The overall goal of this proposal is to elucidate the role of HIV-specific CD8 T-cells in the gastrointestinal mucosa in controlling viral replication an dissemination. The gastrointestinal (GI) mucosa is a major site of HIV transmission, a critical early site of viral replication and CD4 depletion, as well as the largest lymphoid organ in the body. Accordingly, host defenses in this tissue may be critical in determining clinical outcome. The GI tract is also a unique mucosal tissue with innate and adaptive defenses that are carefully regulated to maintain a delicate balance between immune tolerance to commensal bacteria and food antigens versus the ability to mount rapid immune responses to pathogens. During acute HIV/SIV infection, as lamina propria CD4 T-cells are depleted, there is an expansion and/or influx of CD8 T-cells;however, these cells fail to clear infection or prevent widespread virus dissemination. This rapid depletion of gut CD4 T-cells, and their slow reconstitution in patients on HAART, suggests that mucosal CD8 T-cell responses are inadequate or dysfunctional in most individuals.
In Specific Aim 1, we will test the hypothesis that tissue- specific mechanisms, including transcriptional and/or epigenetic regulation, limit perforin-mediated CD8 T-cell effector functions in the gastrointestinal mucosa.
In Specific Aim 2, we will focus on mucosal T-cell responses in individuals diagnosed with acute/early HIV infection, generally less than 30 days post-seroconversion. We will test the hypotheses that (a) robust mucosal CD8 T-cell responses during early infection are predictive of low viral load set-point;and (b) HAART initiation during early infection will lead to blunted mucosal CD8 T-cell responses, but may preserve mucosal integrity.
In Specific Aim 3, we will study mucosal T-cell responses in patients with chronic HIV infection at opposite ends of the clinical spectrum: HIV controllers, with VL <2,000 copies/mL in the absence of HAART, and non-controllers, with VL >10,000 copies/mL in the absence of HAART. We will test the prediction that mucosal CD8 T-cells in HIV Controllers strongly express perforin and other cytotoxic granule constituents, while mucosal CD8 T-cells in HIV non-controllers display an 'exhausted'phenotype that may be partially reversed by HAART. These studies address important unanswered questions regarding the regulation of mucosal immune responses, which are of particular significance for the design of vaccine approaches aimed at induction of mucosal CD8 T-cell responses.
The gastrointestinal tract is an early target of HIV infection, and also houses most of the body's white blood cells, which are capable of fighting infection. The goal of this project is to better understand how immune responses in the gastrointestinal (GI) tract are regulated, and how this regulation affects the body's ability to respond to viral pathogens such as HIV. We will study how killer T-cells in the GI tract responds to stimulation in three groups of patients: healthy individuals, patients with very early HIV infection, and patients with chronic HIV infection. We hope that these studies will provide new information about immune regulation, which will ultimately be useful for the design of vaccines to prevent HIV infection as well as therapies to treat persons with HIV/AIDS.
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|Hatano, Hiroyu; Yukl, Steven A; Ferre, April L et al. (2013) Prospective antiretroviral treatment of asymptomatic, HIV-1 infected controllers. PLoS Pathog 9:e1003691|
|Hayes, Timothy L; Asmuth, David M; Critchfield, J William et al. (2013) Impact of highly active antiretroviral therapy initiation on CD4(+) T-cell repopulation in duodenal and rectal mucosa. AIDS 27:867-77|
|Sandberg, Johan K; Dias, Joana; Shacklett, Barbara L et al. (2013) Will loss of your MAITs weaken your HAART [corrected]? AIDS 27:2501-4|
|Shaw, Julia M; Hunt, Peter W; Critchfield, J William et al. (2013) Short communication: HIV+ viremic slow progressors maintain low regulatory T cell numbers in rectal mucosa but exhibit high T cell activation. AIDS Res Hum Retroviruses 29:172-7|
|Presicce, Pietro; Shaw, Julia M; Miller, Christopher J et al. (2012) Myeloid dendritic cells isolated from tissues of SIV-infected Rhesus macaques promote the induction of regulatory T cells. AIDS 26:263-73|
|Shaw, Julia M; Hunt, Peter W; Critchfield, J William et al. (2011) Increased frequency of regulatory T cells accompanies increased immune activation in rectal mucosae of HIV-positive noncontrollers. J Virol 85:11422-34|
|Shacklett, Barbara L; Ferre, April L (2011) Mucosal immunity in HIV controllers: the right place at the right time. Curr Opin HIV AIDS 6:202-7|
|Shacklett, Barbara L; Greenblatt, Ruth M (2011) Immune responses to HIV in the female reproductive tract, immunologic parallels with the gastrointestinal tract, and research implications. Am J Reprod Immunol 65:230-41|
|Hatano, Hiroyu; Hayes, Timothy L; Dahl, Viktor et al. (2011) A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis 203:960-8|
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