innate immune mediators, effects of HIV-induced immunosupression secretion on innate immune proteins that results in changes in the diversity of the mucosal microbiota throughout several GI mucosal sites, and the effect on mucosal microbiota alter secretion of immune mediators, which in turn affect HIV replication. The knowledge gained from the proposed studies may lead to mechanisms to suppress HIV replication, alter the natural history of HIV disease and decrease the susceptibility of mucosal sites to HIV infection.

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Project 4

Drs. Daniel Malamud and William Abrams
Antibacterial and antiviral activities related to the innate host defense system in saliva .

To better understand the uniqueness of the oral cavity during HIV infection and subsequent therapy, this project hopes to define the functional relationships among HIV, specific soluble host defense molecules and oral bacteria. We will focus on addressing how the oral cavity responds to HIV, how host defense molecules and cytokines are modulated during HIV infection and subsequent therapy, how antiviral and antibacterial activities change during HIV infection, and how a comparison of the HIV-1 variants in the oral cavity, gut, and blood that may be influenced by local host factors. Ultimately we hope to understand why rectal transmission of HIV is much more efficient than oral transmission and how this information could be used to decrease the rate of HIV infection. In order to accomplish these goals we will quantitate a subset of soluble innate host factors that are known to interact with both HIV and bacteria, quantitate the anti-HIV and antibacterial activity of samples from HIV-, HIV+, and HIV+/HAART subjects as well as from individual purified proteins and to determine whether oral and rectal tissues differ in their susceptibility to HIV infection in vitro, and characterize genetic and phenotypic features of the HIV reservoir in the oral cavity, blood, and gastrointestinal tract.

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Clinical Core

Drs. Joan Phelan, Pat Corby, William Abrams, and Judith Aberg
Clinical phases of the program.

The Clinical Core enrolle subjects (85 HIV+ ART-na´ve subjects and 85 HIV- subjects) over a 3 year period. All subjects will be consented. The subjects will be clinically followed at 24 week intervals over a 2 year period. The saliva, plaque and buccal mucosal tissue samples collected from these subjects will be provided to the research projects. From the total population of subjects, a subpopulation will be recruited for Project 3 study on gastrointestinal innate immunity. Demographic and laboratory data collected by the Clinical Core is collected by the Biostatistics Group for data management and analysis.

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Biostatistical Core

Robert Norman, Gene Fisch, and David Fenyö

The Biostatistical Group will provide an infrastructure for data management and analysis, and correlate results data between the research projects and the Clinical Core, as well as perform internal analysis of data.

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