HIV-1 Disturbs Treg in the Thymus
Christel Uittenbogaart, University of California Los Angeles
Basic Biomedical Sciences
Innovative, Developmental, Exploratory Award (IDEA)
Natural regulatory T cells (Treg) develop in the thymus and are critical for the proper control of immune responses. Still their role in HIV-1 infection remains unclear and may depend on the disease stage. Treg may be beneficial by limiting general non-specific immune activation that is a hallmark of the chronic phase of HIV-1 infection, but may also be detrimental by suppressing HIV-specific immune responses in the acute phase of infection. We have shown using the conventional SCID hu thy/liv mouse model that acute HIV-1 infection induces an accumulation of Treg in the human thymus and that thymic Treg are more productively infected by a R5-HIV-1 than by an X4-HIV-1. We hypothesize that HIV-1 infection in the thymus alters the thymic output of Treg to peripheral lymphoid tissues leading to an imbalance between Treg and effector T cells, hence to an improper control of immune responses (including autoimmunity) and thereby to chronic HIV-1 infection.
We propose to use our established methods as well as novel approaches and unique reagents to investigate the mechanisms underlying the differential susceptibility of thymic Treg to R5 and X4-HIV-1 infection in vitro and in vivo.
- In vitro: To determine the differential permissiveness of CD4+CD25+CD127- thymocytes to R5- and X4-HIV 1 as well their susceptibility to HIV 1 induced apoptosis. The question of a potential induction of FoxP3 expression in the thymus by HIV 1 will have to be addressed. The suppressive ability of Treg from infected thymus will also be measured.
- In vivo: To investigate whether the accumulation of FoxP3+ cells in the thymic has an impact in the periphery, we propose to use our novel humanized mouse model. “Humanized” mice will be infected with R5- or X4-HIV 1. Then recent thymic emigrants (RTE) will be measured among Treg and conventional T cells. In addition, variation of FoxP3 expressing T cells (Treg) will be measured in peripheral blood, spleen and lymph nodes of the infected mice.
Information gained from the proposed experiments will improve our understanding of the role of regulatory T cells in HIV 1 pathogenesis and has potential implications for novel treatments of HIV 1 infected individuals.