The University of North Carolina Center for AIDS Research Grant uri icon

abstract

  • The human immunodeficiency virus (HIV) is responsible for acquired immunodeficiency syndrome (AIDS). HIV remains one of the world?s most serious health problems. Mucosal sites represent the primary routes of HIV transmission, yet the oral mucosa appears uniquely resistant to HIV-1 infection. The risk of adults becoming infected through the oral route appears to be relatively low and it is generally assumed that HIV transmission does not occur through casual oral contact, even among patients with a high viral load. Although HIV RNA can be detected in saliva, the difficulty in culturing HIV from oral samples suggests that the oral cavity is not a source of infectious virus and that transmission through the oral route is inefficient. Since the oral cavity is not conducive to either infection or transmission of HIV, characterizing the responsible resistance factors and their mechanisms of action may identify new opportunities for interference with viral acquisition at other mucosal sites. People with advanced HIV infection are vulnerable to life-threatening malignancies and opportunistic infections such as candidiasis. Candida albicans is a polymorphic fungus and a commensal microorganism that colonizes the human oral cavity in healthy people. However, in the immunocompromised host, C. albicans becomes an aggressive pathogen. In fact, oropharyngeal candidiasis affects up to 50% of untreated HIV positive subjects and 90% of AIDS patients (CD4 = 200). Epidemiological studies show that vaginal candidiasis is highly correlated with increased estrogen levels and depletion of Lactobacilli spp., but is not clearly associated with AIDS immunosuppression. Intriguingly, HIV-1 directly interacts with C. albicans and this interaction abrogates the production of HIV-1 by infected cells. Our unpublished preliminary data provides new insights into the mechanisms by which C. albicans acts against HIV-1. The putative pathway by which C. albicans affects HIV-1 infection involves: i) the modulation of natural HIV inhibitor chemokines; ii) the upregulation of IFN-a and iii) the upregulation of antiviral restriction factors. Therefore, our hypothesis is that C. albicans modulates HIV pathogenesis and thus the oral mycobiome can contribute to the resistance of HIV infection seen in the oral cavity. To explore our hypothesis, we propose a comprehensive and complementary research plan. The specific aims are as follows: 1) Determine how candida driven responses impact early events in HIV infection. Elucidate the C. albicans -induced host signaling pathways by inhibiting TLR2/TLR4/Mannose receptors that are critical to the expression of a) natural HIV competitors (CXCR4/5 ligands RANTES, MIP-1?/? and SDF-1) and of b) antiviral restriction factors APOBEC3G, APOBEC3F, and tetherin and 2) Identify the transcriptional signatures of different strains of C. albicans. Characterize C. albicans with high (C. albicans strain SC 5314) or low (C. albicans strain GDH18) anti-HIV activity and identify the metabolic signatures of different strains of C. albicans by RNA seq. In contrast to the commensalism/parasitism relation, the oral mycobiome could be involved in oral resistance by reducing the transmission of HIV-1.

date/time interval

  • August 2018 - July 2019