A large proportion of HIV-infected adults and children suffer motor and cognitive impairment, referred to as AIDS Dementia Complex (ADC). SIV is excellent model for the study of ADC because it causes clinical and pathological manifestations similar to those of human immunodeficiency virus (HIV); further, macaques can be inoculated with cloned, characterized viruses, and euthanized at different stages of infection to study tissue changes and virus gene expression (an animal model is essential for studies of acute infection). The hypothesis to be tested in these studies is that whereas many virus strains enter the CNS in trafficking cells, only neurovirulent strains replicate productively in the CNS. Virus infection and spread in the CNS is dependent on expression of co-receptors by CNS cells. Virus replication in the CNS parallels that in the periphery and results in activation of CNS cells and production of cytokines and chemokines which induce cell adhesion molecules and recruit additional inflammatory cells, resulting in clinical and pathological changes. To examine this hypothesis, the research will undertake two animal studies. To study events occurring during the acute stages of infection and at the beginning of the stage of clinical quiescence, they will co-inoculate 24 macaques with SIV/17E-Fr and SIV/DeltaB670, an approach that produces a high incidence of neurological disease, and will euthanize 6 macaques at 1, 2, or 4 weeks p.i. (acute infection), and at 12 weeks p.i. (clinical quiescence). To study neurological disease in long-term infection, the researchers will co-inoculate 12 macaques and euthanize them during the terminal stages of disease. The specific virus genotypes that enter and replicate in the CNS early in infection will be examined to determine whether selection takes place at the level of virus entry or replication. The specific chemokine receptors utilized by macrophage-tropic and neurovirulent strains will be identified in cultured primary macrophages, microglia, and brain endothelial cells. The findings will be correlated with chemokine receptor expression and virus replication in vivo. Viral load will be measured in the CNS and the periphery to determine whether virus replication occurs in parallel in these two compartments, indicating that the immune system is a major factor regulating viral load in the CNS as it is in the periphery. The CNS of all infected macaques will be examined for expression of pro-inflammatory molecules (MHC, Class II, chemokine receptors, cell adhesion molecules), and the results will be correlated with viral load and the genotype(s) present in the CNS.
Showing the most recent 10 out of 15 publications
