HIV-1 associated encephalopathy can show either minor or severe cognitive impariments refered to as the AIDS dementia complex as well as motor dysfunction. HIV-1 causes damage in the human brain through both direct infection and indirect mechanisms through viral structural or non-structural proteins. We have found that HIV-1 infection in children results in a different pathological consequence than in adults. There is loss of neurons, calcifications in basal ganglia structures, and cortial atrophy. We have also identified HIV-1 infection in cells that are phenotypically progenitor cells, nestin positive. These cells reside in the subventricular zone and hippocampus. In a series of 9 autopsy brain tissues, we have found a number of HIV-1 infected nestin positive cells using laser capture microdissection and PCR of viral sequences. This confirms the laboratory finding of the susceptibility of HIV-1 to infect a cell line of human brain derived progenitor cells. The ability of HIV-1 proteins, particularly tat, which is a transactivating protein to regulate cellular functions helps explain the dysfunction of the nervous system in brain tissue where there is little evidence of active virus multiplication. In a clinical study of pediatric AIDS cases of patients with long clinical history of AIDS but treated for extended period of time with HAART or multiple drug combination therapy, many of these patients show cognitive slowing and some motor skill decline compared with age matched groups. Whether this results from the low level persistence of HIV-1 in the brain, periodic stimulation of inflammator cytokines, or drug toxicity is not known. Continuted clinical follow up, neuropyschology testing, evaluation of inflammation in the brain through testing of CSF, and brain imaging are being conducted through protocols at the NIH CC.
| Eugenin, E A; King, J E; Hazleton, J E et al. (2011) Differences in NMDA receptor expression during human development determine the response of neurons to HIV-tat-mediated neurotoxicity. Neurotox Res 19:138-48 |
| Li, Wei; Henderson, Lisa J; Major, Eugene O et al. (2011) IFN-gamma mediates enhancement of HIV replication in astrocytes by inducing an antagonist of the beta-catenin pathway (DKK1) in a STAT 3-dependent manner. J Immunol 186:6771-8 |
| Bachis, Alessia; Biggio, Francesca; Major, Eugene O et al. (2009) M- and T-tropic HIVs promote apoptosis in rat neurons. J Neuroimmune Pharmacol 4:150-60 |
