HIV-1 infection facilitates Alzheimer's disease pathology in humanized APP knock-in immunodeficient mice.

Abstract

Objectives: Amyloid-β (Aβ) plaque deposition in the brain is a principal pathological feature of both Alzheimer's disease (AD) and progressive human immunodeficiency virus type one (HIV-1) infection. Both enable Aβ assembly and Aβ protein aggregation. The potential link between HIV-1 and AD remains uncertain, supporting the need for a reliable animal model. HIV-1 is tropic and pathogenic for humans. It does not replicate in mice. The restricted species tropism has slowed progress in basic research activities. The current study seeks to correct animal model limitations.

Methods: We created an AD mouse to address the need to develop an small animal model that allows studies of viral infection by making a knock-in (KI) with the human amyloid precursor protein (APP)^KM670,671NL Swedish mutation to the mouse genome. The resulting founder mice were crossed with immunodeficient NOG (NOD. Cg-Prkdc ^scid Il2rg ^tm1Sug Tg(CMV-IL-34)1/Jic) to generate NOG/APP^KM670,671NL/IL-34 (NAIL) mice. The mice were reconstituted with human hematopoietic stem cells to generate NAIL mice with functional adaptive and innate human immune systems. Four-month-old, humanized NAIL mice were infected with HIV-1_ADA, a macrophage-tropic viral strain then evaluated for viral infection and AD pathology.

Results: Productive HIV-1 infection was confirmed by plasma HIV-1 RNA levels in infected NAIL mice. The viral load increased by tenfold between day 10 and day 25 post-infection. By day 25, viral DNA confirmed the establishment of HIV-1 reservoirs in CD45+ cells from the immune tissues of infected NAIL mice. Additionally, p24 measurements in lymphoid and brain tissues of NAIL mice validated productive HIV-1 infection. Amyloid burden from infected NAIL mice was increased. Immunofluorescence staining revealed co-localization of Aβ fibrils and HLA-DR⁺ microglia in infected NAIL mice.

Conclusions: These results highlight the AD-HIV model's unique pathobiological and infectious features where the viral and immune responses can now be measured.