Comparing Current and Next-Generation Humanized Mouse Models for Advancing HIV and HIV/Mtb Co-Infection Studies

Abstract

In people living with HIV, Mycobacterium tuberculosis (Mtb) is the major cause of death. Due to the increased morbidity/mortality in co-infection, further research is urgently required. A limiting factor to research in HIV and HIV/Mtb co-infection is the lack of accessible in vivo models. Next-generation humanized mice expressing HLA transgenes report improved human immune reconstitution and functionality, which may better recapitulate human disease. This study compares well-established huNRG mice and next-generation HLA I/II-transgenic (huDRAG-A2) mice for immune reconstitution, disease course, and pathology in HIV and TB. HuDRAG-A2 mice have improved engraftment of key immune cell types involved in HIV and TB disease. Upon intravaginal HIV-1 infection, both models developed significant HIV target cell depletion in the blood and tissues. Upon intranasal Mtb infection, both models sustained high bacterial load within the lungs and tissue dissemination. Some huDRAG-A2 granulomas appeared more classically organized, characterized by focal central necrosis, multinucleated giant cells, and foamy macrophages surrounded by a halo of CD4+ T cells. HIV/Mtb co-infection in huNRG mice trended towards worsened TB pathology and showed potential for modeling co-infection. Both huNRG and huDRAG-A2 mice are viable options for investigating HIV and TB, but the huDRAG-A2 model may offer advantages.

A Novel Humanized Mouse Model for HIV and Tuberculosis Co-infection Studies

“…This poses restrictions on experimentation using NHPs, which require specialized infrastructure and personal training that is not widely available 8 . However, this limitation has been circumvented to some extent by the use of immunocompromised mice strains that can engraft human stem cells and differentiate them into a variety of human immune cells, allowing for both HIV and Mtb infection and viral replication 14, 15, 18, 19, 47 . We show that the NSG-SGM3 mice allow stem cells to differentiate into a range of immune cells becoming susceptible to HIV infection and viral replication.…”

“…Importantly, Mtb latently infected macaques coinfected with SIV results in reproducible LTBI reactivation 13 , providing a reliable model for HIV/Mtb research. However, NHPs require specialized infrastructure for experimentation and are cost-restrictive, and are not readily available in the majority of animal facilities 14,15 , The use of other small animal models, such as rodents poses different challenges. Although inbred and genetic knockout mice are easily available, and readily infective using Mtb, most strains of mice are not a natural host for HIV, which require human CD4 + T cells to establish infection.…”

“…17 . Fortunately, humanized mouse models, the immunodeficient mice that have been reconstituted with a human immune system, appears to be a promising small animal model for HIV and Mtb reseach 14, 15, 18, 19 . They have been extensively used for evaluating HIV gene therapy and therapeutics 20, 21 , and recently, the NSG (NOD scid gamma)-based humanized BLT mice were developed for analyzing Mtb and HIV/ Mtb co-infections 15, 18, 22 .…”

“…Importantly, Mtb latently infected macaques co-infected with SIV results in reproducible LTBI reactivation 13 , providing a reliable model for HIV/ Mtb research. However, NHPs require specialized infrastructure for experimentation and are cost-restrictive, and are not readily available in the majority of animal facilities 14, 15 ,…”

Recent Developments in NSG and NRG Humanized Mouse Models for Their Use in Viral and Immune Research

“…The use of humanized mouse models has made HIV-1 research more cost-effective and more accessible to scientists around the world. Currently, NRG mice and other humanized mouse models have become a useful preclinical tool to examine the direct interaction between HIV-1 and the human immune system, and have allowed investigations on more complex clinical problems such as the HIV/cART-associated hepatitis, the persistence of HIV infections, and the immune response to co-infections with other microorganisms such as Mycobacterium tuberculosis [ 99 ].…”