Efficient Inhibition of HIV Replication in the Gastrointestinal and Female Reproductive Tracts of Humanized BLT Mice by EFdA

Shanmugasundaram, Uma; Kovářová, Martina; Ho, Phong T.; Schramm, Nathaniel J.; Wahl, Angela; Parniak, Michael A.; García, J. Víctor

doi:10.1371/journal.pone.0159517

Cited by 18 publications

(18 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several recent studies demonstrated that oral administration of antiretroviral drugs could potently reduce HIV-1 plasma viral loads and provide preexposure prophylaxis for the transmission of HIV-1. For example, 4=-ethynyl-2-fluoro-2=-deoxyadenosine (EFdA), a nucleoside analog reverse transcriptase inhibitor that was reconstituted in phosphate-buffered saline (PBS) and administered orally to BLT mice by oral gavage, efficiently inhibited HIV-1 replication in gastrointestinal and female reproductive tracts of humanized BLT mice (55). Similarly, a single-drug or a two-drug regimen (RAL, EFdA, or TDF plus FTC) were freshly dissolved in various buffers and then administered by oral gavage to a BALB/c-Rag2 Ϫ/Ϫ ␥c Ϫ/Ϫ (RAG-hu) mouse model (56), a SCID-hu Thy/Liv and BLT mouse model, and a rhesus macaque model (57), consequently providing a rapid suppression of HIV-1 viremia.…”

Section: Discussionmentioning

confidence: 99%

HIV Replication and Latency in a Humanized NSG Mouse Model during Suppressive Oral Combinational Antiretroviral Therapy

Satheesan

Burnett

et al. 2018

J Virol

View full text Add to dashboard Cite

Although current combinatorial antiretroviral therapy (cART) is therapeutically effective in the majority of HIV patients, interruption of therapy can cause a rapid rebound in viremia, demonstrating the existence of a stable reservoir of latently infected cells. HIV latency is therefore considered a primary barrier to HIV eradication. Identifying, quantifying, and purging the HIV reservoir is crucial to effectively curing patients and relieving them from the lifelong requirement for therapy. Latently infected transformed cell models have been used to investigate HIV latency; however, these models cannot accurately represent the quiescent cellular environment of primary latently infected cells For this reason, humanized murine models have been developed for screening antiviral agents, identifying latently infected T cells, and establishing treatment approaches for HIV research. Such models include humanized bone marrow/liver/thymus mice and SCID-hu-thy/liv mice, which are repopulated with human immune cells and implanted human tissues through laborious surgical manipulation. However, no one has utilized the human hematopoietic stem cell-engrafted NOD/SCID/IL2rγ (NSG) model (hu-NSG) for this purpose. Therefore, in the present study, we used the HIV-infected hu-NSG mouse to recapitulate the key aspects of HIV infection and pathogenesis Moreover, we evaluated the ability of HIV-infected human cells isolated from HIV-infected hu-NSG mice on suppressive cART to act as a latent HIV reservoir. Our results demonstrate that the hu-NSG model is an effective surgery-free system in which to efficiently evaluate HIV replication, antiretroviral therapy, latency and persistence, and eradication interventions. HIV can establish a stably integrated, nonproductive state of infection at the level of individual cells, known as HIV latency, which is considered a primary barrier to curing HIV. A complete understanding of the establishment and role of HIV latency would greatly enhance attempts to develop novel HIV purging strategies. An ideal animal model for this purpose should be easy to work with, should have a shortened disease course so that efficacy testing can be completed in a reasonable time, and should have immune correlates that are easily translatable to humans. We therefore describe a novel application of the hematopoietic stem cell-transplanted humanized NSG model for dynamically testing antiretroviral treatment, supporting HIV infection, establishing HIV latency The hu-NSG model could be a facile alternative to humanized bone marrow/liver/thymus or SCID-hu-thy/liv mice in which laborious surgical manipulation and time-consuming human cell reconstitution is required.

show abstract

Section: Discussionmentioning

confidence: 99%

HIV Replication and Latency in a Humanized NSG Mouse Model during Suppressive Oral Combinational Antiretroviral Therapy

