Mucosal surfaces play multiple roles in the transmission and pathogenesis of HIV-1. Transmission of HIV-1 occurs primarily across rectal and reproductive tract mucosal surfaces and the local microenvironment is known to affect the success of transmission. In addition, intestinal tissues are key compartments in which there is early and sustained loss of CD4+ T helper cells. As with all lymphoid tissues, the gastrointestinal (GI) tract is highly dynamic with immune cells trafficking in and out of the tissue parenchyma. This movement of cells is driven in large part by chemokines. As critical components of the mucosal immune system, chemokines play multiple direct and indirect roles in the transmission of HIV-1 and the related simian virus, SIV, as well as subsequent pathogenesis. We will address the roles of chemokines and inflammation in SIV transmission and control of viral replication in the studies proposed here and are uniquely poised to intervene to augment or neutralize mucosal chemokines in vivo. With regard to the transmission of SIV, CCL20 has been linked to inflammatory milieus that facilitate SIV mucosal transmission, consistent with its proinflammatory properties. CCL20 also has direct anti-HIV properties and stimulates the viral restriction factor APOBEC3G. Further it is a critical homing signal for mucosal Th17 cells, which are lost during SIV infection. In these studies we will explore the mucosally-expressed subset of chemokines in the transmission and pathogenesis of SIV, focusing on CCL20. We are uniquely poised with simianized mAb that neutralizes CCL20, and a depth of understanding of chemokine expression and function, to determine the role that CCL20 and other chemokines play in SIV transmission and pathogenesis. Our overall hypothesis is that inhibition of chemokine-driven inflammation will reduce SIV transmission and pathogenesis. To address this hypothesis, our Specific Aims are to: (1) Determine the role of CCL20 in SIV mucosal transmission and viral control;(2) Define the mechanisms of action of anti-chemokine therapy via identification of its effects on macaque tissues;and (3) Identify new functional and expression control aspects of CCL20 biology.
Chemokines are immunomodulatory proteins secreted to recruit immune cells to tissue microenvironments during normal and pathologic immune processes. The expression of chemokines that cause inflammation is thought to contribute to the transmission of HIV-1. Anti-chemokine therapies that combat this inflammation could reduce the likelihood of HIV-1 transmission. Findings from these studies will improve our understanding of mucosal inflammation, anti-inflammatory therapies, and HIV-1 transmission, and could impact approaches to combating HIV-1 transmission.
