Arterivirus Infection: Lactate Dehydrogenase-Elevating Virus Infection

Lactate dehydrogenase-elevating virus (LDV) belongs to the family Arteriviridae. LDV was initially discovered as a contaminant of a transplantable tumor that caused sig­nificant elevation of lactate dehydrogenase (LDH) in plasma of inoculated mice.

Epizootiology and Pathogenesis

The prevalence of LDV among contemporary mouse colonies is unknown, since serological surveillance sel­dom includes this agent. It is endemic, but not universal, in wild mouse populations throughout the world. LDV is highly specific to the mouse and also has a very restricted cell tropism for a specific subset of macrophages (F4/80- positive) and, under some circumstances, neural tissue. The primary means of natural transmission is through bite wounds among fighting mice, but studies also sug­gest that it can be sexually transmitted. In addition, LDV is inefficiently transmitted by direct contact, even though the virus is excreted in feces, urine, milk, saliva, and semen. Maternal transmission to the fetus can occur, but occurs only during the acute, high-viremic stage and is regulated by maternal immune status, devel­opmental stage of the fetus, and a strong gradient of placental and umbilical cord trapping of virus immune complexes. Infection of the fetus is favored at 13-14 days or more of gestation. Fetal susceptibility is due to devel­opment of susceptible F4/80-positive macrophages. For these reasons, LDV seldom infects fetuses under natural conditions.

Different quasispecies of LDV exist, including LDV-P and LDV-vx, which prevail in laboratory mice.

At this stage, antigen and RNA-positive cells are present in many tissues. There is rapid exhaustion of the target cell population, resulting in subsequent attenuation of the level of viremia, which persists at a lower level throughout life. At this stage, there are few or no infected cells in most tissues, with the exception of spleen, lymph node, and testes. The drop in levels of viremia occurs prior to acquired immunity and has similar kinetics in athymic nude mice and chemically immunosuppressed mice. There is also immunosuppression due to clonal exhaustion of cytotoxic T cells as well as virus-induced inhibition of IL-4 with suppression of helper T cells. Depletion of the target subpopulation of macrophages results in impaired clearance of plasma enzymes, includ­ing LDH, with 5- to 10-fold elevations. This phenome­non is not specific to LDH, as several other enzymes are also significantly elevated. Immune clearance of the virus is precluded due to the presence of 3 large N-linked polylactosaminoglycan chains on the short ectodomain of the envelope glycoprotein, VP-3P, which carries the neutralization epitope. These persistent viruses, there­fore, are resistant to neutralizing antibody. LDV infec­tion stimulates a strong polyclonal antibody response, with the formation of immune complexes, but immune complex disease does not seem to occur.

Some variants of LDV, such as LDV-C and LDV-v, infect not only macrophages but also anterior horn neurons of C58, AKR, C3H/Fg, and PL mice.

Pathology

Clinical signs or lesions are not seen in naturally infected mice, and lesions are minimal in experimentally infected immunodeficient mice. Experimentally inoculated mice develop transient necrosis of T-cell areas of lymphoid tissues, pyknosis of reticuloendothelial cells, and leu­kopenia within 72 hours after inoculation. As infection proceeds, these changes disappear, and there is gener­alized splenomegaly and lymphadenomegaly with expanded germinal center formation due to polyclonal B-cell activation. Central nervous system disease in experimentally infected, immunosuppressed C58, AKR, C3H/Fg, and PL mice consists of mononuclear leukocytic infiltrates in the ventral, and to a lesser extent dorsal, horns of the spinal cord, scattered neuro­nolysis with apoptosis, and perivasculitis. C57BL mice infected with LDV develop mild to moderate nonsup­purative leptomeningitis, myelitis, and occasionally radiculitis without clinical signs.

Diagnosis

Serological methods for LDV antibody have not been generally used because of difficulties with antigen-anti­body complexes and polyclonal B-cell activation. Never­theless, antibody can be effectively detected using purified LDV virions or infected cells as antigen. LDV replicates in primary macrophage cell cultures but causes no cytopathic effect. The gold standard for LDV diagno­sis in the past has been measurement of plasma LDH enzymes in mice given serial dilutions of test material, but now PCR is used for confirmation, since LDH is not specific for LDV infection. Differential diagnoses include any agent or disease that causes enzyme elevations, but other enzyme elevations are not as high or persistent. Neurologic LDV lesions must be distinguished from spinal cord lesions induced by mouse encephalomyelitis virus (MEV), MHV, or retrovirus. LDV can be eliminated from transplantable tumors by growth in vitro, or by passage in athymic rats, both of which lack the necessary mouse macrophage subpopulations needed to sustain infection.