Advancing our understanding of HIV co-infections and neurological disease using the humanized mouse

Abstract

Humanized mice have become an important workhorse model for HIV research. Advances that enabled development of a human immune system in immune deficient mouse strains have aided new basic research in HIV pathogenesis and immune dysfunction. The small animal features facilitate development of clinical interventions that are difficult to study in clinical cohorts, and avoid the high cost and regulatory burdens of using non-human primates. The model also overcomes the host restriction of HIV for human immune cells which limits discovery and translational research related to important co-infections of people living with HIV. In this review we emphasize recent advances in modeling bacterial and viral co-infections in the setting of HIV in humanized mice, especially neurological disease, and Mycobacterium tuberculosis and HIV co-infections. Applications of current and future co-infection models to address important clinical and research questions are further discussed.

Keywords: Co-infections; Hepatitis B virus; Hepatitis C virus; Human immunodeficiency virus; Humanized mouse; Mycobacterium tuberculosis; Neisseria gonorrhoeae; Small animal model.

Fig. 1

HIV Infection of Multiple Tissue Compartments Supports Potential for Co-infection Investigations in HIS Mice, including in CNS. Results shown in A–D are from mice that were infected with 2500 TCID₅₀ of HIV JR-CSF using an i.v. route and tissue collected after 3 weeks of infection. Autopsy specimens of human brain displaying HIV encephalitis are shown in E and F Formalin-fixed and paraffin embedded tissue sections were cut, dewaxed, and viral RNA (A–E) or DNA (F) detected by using in situ hybridization with probes specific to the HIV-1 gag gene using RNA Scope® or DNA Scope® (ACD Bio) (A–F). Staining was visualized with bright field microscopy. Representative images of results from mice used in various studies is shown. Results displayed in G–I are from HIS BLT mice infected i.n. with 10² CFU of Mtb H37Rv for 4 weeks. Shown is development of TB encephalitis as visualized with H&E (G) and pockets of AFB (H) in the inflammatory lesion. Brains of Mtb-infected mice lacking significant neuropathology (I) also occasionally presented with a rare AFB (I). These results are illustrative of observations from several different studies performed with humanized NSG-BLT mice with mono-infections of HIV or Mtb

Fig. 2

Humanized Mouse Model for Testing Drug Efficacy in Setting of Co-infection. A Experimental design for study to test potential for Mtb infection to alter ART efficacy in HIS mice with HIV infection. Humanized mice (n = 10) were infected i.v. with 2500 TCID₅₀ HIV-1 JR-CSF. At 5 weeks following HIV infection, plasma samples were analyzed for presence of HIVp24 capsid protein. Subsequently, mice were infected with PBS (mock, n = 5) or 10² CFU of Mtb H37Rv (n = 5) for another 5 wk. ART was begun in both groups 1 wk post-infection with Mtb. B Shown is production of HIV p24 capsid protein as detected in serum with a diagnostic ELISA at 5 wk p.i. with HIV, and following 3 and 5 wk of ART treatment. ART was delivered by daily i.p. injection of Emtricitabine (140-200 mg/kg body weight), Raltegravir (56-80 mg/kg body weight), and Tenofovir (146-208 mg/kg body weight). The HIV p24 capsid protein was detected using a commercially available ELISA (Zeptometrix) and results are shown as pg/ml of plasma. Significant differences between post-infection and post-ART treatment are indicated with *p < 0.05, **p < 0.01, and ***p < 0.001, and ****p < 0.0001