A germ-free humanized mouse model shows the contribution of resident microbiota to human-specific pathogen infection

Wahl, Angela; Yao, Wenbo; Liao, Baolin; Chateau, Morgan; Richardson, Cara; Ling, Liuyi; Franks, Adrienne; Senthil, Kannaki; Doyon, Geneviève; Li, Fengling; Frost, Joshua; Whitehurst, Christopher B.; Pagano, Joseph S.; Fletcher, Craig; Azcarate‐Peril, M. Andrea; Hudgens, Michael G.; Rogala, Allison R.; Tucker, Joseph D.; McGowan, Ian; Sartor, R. Balfour; Garcia, J. Victor

doi:10.1038/s41587-023-01906-5

Cited by 6 publications

(3 citation statements)

References 99 publications

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“…Administration of metformin in PWH under ART reduced inflammation, viral transcription, and immune infiltration of CD4 þ T cells in the colon, including Th17 cells [60]. In addition, a recent study reports that CCR5 þ CD4 þ T cells are more abundant in the intestine of conventional mice compared to germ-free mice, possibly indicating that the existing microbiota partially dictates HIV susceptibility and persistence [61]. Consequently, HIV RNA levels were higher in plasma and tissues of conventional mice humanized mice compared with germ-free humanized mice [61].…”

Section: Gastrointestinal Tractmentioning

confidence: 99%

“…In addition, a recent study reports that CCR5 þ CD4 þ T cells are more abundant in the intestine of conventional mice compared to germ-free mice, possibly indicating that the existing microbiota partially dictates HIV susceptibility and persistence [61]. Consequently, HIV RNA levels were higher in plasma and tissues of conventional mice humanized mice compared with germ-free humanized mice [61]. Modifying the microbiota may therefore be a helpful strategy to diminish gut HIV-associated persistent inflammation, although no direct changes to immune activation were observed after fecal microbiota transplantation in PWH on ART [62].…”

Section: Gastrointestinal Tractmentioning

confidence: 99%

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Targeting HIV persistence in the tissue

Pieren,

Benítez-Martínez,

Genescà

2024

Current Opinion in HIV and AIDS

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Purpose of review The complex nature and distribution of the HIV reservoir in tissue of people with HIV remains one of the major obstacles to achieve the elimination of HIV persistence. Challenges include the tissue-specific states of latency and viral persistence, which translates into high levels of reservoir heterogeneity. Moreover, the best strategies to reach and eliminate these reservoirs may differ based on the intrinsic characteristics of the cellular and anatomical reservoir to reach. Recent findings While major focus has been undertaken for lymphoid tissues and follicular T helper cells, evidence of viral persistence in HIV and non-HIV antigen-specific CD4+ T cells and macrophages resident in multiple tissues providing long-term protection presents new challenges in the quest for an HIV cure. Considering the microenvironments where these cellular reservoirs persist opens new venues for the delivery of drugs and immunotherapies to target these niches. New tools, such as single-cell RNA sequencing, CRISPR screenings, mRNA technology or tissue organoids are quickly developing and providing detailed information about the complex nature of the tissue reservoirs. Summary Targeting persistence in tissue reservoirs represents a complex but essential step towards achieving HIV cure. Combinatorial strategies, particularly during the early phases of infection to impact initial reservoirs, capable of reaching and reactivating multiple long-lived reservoirs in the body may lead the path.

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Section: Gastrointestinal Tractmentioning

confidence: 99%

Section: Gastrointestinal Tractmentioning

confidence: 99%

Targeting HIV persistence in the tissue

Pieren,

Benítez-Martínez,

Genescà

2024

Current Opinion in HIV and AIDS

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“…Our collaborative studies demonstrated that a treatment (apolipoprotein A-I mimetic synthetic peptides designed to mimic apolipoprotein; and A-1 to remove excess cholesterol) could attenuate macrophage activation, and reduce systemic and gut inflammation in chronically treated HIV in humanized mice [ 234 , 235 ]. With the recent development of the germ-free humanized mice model, additional studies are now seeking to investigate the contribution of resident microbiota to human specific pathogen infection, including HIV [ 242 ]. In summary, humanized mouse models have emerged as a versatile animal model that can be used to support mechanistic and preclinical studies of HIV infection and ART-related metabolic stress and T cell dysfunction, including studies of drug treatment, supplement treatment and genetic manipulation.…”

Section: Current Approaches To Modeling Pathogenesis and Studying The...mentioning

confidence: 99%

Examining Chronic Inflammation, Immune Metabolism, and T Cell Dysfunction in HIV Infection

Mu,

Patankar,

Kitchen

et al. 2024

Viruses

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Chronic Human Immunodeficiency Virus (HIV) infection remains a significant challenge to global public health. Despite advances in antiretroviral therapy (ART), which has transformed HIV infection from a fatal disease into a manageable chronic condition, a definitive cure remains elusive. One of the key features of HIV infection is chronic immune activation and inflammation, which are strongly associated with, and predictive of, HIV disease progression, even in patients successfully treated with suppressive ART. Chronic inflammation is characterized by persistent inflammation, immune cell metabolic dysregulation, and cellular exhaustion and dysfunction. This review aims to summarize current knowledge of the interplay between chronic inflammation, immune metabolism, and T cell dysfunction in HIV infection, and also discusses the use of humanized mice models to study HIV immune pathogenesis and develop novel therapeutic strategies.

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