Simian immunodeficiency virus (SIV)-related neuropathogenesis has been observed in 90% of pig-tailed macaques infected with strain SIVsmmFGb, making it an excellent system for studying human immunodeficiency virus (HIV)-associated neurological disease. To investigate the genetics of SIV neurovirulence, infectious molecular clones were generated from the brain of a SIVsmmFGb-infected pig-tailed macaque. One clone, BPZm.12, displayed a macrophage-restricted phenotype not previously described; this clone replicated to high levels in macrophages, but did not replicate in peripheral blood mononuclear cells (PBMC) until at least 21 days postinfection. Sequence analysis of the env gene of BPZm.12 revealed the substitution of a serine residue for a highly conserved proline residue at position 629 in gp41. A mutant clone, which contained the conserved proline to serine (BPZm.12-629P), was able to replicate in both macrophages and PBMC without delay. A mutant of an unrelated dual tropic molecular clone PBj6.6, substituting proline for serine (PBj6.6-629S), replicated to high levels in macrophages, but did not replicate in PBMC at any time point. These data indicated that a single determinant in gp41 of an SIV clone changed its phenotype from macrophage tropic to dual tropic.

The fatal disease induced by SIVsmmPBj4 clinically resembles endotoxic shock, with the development of severe gastrointestinal disease. While the exact mechanism of disease induction has not been fully elucidated, aspects of virus biology suggest that immune activation contributes to pathogenesis. These biological characteristics include induction of peripheral blood mononuclear cell (PBMC) proliferation, upregulation of activation markers and Fas ligand expression, and increased levels of apoptosis. To investigate the role of immune activation and viral replication on disease induction, animals infected with SIVsmmPBj14 were treated with one of two drugs: FK-506, a potent immunosuppressive agent, or PMPA, a potent antiretroviral agent. While PBMC proliferation was blocked in vitro with FK-506, pig-tailed macaques treated preinoculation with FK-506 were not protected from acutely lethal disease. However, these animals did show some evidence of modulation of immune activation, including reduced levels of CD25 antigen and FasL expression, as well as lower tissue viral loads. In contrast, macaques treated postinoculation with PMPA were completely protected from the development of acutely lethal disease. Treatment with PMPA beginning as late as 5 days postinfection was able to prevent the PBj syndrome. Plasma and cellular viral loads in PMPA-treated animals were significantly lower than those in untreated controls. Although PMPA-treated animals showed acute lymphopenia due to SIVsmmPBj14 infection, cell subset levels subsequently recovered and returned to normal. Based upon subsequent CD4+ cell counts, the results suggest that very early treatment following retroviral infection can have a significant effect on modifying the subsequent course of disease. These results also suggest that viral replication is an important factor involved in PBJ-induced disease. These studies reinforce the idea that the SIVsmmPBj model system is useful for therapy and vaccine testing.

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