Viral Replication and Pathogenicity
Session Day and Time: Thursday 1:30 - 3:30 pm
Room: Hall A
Background: Chemokines are small chemo-attractant cytokines that mediate cell trafficking during immune inductive and effector activities. Dysregulation of their expression might contribute to the pathogenesis of HIV-1 and the related simian immunodeficiency virus (SIV). Using the SIV/macaque model, we have examined the effects of pathogenic infection on the expression of homeostatic and inflammatory chemokines in secondary lymphoid tissues.
Methods: DNA filter array hybridization was used to identify genes differentially expressed in lymphoid tissues from rhesus macaques (Macaca mulatta) infected with the pathogenic SIV/DeltaB670 isolate. Real-time RT-PCR and in situ hybridization coupled with quantitative image analysis were used to confirm differential gene expression and to assess the patterns of expression directly in tissues. Based on these initial findings, and to facilitate cost-effective profiling of macaque gene expression, we fabricated and validated a macaque-specific DNA microarray containing > 75 rhesus macaque immunologically-relevant cDNAs, including 29 chemokine cDNAs.
Results: In lymph node and spleen, SIV infection increased the expression of inflammatory chemokines (CXCL9/Mig and CXCL10/IP-10), as well as homeostatic chemokines (CCL19/MIP-3b and CCL20/MIP-3a). CXCL9 and CXCL10 recruit activated T-lymphocytes and are inducible by IFN-g, which was also expressed to high levels after infection. CCL19 and CCL20 control the trafficking of potent antigen-presenting dendritic cells (DC) and na´ve T-lymphocytes. Subsequent in situ hybridization analyses demonstrated that the expression of DC-associated markers, DC-SIGN, DC-LAMP, and DECTIN-1 were elevated during acute infection, but reduced to extremely low levels during AIDS in lymph node and spleen, relative to uninfected controls. These findings are currently being confirmed and extended using our macaque DNA microarray.
Conclusions: Our findings that SIV infection dysregulates inflammatory and homeostatic chemokine expression are consistent with a model in which altered expression of multiple chemokines leads to inappropriate homing of immuno-regulatory DC and na´ve and memory T-lymphocytes to lymphoid tissues. Collectively, these alterations are likely to lead over time to ongoing viral replication, loss of peripheral immune function, and loss of local antigen presentation function, thereby contributing to systemic immunodeficiency.