HIV-1 Nef severely impairs thymocyte development and peripheral T-cell function by a CD4-independent mechanism
✍ Scribed by Daniel Pennington; Sharon Jenkins; Hugh Brady; Colin Miles; Elaine Dzierzak; David Abraham
- Publisher
- Blackwell Publishing
- Year
- 1997
- Tongue
- English
- Weight
- 522 KB
- Volume
- 1
- Category
- Article
- ISSN
- 1360-7413
No coin nor oath required. For personal study only.
✦ Synopsis
Nef is a regulatory protein of the human and simian immunodeficiency viruses (HIV and SIV) whose role in infection and the viral life cycle are not fully understood. In T‐lymphocytes Nef down‐regulates cell‐surface CD4, and has been implicated in an increase in infectivity at low primary viral isolate titres. Additionally, the SIV nef gene is necessary for viraemia and AIDS‐like pathogenesis in rhesus macaques. We report here in an in vivo murine transgenic model that thymocyte and T‐cell‐specific nef gene expression results in a marked decrease in thymic cellularity from 16 days post coitus. This reduction in thymocyte cell number is independent of CD4 expression and Nef‐induced CD4 down‐regulation, but can be restored by expressing a constitutively active p56__^lck^__^F505^ gene. Functional analyses have revealed a severe decrease in thymocyte and T‐cell proliferation in response to both T‐cell‐receptor‐ and mitogen‐mediated stimuli. In addition, a significant proportion of Nef‐expressing peripheral T‐cells display cell‐surface characteristics associated with cellular activation. These results suggest that Nef expression in developing thymocytes can severely reduce the regeneration capacity of the immune system, whereas expression in mature T‐cells dramatically decreases their potential to respond to antigen. With the recent recognition of a persistently high viral load in HIV‐infected individuals, these findings have important implications for the mechanism of the progressive deterioration of the immune system that leads to AIDS.