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Blocking HIV-1 Infection by Chromosomal Integrative Expression of Human CD4 on the Surface of Lactobacillus acidophilus ATCC 4356.

ABSTRACT: Lactobacillus bacteria are potential delivery vehicles for biopharmaceutical molecules because they are well-recognized as safe microorganisms that naturally inhabit the human body. The goal of this study was to employ these lactobacilli to combat human immunodeficiency virus type 1 (HIV-1) infection and transmission. By using a chromosomal integration method, we engineered Lactobacillus acidophilus ATCC 4356 to display human CD4, the HIV-1 receptor, on the cell surface. Since human CD4 can bind to any infectious HIV-1 particles, the engineered lactobacilli can potentially capture HIV-1 of different subtypes and prevent infection. Our data demonstrate that the CD4-carrying bacteria are able to adsorb HIV-1 particles and reduce infection significantly in vitro and also block intrarectal HIV-1 infection in a humanized mouse model in preliminary tests in vivo Our results support the potential of this approach to decrease the efficiency of HIV-1 sexual transmission.IMPORTANCE In the absence of an effective vaccine, alternative approaches to block HIV-1 infection and transmission with commensal bacteria expressing antiviral proteins are being considered. This report provides a proof-of-concept by using Lactobacillus bacteria stably expressing the HIV-1 receptor CD4 to capture and neutralize HIV-1 in vitro and in a humanized mouse model. The stable expression of antiviral proteins, such as CD4, following genomic integration of the corresponding genes into this Lactobacillus strain may contribute to the prevention of HIV-1 sexual transmission.

SUBMITTER: Wei W

PROVIDER: S-EPMC6450108 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Blocking HIV-1 Infection by Chromosomal Integrative Expression of Human CD4 on the Surface of Lactobacillus acidophilus ATCC 4356.

Wei Wenzhong W Wiggins Joshua J Hu Duoyi D Vrbanac Vladimir V Bowder Dane D Mellon Michael M Tager Andrew A Sodroski Joseph J Xiang Shi-Hua SH

Journal of virology 20190403 8

<i>Lactobacillus</i> bacteria are potential delivery vehicles for biopharmaceutical molecules because they are well-recognized as safe microorganisms that naturally inhabit the human body. The goal of this study was to employ these lactobacilli to combat human immunodeficiency virus type 1 (HIV-1) infection and transmission. By using a chromosomal integration method, we engineered <i>Lactobacillus acidophilus</i> ATCC 4356 to display human CD4, the HIV-1 receptor, on the cell surface. Since huma ...[more]

PMID: 30728264

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Project description:Background: Ischemia-reperfusion injury (IRI) is one of the main causes of acute kidney injury. Our previous results have shown that anti-oxidative stress decreased in the renal IRI model. This study aimed to investigate the effect of Lactobacillus acidophilus ATCC 4356 on oxidative stress, inflammation, and intestinal flora in renal IRI. Methods: The model of renal IRI was established by cross-clamping the renal pedicle with non-traumatic vascular forceps. H&E staining was applied to observe the damage of kidney tissue in each group. The concentrations of serum blood urea nitrogen (BUN), creatinine (Cre), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) were detected by biochemical kit. ELISA measured the concentrations of interleukin (IL)-1β, IL-8, IL-4, and IL-10. qRT-PCR was performed to detect molecular expressions of ATCC 4356, oxidative stress-related factors [nuclear factor-related factor 2 (Nrf2), heme oxygenase 1 (HO-1)], inflammatory factors [tumor necrosis factor (TNF)-α, IL-1β, IL-8, interferon (IFN)-γ, IL-4, IL-10], and apoptosis-related factors [caspase 3, Bax, Bcl2, high-mobility group box protein 1 (HMGB1)]. Except for ATCC 4356, the protein expression of the above indicators was detected by Western blot. The apoptosis level of renal tissue cells was detected by TdT-mediated dUTP nick end labeling (TUNEL). 16S rDNA gene sequencing was used to detect the changes of microbial species in the contents of the duodenum and screen out the differentially expressed flora. Results: Both the glomeruli and renal tubules of ischemia/reperfusion (I/R) mice were severely damaged. H&E result displayed that L. acidophilus ATCC 4356 attenuated the infiltration of inflammatory cells caused by I/R. ATCC 4356 reduced the high expression of BUN and Cre in I/R mice with a dose effect. It also reduced the high expression of MDA, TNF-α, IL-1β, IL-8, IFN-γ, caspase 3, Bax, and HMGB1 in I/R mice, while it increased the low expression of SOD, GSH, Nrf2, HO-1, IL-4, IL-10, and Bcl2 in I/R mice. ATCC 4356 inhibited the high level of apoptosis in the kidney tissue of I/R mice. In IRI mice, the top 3 different gut microbiota were Helicobacter, cultivated_bacterium, and k__Bacteria_ASV_3 compared with sham mice. Oral L. acidophilus ATCC 4356 reversed this change. Conclusion: L. acidophilus ATCC 4356 attenuated renal IRI through anti-oxidative stress and anti-inflammatory response and improved the intestinal microbial distribution.

Dataset Information

Blocking HIV-1 Infection by Chromosomal Integrative Expression of Human CD4 on the Surface of Lactobacillus acidophilus ATCC 4356.

Publications

Blocking HIV-1 Infection by Chromosomal Integrative Expression of Human CD4 on the Surface of Lactobacillus acidophilus ATCC 4356.

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