Investigating the effect of oral microbiome on cognition in HIV-infected chronic cannabis users

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Project Summary In the context of human immunodeficiency virus (HIV) infection, cannabis use is an important topic and is the most commonly used drug among HIV-infected individuals. Positive and negative effects of cannabis use in the context of HIV have been reported for various biological processes, including cognitive performance and immune function. Reports vary from cannabis enhancing cognitive function to causing synergistic decline in cognition. Thus, the exact role and limits of chronic cannabis use on HIV cognition under immune perturbations remain unclear. The aim of the present study is to investigate the effects of cannabis-associated oral microbiome on neurocognitive performance in HIV disease by focusing on clinical (Aim 1) and preclinical (Aim 2) neuroHIV models. We and other colleagues have found that Actinomyces species bacteria (e.g. A. meyeri and A. odontolyticus) in the oral cavity of humans, are enriched in the saliva from chronic cannabis users compared to non-users and A. meyeri is enriched in HIV-infected individuals compared to uninfected individuals. But oral A. species enrichment was not demonstrable in tabacco smokers or chronic cocaine users. Further, oral enrichment of A. meyeri was associated with younger age of first cannabis use. Here, we aim to investigate if A. species bacteria has a significant role in HIV neuropathogenesis. To achieve this goal, in Specific Aim 1, HIV cannabis users will be assessed to determine the link between cannabis use-associated oral microbiome (i.e., enrichment of A. meyeri) and cognitive performance by focusing on 1) saliva bacteriome and mycobiome and plasma translocation of A. species bacterial antigens; 2) molecular mechanisms of A. species bacteria mediated TLR2 signaling pathway activation in myeloid cells; 3) neurocognitive performance and its association with microbiome. Specific Aim 2 will make use of two well-established transgenic (tg) mouse models of neuroHIV, including the HIV Tg26 tg and the HIV Tat tg mice, to allow us to determine: 1) the chronic effects of THC and CBD exposure on neurocognition and neuropathology; 2) the chronic effects of THC and CBD exposure on enrichment of A. species bacteria and myeloid cell infiltration to the brain under antiretroviral (ART) drugs; and 3) the mechanisms of cannabis-associated A. meyeri bacteria on neurocognition, neuropathology, and endocannabinoid levels. Understanding the role of chronic cannabis use on oral microbiome and it’s effects on neurocognitive performance in HIV disease is critical to determine its therapeutic benefits and limits in the treatment of patients with accelerated central nervous system pathogenesis under traditional combination antiretroviral therapy (cART).