An advanced BLT-humanized mouse model for extended HIV-1 cure studies

Abstract

HIV-1 latency can be maintained in TKO-BLT mice over extended periods on ART and rapid viral rebound occurs following therapy removal. The additional 15-18 weeks of healthy longevity compared with other BLT models provides sufficient time to examine the decay kinetics of the latent reservoir as well as observe delays in recrudescence in HIV-1 cure studies.

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

“…BLT-humanized mice have systemic tissue reconstitution with human immune cells, including in mucosal tissues, which enables mucosal transmission [36][37][38][39][40][41][42][43] and recapitulates the main route of HIV transmission in humans [36][37][38][39][40][41][42][43][44]. Other hallmarks of HIV infection and replication in BLT-humanized mice include robust T cell depletion [36,42], central nervous system infiltration [45,46], immune response [35,[47][48][49][50], and latency [51][52][53]. The BLT-humanized mouse model is a robust platform for evaluating HIV prevention and cure strategies, including antiretroviral therapy, pre-exposure prophylaxis (PrEP), latency reversing agents (LRA), vaccination, proviral excision, and T cell engineering (Table 1).…”

“…Additionally, BLT-humanized mice are prone to GvHD, which limits the experimental window these animals can be utilized to approximately 6 months post-engraftment [54,55]. However, BLT-humanized mice constructed with a C57BL/6 immunodeficient background are resistant to GvHD [35,53]. Another disadvantage involves the use of human fetal tissues in constructing the model; these tissues are not readily available.…”

“…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…”

Humanized Mouse Model of HIV-1 Latency with Enrichment of Latent Virus in PD-1 + and TIGIT + CD4 T Cells

“…Several humanized mouse models have been developed to study HIV-1 replication and latency (30,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Mice containing human CD4 T cells support both R5-and X4-tropic HIV-1 infections (reviewed in reference 45) and respond to treatment with ART, typically administered by intraperitoneal (i.p.)…”

Future Vistas in Alpha Therapy of Infectious Diseases

“…Although RIT can cause both transient and long-term myelodysplasia, neutropenia, and thrombocytopenia in patients with cancer, the overall safety record of RIT is strong [1] and is particularly important in light of the continuing high mortality and low success rates of bone marrow transplants and gene therapy approaches for treating HIV [29]. Currently we are developing novel human antibodies to gp41 with better penetration through the intact BBB that will be subsequently tested first in the state-of-theart humanized HIV mouse model triple-knockout mice engrafted with fetal human bone marrow, liver, thymus (TKO-BLT mice) [30] followed by studies in simian/human immunodeficiency virus-infected nonhuman primates.…”