Toxoplasma gondii is a common opportunistic pathogen in HIV+ individuals. Although the immunocompromised state induced by HIV infection clearly promotes T. gondii expansion, it is unclear whether T.gondii itself might influence HIV growth either positively or negatively. Previous studies in our lab have provided evidence for both effects with T.gondii stimulating HIV LTR activity in transgenic mice and on the other hand the parasite inhibiting R5 HIV infection of human T cells through its production of a chemokine mimic, cyclophilin, that binds to the viral co-receptor CCR5. In collaborative work with Leonid Margolis (NICHD) recently accepted for publication, we extended this analysis of HIV-T.gondii interactions to a more physiologic model which employs infection of explanted human lymphoid tissue. We demonstrated that both pathogens readily replicate in ex vivo infected blocks of human tonsillar tissue. Importantly, we found that live T. gondii preferentially inhibits replication of R5 versus X4 HIV-1 isolates in the coinfected tissue blocks, an outcome that was not attributable to parasite induced depletion of the target CD4+ T lymphocytes. This inhibition of R5 viral replication could be reproduced by treatment of the tissue blocks with recombinant T. gondii cyclophilin suggesting blockade of CCR5 by this parasite protein as a possible mechanism. These ex vivo findings demonstrate that in human lymphoid tissues T.gondii has an inhibitory rather than stimulatory influence on HIV replication and raise the possibility that in co-infected individuals, T. gondii may influence the overall outcome of viral infection by preferentially suppressing R5 variants. In a second major project carried out this year, we have studied the stimulation of dendritic cells (DC) by T. gondii infection in vivo. DC provide a major source of IL-12, a cytokine critical for host resistance to this protozoan pathogen and thus this response is a key element in determining innate immunity to the parasite. Earlier work from the lab involving injection of a soluble tachyzoite extract, STAg, implicated CD8 alpha + DC as the major cell producing IL-12p40 in response to the parasite and moreover argued that the response does not require priming of these cells by IFN-gamma or other T cell/NK cell products. In contrast when we analyzed the DC responding to live T. gondii infection using IL-12 p40 reporter mice and an avirulent parasite strain, only CD8 alpha- CD11b high DC were observed to produce p40 and this response was greatly reduced when IFN-gamma or NK cells were depleted in vivo by antibody treatment. These findings suggest that IL-12 production by live infection (in contrast to STAg injection) may involve a different DC population that requires prior priming from another sentinel cell responding to the invading parasite.
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