Pathogenesis of SIV Pneumonia: Selective Replication of Viral Genotypes in the Lung

Abstract

Lymphocytic interstitial pneumonia of HIV-infected individuals and SIV pneumonia of macaques are both characterized by diffuse infiltration of the lungs with lymphocytes, plasma cells, and macrophages. This study was undertaken to determine whether there are specific, macrophage-tropic genotypes that selectively replicate in the lung of macaques with SIV pneumonia, as in SIV encephalitis. Using a rapid, reproducible SIV/macaque model of AIDS, 11 pig-tailed macaques were intravenously inoculated with an immunosuppressive viral strain, SIV/DeltaB670, and a macrophage-tropic molecule clone, SIV/17E-Fr, and euthanized at 3 months postinoculation. All 11 macaques had severe (6 macaques) or moderate (5 macaques) pneumonia. To identify the viral genotypes that were replicating in the lung parenchyma, bronchoalveolar lavage (BAL) cells, and peripheral blood mononuclear cells (PBMC) of each macaque, RNA was isolated and the SIV env V1 region was amplified, cloned, and sequenced. Lung homogenates and BAL cells contained a more limited repertoire of viral genotypes than PBMC. SIV/17E-Fr was the major genotype in the lungs of 5 macaques and in BAL cells of 6 macaques. The remainder of the macaques had SIV/17E-Fr and the macrophage-tropic strains of SIV/DeltaB670 clones 2 and 12. In contrast, SIV/17E-Fr was the predominant strain in the PBMC of only 3 of 11 macaques. The viral strain that predominated in PBMC was rarely the strain that predominated in the lungs (only 3 of 11 macaques). The severity of pulmonary lesions did not correlate with the levels of viral RNA in lung homogenates or in plasma. However, when only SIV/17E-Fr was expressed in the lung, the viral load in the lung was significantly higher (P = 0.016) than when SIV/DeltaB670 was present alone or in combination with SIV/17E-Fr. These data suggest that SIV pneumonia is associated with selective replication of specific macrophage-tropic genotypes in the lung and that SIV/17E-Fr has a selective advantage for replication in the lung.

CD4-Independent Entry and Replication of Simian Immunodeficiency Virus in Primary Rhesus Macaque Astrocytes Are Regulated by the Transmembrane Protein

“…5). To identify the genotypes of the SIV/DeltaB670 swarm that replicated in astrocytes, total cellular RNA was isolated from the infected astrocyte cultures, RT-PCR was performed, the V1 regions of the env genes were cloned, and DNA sequencing was performed as previously described (2,3). Only Cl-3 and Cl-12, the previously described macrophage-tropic, CD4-independent genotypes, replicated in infected astrocyte cultures (sequencing data not shown).…”

“…For SIV, CCR5 is the main coreceptor utilized by Env proteins, irrespective of viral tropism (30). However, coreceptor specificity is not the only determinant of viral tropism, and several alterations within the SU and transmembrane (TM) portions of the Env protein of HIV (21,31) and SIV (1,3,19,20,24,35,37) that are characteristic of viruses with the ability to replicate in nontraditional cellular targets and cause tissuespecific disease have been described. Several SIV tissue isolates from the brain and lung have unique Env features, in particular a reduced dependence on CD4, allowing these viruses to infect cells that express relatively low surface levels of CD4 and thereby perpetuating an expanded host cell tropism (14,34).…”

Simian Human Immunodeficiency Virus-Associated Pneumonia Correlates with Increased Expression of MCP-1, CXCL10, and Viral RNA in the Lungs of Rhesus Macaques

“…Productive replication of the virus becomes prominent in macrophages following loss of both cellmediated immunity and CD4 ϩ T cells. [25][26][27] Pulmonary cells from asymptomatic patients are known to contain proviral DNA although at lower levels than during the late stages of disease. 28 The relationship between systemic virus load and the pool of viruses replicating in the lung remains poorly understood.…”

Role of Microglial Cells in Selective Replication of Simian Immunodeficiency Virus Genotypes in the Brain

“…The AID 50 was calculated using software developed by John Spouge (57). The SIV/DeltaB670 stock consists of at least 22 different genotypes characterized by nucleotide sequencing of the hypervariable region V1 of the envelope gene (2) and includes both the macrophage-and lymphocyte-tropic strains (6,7,50). SIV/DeltaB670 induces the full range of SIV-associated disease, including immunosuppression, encephalitis (37,65), and pneumonia (8,36).…”