LYMPHOCYTE-TROPIC SIMIAN IMMUNODEFICIENCY VIRUS CAUSES PERSISTENT INFECTION IN THE BRAINS OF RHESUS-MONKEYS

Molecularly cloned SIV(mac)239 is the prototypical SIVmac lymphocyte-t ropic virus that replicates productively in lymphocytes but poorly in macrophages. In macaques, the virus causes activation and productive i nfection of T lymphocytes which invade the central nervous system (CNS ) early after infection in the animal. However, infected animals devel op immunosuppression and AIDS but rarely overt neurological disease. I n this study, we examined multiple regions of the brain and spinal cor d for the presence of SIV env sequences and histological lesions in fi ve macaques that had been infected with SIV(mac)239 for 1.7 to 2.25 ye ars. Histopathological examination of the brain revealed no lesions co nsistent with encephalitis; however, viral DNA was found in all five b rains. In one animal the virus caused infection in a widely disseminat ed pattern from the frontal cortex to the distal end of the spinal cor d, whereas in the other four animals infection in the CNS occurred in a nonspecific, focal pattern. Sequence analyses were performed on gp12 0 sequences isolated from selected regions of the CNS and compared to gp120 sequences isolated from corresponding lymph nodes, a tissue know n to support productive replication of SIV(mac)239. Examination of the viral sequences from the CNS tissue from two animals (macaques 10F an d 14F) revealed a low mutation rate when compared to the sequences iso lated from the lymph node tissues. The percentage change in the amino acid sequence was approximately 1% for CNS clones Versus greater than or equal to 3% for clones isolated from the lymph node. The majority o f the CNS viral sequences of macaques 10F and 14F had none of the gene tic markers shown in a previous study to be associated with macrophage -tropic variants and indeed retained a nucleotide sequence of similar to the original lymphocyte-tropic virus used for inoculation despite a lmost 2 years of persistent infection in the animals. Construction of chimeric viruses with V1-V5 regions of selected macaque 10F and macaqu e 14F CNS-gp120 clones confirmed the predicted lymphocyte-tropic natur e of these env genes. In contrast, the gp120 sequences isolated from t he CNS tissue of one of the other three animals (macaque 13F) had a mu tation rate comparable to that observed for the lymph node clones. The CNS clones from this animal had amino acid substitutions that were pr eviously shown to be associated with macrophage tropism. Compared to t he chimeric Viruses constructed with V1-V5 sequences from macaques 10F and 14F, viruses constructed with the V1-V5 sequences of several maca que 13F brain clones did not yield infectious virus. These data sugges t that following entry into the CSF early during infection in the anim als, SIV(mac)239 caused infection in the CNS. In some animals, the Vir al env sequences recovered by the PCR suggested that minimal replicati on had occurred, whereas in another macaque virus replication had prog ressed with gradual selection of a more macrophage-tropic genotype. (C ) 1995 Academic Press, Inc.