PATHOGENESIS OF SIMIAN IMMUNODEFICIENCY VIRUS ENCEPHALITIS - VIRAL DETERMINANTS OF NEUROVIRULENCE

To examine the relationship between macrophage tropism and neurovirule nce, macaques were inoculated with two recombinant hybrid viruses deri ved from the parent viruses SIVmac239, a lymphocyte-tropic, non-neurov irulent clone, and SIV/17E-Br, a macrophage-tropic, neurovirulent viru s strain. The first recombinant, SIV/17E-Cl, contained the portion of the env gene that encodes the surface glycoprotein and a short segment of the transmembrane glycoprotein of SIV/17E-Br in the backbone of SI Vmac239. Unlike SIVmac239, SIV/17E-Cl replicated productively in macro phages, demonstrating that sequences in the surface portion of env det ermine macrophage tropism, None of five macaques inoculated with SIV/1 7E-Cl developed simian immunodeficiency virus (SIV) encephalitis. The second recombinant, SIV/17E-Fr, which contained the entire env and nef genes and the 3' long terminal repeat of SIV/17E-Br in the SIVmac239 backbone, was also macrophage tropic, Six of nine macaques inoculated with SIV/17E-Fr developed SIV encephalitis ranging from mild to modera te in severity, indicating a significant (P = 0.031) difference in the neurovirulence of the two recombinants, In both groups of macaques, C D4(+) cell counts declined gradually during infection and there was no significant difference in the rate of the decline between the two gro ups of macaques, This study demonstrated that macrophage tropism alone is not sufficient for the development of neurological disease, In add ition, it showed that while sequences in the surface portion of the en velope gene determine macrophage tropism, additional sequences derived from the transmembrane portion of envelope and/or nef confer neurovir ulence.