Abstract

HIV/AIDS is raging and causing millions of deaths around the world. The major challenge in treating HIV/AIDS is the establishment of HIV reservoirs where the viruse escapes both drug and immune system attempts at eradication. Throughout the course of HIV/AIDS, productive HIV infection occurs primarily in the lymphoid follicles or germinal centers (GC) surrounding follicular dendritic cells (FDC). In the GCs, FDCs trap and maintain infectious HIV for years and provide these infectious viruses to the host cells. FDCs also attract B and T cells into the GCs and increase the ability of CD4+ T cells to be infected. Additionally, FDCs also mediate the increase of HIV replication in HIV-infected CD4+ T cells. Recently, several clinical cases and in vitro studies suggest that alpha-1-antitrypsin (AAT) might inhibit HIV infection and replication. Therefore, I hypothesized that AAT inhibited both the infection and replication of HIV in primary CD4+ T cells. I also postulated that AAT inhibited the FDC-mediated contributions that potentiate HIV infection and replication. To test whether AAT inhibited HIV infection in lymphocytes, CD4+ T cells were pretreated with AAT and then incubated with HIV to detect HIV infection. To exam whether AAT inhibited HIV replication, infected CD4+ T cells were cultured with AAT to detect the replication of HIV. To determine whether AAT blocked the FDC-mediated contributions to HIV pathogenesis, activated or resting FDCs were treated with AAT to detect the trapping and maintenance of HIV. The results suggested that AAT inhibited HIV entry into CD4+ T cells by directly interacting with gp41 and thereby inhibiting the interaction between HIV and CD4+ T cells. AAT also inhibited HIV replication in infected CD4+ T cells. Further study revealed that AAT interacted with low-density lipoprotein-receptor related protein to mediate the internalization of AAT through a clathrin-dependent endocytic process in CD4+ T cells. Subsequently, internalized AAT was transported from the endosome to the lysosome and then released into the cytosol. In the cytosol, AAT directly interacted with IκBα to block its polyubiquitinylation at lysine residue 48, which resulted in the accumulation of phosphorylated/ubiqutinylated IκBα in the cytosol. In turn, the dissociation of IκBα from NF-κB was blocked, which thereby inhibited the nuclear translocation and activation of NF-κB. Additionally, AAT also down-regulated FDC-CD32 and FDC-CD21 expression, which are regulated by NF-kB, thereby inhibiting the trapping and maintenance of HIV on FDCs. Hence, AAT not only suppresses HIV replication, but also blocks HIV replication in CD4+ T cells. Moreover, AAT also inhibits the activation of FDCs thereby affecting the trapping and maintenance of HIV.

Degree

PhD

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Rights

http://lib.byu.edu/about/copyright/

Date Submitted

2012-03-08

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd5045

Keywords

HIV replication, HIV infection, HIV reservoir, Tummor necrosis factor α, Iκ, Bα, Type II Fc gamma receptor, Type II complement receptor

Share

COinS