The role of the CDR2- and CDR3-like domains of CD4 in binding to the HIV- 1 gp120 envelope glycoprotein has been further examined with monoclonal antibodies to the CDR3-like domain and derivatized peptides from the CD4(81-92) [CDR3-like] region of CD4.Antibodies to the CDR2- and CDR3-like domain of CD4 can bind simultaneously to discrete epitopes on the CD4 molecule, yet both block gpl20 binding to CD4, demonstrating separate binding sites for gpl20 within the CDR2 and CDR3-like domains of CD4. CDR3- and CDR2-directed antibodies, block in vitro infection by primary/clinical pediatric isolates of HIV-1 resistant to soluble CD4. CD4(81-92) peptides block infection of some but not all of these isolates. The interaction between CD4 and the HIV-1 gpl20 envelope glycoprotein involves multiple sites on both molecules, and a processive series of binding events leading to virus entry and syncytium formation. Infection of juvenile rhesus macaque monkeys with SIVsmm is a model for the AIDS dementia complex and the involvement of the central nervous system in HIV disease. The neurochemical and immunochemical sequelae of SIV infection leading to motor and cognitive deficits is under examination in the brains of SIV-infected macaques. Diffuse regional cerebrocortical astrogliosis and increased expression of somatostatin mRNA have been noted in the frontal and parietal cortices of SIV-infected monkeys. Systematic studies will reveal whether or not regional patterns of astrogliosis and neuropeptide dysregulation are markers for, or contributory to, motor and cognitive impairment accompanying SIV infection in the rhesus macaque monkey. Markers and possibly therapeutic proteins can potentially be targeted to the brain during chronic inflammatory states such as HIV infection via transduction of bone marrow cells with retroviral expression vectors, since lymphocytes, perivascular microglia, and extravasated macrophages are of hematogenous origin and may be increased in concentration in the encephalitic CNS.Retrovirally tagged bone marrow stem cells introduced into lethally irradiated donor mice can be found, albeit rarely, in the central nervous system.Attempts to increase brain targeting of retrovirally transduced hematopoietic cells in mouse models of encephalitis are underway.
