Abstract
Humanized mice are emerging as an alternative model system to well-established non-human primate (NHP) models for studying human immunodeficiency virus (HIV)-1 biology and pathogenesis. Although both NHP and humanized mice have their own strengths and could never truly reflect the complex human immune system and biology, there are several advantages of using the humanized mice in terms of using primary HIV-1 for infection instead of simian immunodeficiency virus or chimera simian/HIV. Several different types of humanized mice have been developed with varying levels of reconstitution of human CD45+ cells. In this study, we utilized humanized Rag1KO.IL2RγcKO.NOD mice expressing HLA class II (DR4) molecule (DRAG mice) infused with HLA-matched hematopoietic stem cells from umbilical cord blood to study early events after HIV-1 infection, since the mucosal tissues of these mice are highly enriched for human lymphocytes and express the receptors and coreceptors needed for HIV-1 entry. We examined the various tissues on days 4, 7, 14, and 21 after an intravaginal administration of a single dose of purified primary HIV-1. Plasma HIV-1 RNA was detected as early as day 7, with 100% of the animals becoming plasma RNA positive by day 21 post-infection. Single cells were isolated from lymph nodes, bone marrow, spleen, gut, female reproductive tissue, and brain and analyzed for gag RNA and strong stop DNA by quantitative (RT)-PCR. Our data demonstrated the presence of HIV-1 viral RNA and DNA in all of the tissues examined and that the virus was replication competent and spread rapidly. Bone marrow, gut, and lymph nodes were viral RNA positive by day 4 post-infection, while other tissues and plasma became positive typically between 7 and 14 days post-infection. Interestingly, the brain was the last tissue to become HIV-1 viral RNA and DNA positive by day 21 post-infection. These data support the notion that humanized DRAG mice could serve as an excellent model for studying the trafficking of HIV-1 to the various tissues, identification of cells harboring the virus, and thus could serve as a model system for HIV-1 pathogenesis and reservoir studies.
Highlights
Human immunodeficiency virus-1 (HIV-1), the virus that causes acquired immunodeficiency disease is transmitted mainly through the sexual route [1]
We examined various tissues of the humanized DRAG mouse at different time points post-infection following an intravaginal infection with primary human immunodeficiency virus (HIV)-1
Having established that the virus was present and actively replicating in the blood, spleen, bone marrow, and the brain of humanized DRAG mice within 21 days post-infection, we focused on the female reproductive tract (FRT), gut, and the lymph nodes, which were of great interest since the gut and the FRT are important organs for seeding and spread of HIV-1 [21,22,23,24,25]
Summary
Human immunodeficiency virus-1 (HIV-1), the virus that causes acquired immunodeficiency disease is transmitted mainly through the sexual route [1]. Insights into HIV-1 transmission in humans have been derived from extensive studies conducted in non-human primate (NHP) models with simian immunodeficiency virus (SIV) [2,3,4]. These NHP studies have highlighted the very early establishment of small populations of founder virus in local areas of entry, early onset of CD4 depletion, and pathological processes in the local areas. These events are followed by an early and a late systemic phase of infection that exert their systemic effects slowly over months to years. The early HIV events that occur before the plasma becomes HIV-1 RNA positive remain largely unknown
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