Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

Veselinović, Milena; Yang, Kuo Hsiung; Sykes, Craig; Remling‐Mulder, Leila; Kashuba, Angela D. M.; Akkina, Ramesh

doi:10.1016/j.virol.2015.12.014

Cited by 8 publications

(5 citation statements)

References 43 publications

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“…Similar trends were seen when studies on mucosal tissue pharmacokinetics of RAL in humanized mice were carried out as in human studies; RAL exhibited higher drug exposure in vaginal and rectal tissues relative to plasma and higher exposure in intestinal mucosa than in plasma [ 51 ].…”

Section: Mouse Studiessupporting

confidence: 52%

Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review

Hassounah

Mésplède

Wainberg

2016

PAI

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Since the discovery of the first inhibitors of HIV replication, drug resistance has been a major problem in HIV therapy, due, in part, to the high mutation rate of HIV. Therefore, the development of a predictive animal model is important to identify impending resistance mutations and to possibly inform treatment decisions. Significant advances have been made possible through use of nonhuman primates infected by SIV, SHIV, and stHIV-1, and use of humanized mouse models of HIV-1 infections. In this review, we describe some of the findings from animal models used for the preclinical testing of integrase strand transfer inhibitors as well as other antiretroviral drugs. These models have led to important findings about the potential role of integrase strand transfer inhibitors in both the prevention and treatment of HIV-1 infection.

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Section: Mouse Studiessupporting

confidence: 52%

Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review

Hassounah

Mésplède

Wainberg

2016

PAI

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“…Other recent humanized mice studies have focused on another class of antiretroviral drug. For example, Veselinovic et al (68) used RAG-hu (BALB/c- Rag1 −/− γ c −/− and BALB/c- Reg2 −/− γ c −/− ) mice to test the pharmacokinetic properties of the HIV integrase strand transfer inhibitor raltegravir; the results indicated that raltegravir concentrations were two logs higher in intestinal mucosa and one log higher in vaginal and rectal tissues than in plasma (similar to the trends observed in human subjects). This finding indicates that humanized mice are suitable for preliminary pharmacokinetic preexposure prophylaxis studies, and that raltegravir appears to be a good candidate for HIV preexposure prophylaxis (68).…”

Section: Recent Hiv Studies In Humanized Micementioning

confidence: 99%

Humanized Mouse Models for Human Immunodeficiency Virus Infection

Marsden

Zack

2017

Annu. Rev. Virol.

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Human immunodeficiency virus (HIV) remains a significant source of morbidity and mortality worldwide. No effective vaccine is available to prevent HIV transmission, and although antiretroviral therapy can prevent disease progression, it does not cure HIV infection. Substantial effort is therefore currently directed toward basic research on HIV pathogenesis and persistence and developing methods to stop the spread of the HIV epidemic and cure those individuals already infected with HIV. Humanized mice are versatile tools for the study of HIV and its interaction with the human immune system. These models generally consist of immunodeficient mice transplanted with human cells or reconstituted with a near-complete human immune system. Here, we describe the major humanized mouse models currently in use, and some recent advances that have been made in HIV research/therapeutics using these models.

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“…These studies have demonstrated effective inhibition of HIV-1 replication, reduction of HIV-1 viral load, and protection from multiple high-dose HIV-1 challenges ( 87 , 88 , 89 , 90 ). Other studies using the NSG-BLT model provided valuable insights into HIV-1 treatment, viral evolution, prevention strategies, dose testing, tissue concentration, and pharmacokinetic data ( 74 , 91 – 95 ). NSG-BLT Hu-mice have also been used to investigate potential treatment methods including anti–human IFN receptor 2 (IFNR2) ( 96 ) and anti-IFN-α/β receptor (IFNAR) antibodies ( 78 ) in conjunction with ARTs to successfully diminish viral reservoir size in lymphoid tissue and delay viral rebound ( 78 , 96 ).…”

Section: Hsc Engraftment Models (Current Generation): Nog Nsg Nrg mentioning

confidence: 99%

“…Different studies reported complete or partial protection against a single dose intrarectal challenge with HIV-1 ( 91 , 94 ). Using the DKO model, tissue distribution of the interventions has also been assessed ( 73 , 74 ). In studies focused on the vaginal route of transmission, many studies examined the efficacy of topical microbicides in DKO and BLT models ( 75 , 92 , 108 – 116 ).…”

Section: Understanding Mucosal Transmission Of Hiv-1 and The Effect Omentioning

confidence: 99%

Advances in Humanized Mouse Models to Improve Understanding of HIV-1 Pathogenesis and Immune Responses

et al. 2021

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Although antiretroviral therapy has transformed human immunodeficiency virus-type 1 (HIV-1) from a deadly infection into a chronic disease, it does not clear the viral reservoir, leaving HIV-1 as an uncurable infection. Currently, 1.2 million new HIV-1 infections occur globally each year, with little decrease over many years. Therefore, additional research is required to advance the current state of HIV management, find potential therapeutic strategies, and further understand the mechanisms of HIV pathogenesis and prevention strategies. Non-human primates (NHP) have been used extensively in HIV research and have provided critical advances within the field, but there are several issues that limit their use. Humanized mouse (Hu-mouse) models, or immunodeficient mice engrafted with human immune cells and/or tissues, provide a cost-effective and practical approach to create models for HIV research. Hu-mice closely parallel multiple aspects of human HIV infection and disease progression. Here, we highlight how innovations in Hu-mouse models have advanced HIV-1 research in the past decade. We discuss the effect of different background strains of mice, of modifications on the reconstitution of the immune cells, and the pros and cons of different human cells and/or tissue engraftment methods, on the ability to examine HIV-1 infection and immune response. Finally, we consider the newest advances in the Hu-mouse models and their potential to advance research in emerging areas of mucosal infections, understand the role of microbiota and the complex issues in HIV-TB co-infection. These innovations in Hu-mouse models hold the potential to significantly enhance mechanistic research to develop novel strategies for HIV prevention and therapeutics.

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Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

Cited by 8 publications

References 43 publications

Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review

Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review

Humanized Mouse Models for Human Immunodeficiency Virus Infection

Advances in Humanized Mouse Models to Improve Understanding of HIV-1 Pathogenesis and Immune Responses

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