It is known that tissue damage such neuronal namely cell death and gliosis are common in HIVE, and this is confirmed by our immunostaining showing re duced staining for the neuronal marker MAP2 in HIVE. However, we do not believe that these tissue damages could have impacted our results on cells expressing activated Rac1, because analysis of brain tissues from HIV seronega tive controls, HIV cases Inhibitors,Modulators,Libraries without encephalitis, and HIVE patients showed that activated Rac1 were mostly expressed in brain macrophages and blood vessels, and none of the sample analyzed showed expression of phos phorylated Rac1 in neurons or astrocytes.

Significant increases in transcription of RAC1 and CTTN were observed only in brain tissues of HIV infected indi viduals, compared to brain tissues of seronegative controls, or infected patients with advanced neurological complica Inhibitors,Modulators,Libraries tions, suggesting that HIV induced transcriptional Inhibitors,Modulators,Libraries regulation of RAC1 and CTTN occurs early in the course of viral infection, which likely coincides with BBB breach and increased trafficking of MPs into the CNS. HIV induced BBB dysfunction and the resulting increased entry of MPs into the CNS are well documented to precede sub sequent CNS complications such as HIVE and HAND. Previous studies also showed increased transcrip tional upregulation of proinflammatory cytokines such as IL6, and STAT1, in brain tissues of HIVnonencephalitic patients, Inhibitors,Modulators,Libraries compared to brain tissues of seronegative controls and HIVE patients, confirming that increased inflam mation and inflammation induced damages that leads to HIVE often precede the onset of HIVE.

Inhibitors,Modulators,Libraries It has also been demonstrated that Rac1 activation is associated with clus tering of cell adhesion molecules, increased production of sellekchem re active oxygen species, and leukocyte transendothelial migration. In HIV induced CNS dysfunction, such oxidative stress events and leukocyte entry into the CNS occur earlier following HIV infection, before the onset of HIVE. Ligand binding to chemokine receptors has been shown to induce activation of signaling that regulate cellular integ rins and adhesion molecules, resulting in rearrangement of the actin cytoskeleton, changes in cell morphology and mi gration. This agrees with our current study, which shows that proteins differentially expressed and activated in HIV infected monocytes following monocyte endothelial communications are associated with functions such as cel lular movement, cell morphology, cell to cell signaling, and post translational modifications. The signaling pathways activated in HIV infected monocytes following monocyte endothelial interaction included those associated with in tegrin and cell junction signaling.