Investigation of HIV-1 pathogenesis using humanized mouse model.

Abstract

Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, is a human-speci virus. Because HIV-1 cannot infect and cause disorders in other animals, it has been an arduous struggle to investigate the dynamics of HIV-1 infection in vivo. In order to understand and elucidate HIV-1 pathogenesis in vivo, we have established a human hematopoietic stem cell-transplanted "humanized" mouse model, which has the potential to maintain human hematopoiesis including human CD4-positive leukocytes under a physiological condition. In HIV-1-infected humanized mice, we reproduced HIV-1 pathogenesis including the gradual decline of peripheral CD4-positive T cells and immune activation.HIV-1 encodes four "accessory" genes, Vif, Vpu, Vpr, and Nef. It is known that these accessory genes are occasionally crucial for viral replication in in vitro cell culture system. However, since there were no adequate animal models for HIV-1 infection, the roles of these HIV-1 accessory genes in viral infection, replication, and pathogenesis in vivo remain unclear. By utilizing humanized mouse model and a series of mutated HIV-1, we have revealed that these viral accessory proteins potently promote viral replication by antagonizing/degrading anti-viral cellular proteins or exploiting a unique subset of human CD4-positive T cells.In this paper, I introduce the findings in HIV-1-infected humanized mouse model particularly focusing on the roles of HIV-1 accessory proteins in viral replication in vivo.