Satheesan

Burnett

et al. 2018

J Virol

View full text Add to dashboard Cite

show abstract

“…Antiviral therapy dCA [45,56] EFdA [57] RAL [45] PD-1 mAb [58] PG16 bNAb [59] PGT121 bNAb [60] 3TC, TDF [61] AZT, ddI, IDV [52] FTC, RPV, DTG [46,57] FTC, TAF, EVG [62] FTC, TDF, DTG [37,46,51,53,63] FTC, TDF, RAL [37,46,51,63] FTC, TDF, RAL, 3B3(Fv)-PE38 immunotoxin [64] FTC, TDF, RAL, IFNα14 [61,65] Pre-exposure prophylaxis (PrEP) C5A peptide [66] Cc-griffithsin [67] CD4 AsiCs [68] CD4-expressing Lactobacillus acidophilus [69] CD4mc P-III-48 [70] DTG-ultra LA [71] EFdA [72] G2-S16 PCD [73] IgA [74] MVC [75] RAL-LA [76] RPV-LA [39,77] siCCR5 LFA-1 I-tsNP [78] TNV gel [79][80][81] VRC01 bNAb [82] FTC, TAF [83] FTC, TDF [36,43,84,85] TAF, EVG…”

Section: Strategy Therapeutic Agent(s) Reference(s)mentioning

confidence: 99%

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

et al. 2020

View full text Add to dashboard Cite

The development of safe and effective combination antiretroviral therapies for human immunodeficiency virus (HIV) infection over the past several decades has significantly reduced HIV-associated morbidity and mortality. Additionally, antiretroviral drugs have provided an effective means of protection against HIV transmission. Despite these advances, significant limitations exist; namely, the inability to eliminate HIV reservoirs, the inability to reverse lymphoid tissues damage, and the lack of an effective vaccine for preventing HIV transmission. Evaluation of the safety and efficacy of therapeutics and vaccines for eliminating HIV reservoirs and preventing HIV transmission requires robust in vivo models. Since HIV is a human-specific pathogen, that targets hematopoietic lineage cells and lymphoid tissues, in vivo animal models for HIV-host interactions require incorporation of human hematopoietic lineage cells and lymphoid tissues. In this review, we will discuss the construction of mouse models with human lymphoid tissues and/or hematopoietic lineage cells, termed, human immune system (HIS)-humanized mice. These HIS-humanized mouse models can support the development of functional human innate and adaptive immune cells, along with primary (thymus) and secondary (spleen) lymphoid tissues. We will discuss applications of HIS-humanized mouse models in evaluating the safety and efficacy of therapeutics against HIV reservoirs and associated immunopathology, and delineate the human immune response elicited by candidate HIV vaccines. In addition to focusing on how these HIS-humanized mouse models have already furthered our understanding of HIV and contributed to HIV therapeutics development, we discuss how emerging HIS-humanized rat models could address the limitations of HIS-mouse models.

show abstract

“…This property is attributable to the fluorine at the 2 position of the adenine base, which renders the compound resistant to degradation by adenosine deaminase (13,14). MK-8591 suppresses HIV-1 and simian immunodeficiency virus (SIV) replication at clinically achievable concentrations in humanized mice and rhesus macaques, respectively (16,(19)(20)(21). In a phase 1b proofof-concept clinical trial, a single 10-mg dose of MK-8591 demonstrated antiviral activity for 10 days in ART-naive, HIV-1-infected participants (22).…”

mentioning

confidence: 99%

“…Although MK-8591 has been shown to potently inhibit HIV-1 and SIV in culture (12)(13)(14)(15)(16)19) and in experimentally infected nonhuman primates and humanized mouse models (16,(19)(20)(21), efforts to evaluate the activity of the drug against HIV-2 are limited; a single report showed that a group B strain (HIV-2 EHO ) is sensitive to the drug in spreading infections of MT-4 cells (14). In addition, the ability of MK-8591 to inhibit HIV-2 mutants that are resistant to other NRTIs is unknown.…”

mentioning

confidence: 99%

MK-8591 (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture

Smith

Masoum

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

There is a pressing need to identify more effective antiretroviral drugs for HIV-2 treatment. Here, we show that the investigational compound MK-8591 (4=-ethynyl-2-fluoro-2=-deoxyadenosine [EFdA]) is highly active against group A and B isolates of HIV-2; 50% effective concentrations [EC 50 ] for HIV-2 were, on average, 4.8-fold lower than those observed for HIV-1. MK-8591 also retains potent activity against multinucleoside-resistant HIV-2 mutants (EC 50 Յ 11 nM). These data suggest that MK-8591 may have antiviral activity in HIV-2-infected individuals.

show abstract

Efficient Inhibition of HIV Replication in the Gastrointestinal and Female Reproductive Tracts of Humanized BLT Mice by EFdA

Cited by 18 publications

References 40 publications

HIV Replication and Latency in a Humanized NSG Mouse Model during Suppressive Oral Combinational Antiretroviral Therapy

HIV Replication and Latency in a Humanized NSG Mouse Model during Suppressive Oral Combinational Antiretroviral Therapy

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

MK-8591 (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture

Contact Info

Product

Resources

About