HIV-induced microbial alterations and inflammation in the lung of humanized mice

Abstract Human immunodeficiency virus (HIV) is a major global health challenge. According to UNAIDS data 2020, approximately 38 million people across the world are living with HIV. Antiretroviral therapy (ART) is not able to clear the viral reservoir, leaving HIV-1 as an uncurable chronic disease. Despite viral suppression by ART, people living with HIV (PLWH) have increased risks for developing chronic lung diseases, such as chronic obstructive pulmonary disease, emphysema, asthma, primary lung cancer, and pulmonary arterial hypertension. Previous studies have demonstrated that chronic lung inflammation predisposes PLWH to pulmonary complications. Efforts to better understand the mechanisms underlying HIV-related lung diseases are needed. The lung microbiome (i.e., a collection of all bacteria residing in the airway) plays a significant role in modulating lung immunity and disease pathogenesis. Accumulating evidence has supported that PLWH on suppressive ART harbor an altered lung microbiome compared to people without HIV infection. The enrichment of bacteria in the genera of Prevotella spp., Veillonella spp., and Streptococcus spp. in the PLWH may contribute to chronic lung inflammation. Human population-based lung microbiome studies have been mostly cross-sectional. They are confounded by genetic and environmental factors and lack mechanistic insights. Longitudinal studies monitoring the dynamics of lung inflammation and microbial alterations are needed to understand the crosstalk between dysregulated immune pathways and lung microbial dysbiosis during HIV infection. Here we propose to use an advanced humanized mouse model to better understand lung inflammation and microbial dysbiosis driven by HIV infection. We have two specific aims to perform. Specific Aim 1 is to characterize the dynamics of lung microbial alterations and immune perturbations at cellular and transcriptional levels in humanized mice from the acute to chronic infection stages. We will also investigate how ART influence lung immunity and lung microbiome. Specific Aim 2 is to examine the role of lung bacterial dysbiosis on the lung immune system and develop novel approaches to reduce or resolve lung inflammation. We expect that our results will provide novel insights into the crosstalk between pulmonary immune tone and the microbiome in the context of HIV infection and pave the way for further mechanistic studies to better understand HIV-associated lung complications.