Pathogenesis of Acute Infection in Rhesus Macaques with a Lymphocyte-Tropic Strain of Simian Immunodeficiency Virus

Abstract

The simian immunodeficiency virus, SIVmac, causes disease affecting multiple organ systems in macaques similar to human immunodeficiency virus infection in humans. Molecularly cloned SIVmac with a strong lymphocyte tropism was used in pathogenesis experiments to correlate viral cell tropism with disease. In 5 animals, exhaustive analyses on viruses from tissues and identification of infected precursor cells were done at multiple times during infection to ensure the virus had not mutated into a macrophage-tropic variant. Viral replication was measured by infectivity, infectious center assays, and in situ hybridization. Lymphocytes produced most virus in tissues, indicating the virus maintained its cell tropism in vivo. Lymphocytes in bone marrow were latently infected and those in the spleen and lymph nodes were productively infected. The virus failed to replicate in the brain after intracerebral inoculation. SIVmac that maintained a strong tropism for lymphocytes and a corresponding poor tropism for macrophages can cause persistent infection and AIDS but not other diseases such as primary pneumonia and encephalitis in rhesus macaques.

Nonhuman primate models of NeuroAIDS

“…Both SIVs cause acute infections characterized by cell-associated and cell-free viremia. Virus-infected cells can be found in the CSF throughout the acute phase, which can last for 2 to 10 weeks (Joag et al , 1994; Sharma et al , 1992a,1992b). During this phase, infection in the CNS is characterized by meningitis and accumulations of mononuclear cells in the Virchow-Robin spaces in the brain.…”

Molecular and biological characterization of a neurovirulent molecular clone of simian immunodeficiency virus

“…In addition, cellular or host factors may contribute to the pathogenesis of HIV-induced CNS disease (50). In the simian immunodeficiency virus (SIV) animal model, SIV-infected macaques develop AIDS and some develop encephalitis (18,22,31,41,42). Monkeys infected with molecular clones of SIV that are predominantly lymphocyte tropic develop AIDS, while those infected with macrophage-tropic SIV also develop encephalitis and interstitial pneumonia (3,18,23,31,41,42).…”

Early Treatment with 9-(2-Phosphonylmethoxyethyl)adenine Reduces Virus Burdens for a Prolonged Period in SIV-Infected Rhesus Macaques

“…12 Polymerase chain reaction amplification of gp!20 sequences from neural tissues Total cellular genomic DNA was extracted from 15 regions of the central nervous system (frontal, parietal, occipital, temporal, and motor cortices; hippocampus; basal ganglia; deep white matter/internal capsule; thalamus; midbrain; pons; medulla; and cervical, thoracic, and lumbar spinal cord) and from dorsal root ganglia, and used as a template in nested polymerase chain reactions (PCR) to amplify SIV gpl20 sequences. The oligonucleotide primers used in the first round were complementary to bases 6565-6591 and 8179-8205 of SPVmac239, while the primers for the second round were complementary to bases 6598-6624 and 8158-8184 of SrVmac239 as previously described.…”

“…16"18 Single-cell suspensions Flow cytometry Cell suspensions from mesenteric lymph nodes (LNCs), spleen (SPCs), and thymus (THCs) were obtained by passing minced tissue through a coarse and then a fine mesh as described. 12 Spleen cell suspensions were further purified by centrifugation through Ficoll-Hypaque density gradients. Assessment of virus infectivity 1.…”

“…In contrast, the virus was infectious in adherent macrophage cultures, with production of viral DNA and some viral proteins, but only limited numbers of virus particles were produced.15 In vivo, the virus caused highly productive infection in CD4+ T cells in lymphoid tissues, while in the brain, which has macrophages (microglia) but few CD4+ T cells, the agent was infectious but did not replicate productively. Therefore, to examine neuroinvasion by the virus in inoculated macaques, we divided the CNS into multiple regions, 12 for the brain and 4 for the spinal cord and dorsal root ganglia, and examined genomic DNA from each region for the presence of viral DNA.…”