forARRA years 1-2funding The goals of this project are to define how HIV-1 interacts with pDC and to elucidate the role of pDC cells in HIV-1 replication and pathogenesis. As the major sensor of viral infections, altered pDC level/activity may playa critical role during HIV-1 disease progression. However, the role of pDC cells in F-IIV infection and pathogenesis is poorly understood, mainly due to the lack of robust in vivo models. The DKO-hu I-4SC model is ideal for this purpose. With a stable functional human immune system, functional pDC cells are developed in normal proportion in all lymphoid organs in DKO-hu mice. HIV-1 establishes persistent infection, with immune hyperactivation and depletion of human CD4 T cells. We have also shown that, during HIV-1 infection, PDC cells are productively infected, activated, depleted and functionally impaired in DKO-hu HSC mice. HIV-1 with the pathogenic R3A Env also efficiently activates PDC in vitro, correlated with its high binding affinity to CD4 receptor and coreceptors. Based on our preliminary findings and reports from Sly-infected monkeys or HIV- infected patients, postulate that HIV-1 intimately interacts with PDC cells, and chronic engaging of PDC during persistent HIV infection wifl deplete or impair PDC activity. The reduced or altered PDC activity contributes to chronic HIV infection, hyperimmune activation and AIDS progression. :off Cap inM f/1 E-C Q?__. =""""""""O 020 -_a '_n We will treat DKO-hu mice with the pDC-specific mAb conjugated with the Saporin toxin, which specifically depletes pDOC,to test the role ofpDOC during iinfectiion. will t...reat DKO-hu mice with the pOC-specific mAb conjugated with the Saporin toxin, which specifically E.., 5q. 8B2. Modified Specific Aim Section for years 3 and 4 NIAlIODfunding (1) Tostudy how HIV-1iinfectionallters homeostasis and function ofhuman pOoeC cells in vivo: b. Does HIV-1 infection affect pDoCe migration and survivatl in lymphoid organsinin viivo? We will iinvestigate the miigration and surviva'l of pDoCecelllsdudruirninggeaeralyrlaynadnldatel-acther-ocnhirconHicIVH-1IVi-n1feicntfieocntionn in DKO-hu mice. CFO CI=L o.3 (2)Toiinvestigate how HIV-1iintteracttswith pODCand impairs pOCactivity: b.. What genes and signaling pathways are atltered in pIoJeC cells """"""""Wanergized~"""""""" by HIV infection in vivo? We wil purify pDoCe cells from mock- or HIV-infected DOKO-hu mice to identify genes that are deregulated by HIV infection. We wil define the signaling defects in pDCe cels inducedby HIV infection. ^-o p-- N.' (3)Todefine role of pOCcelllsin HIV--1iinfection and pathogenesis in vivo: a. Does elevated pDoCe activation affect HIV-1 infection and immuno-pathogenesis? b. Does decreased pDoCe activity viia TLR7f/9 antagonists afect HIV-1 infection and pathogenesiis in vivo? We will study iiffsstitmimulation or ininhibition of pDoCe acttiivation with the agonistic or antatagonistic ligands of TLR7fTLR9 before or during HIV infection will affect HIV replication and immuno-pathogenesis. ' This project wil investigate the modulatiion and rolle of pPoDeC cells in HF-IVfly-1-i infection and pathogenesis in vivo.. Elucidatiion of the mechaniism by which HIV-1 interacts with poDeC cels and their role inri HIV-1 infection and AIDS pathogenesisiswilill faciilliittatete nott only our understandiing of pDoCe biology in HIV patthogenesis, but allso development of novel therapeutic strategies. a-? 010 mawPublic Health Relevance
Showing the most recent 10 out of 23 publications
