How does the Virus Cause Disease?

Pathogenesis means the method by which pathology (e.g. tissue damage) occurs. The virus and the immune response to the viral infection cause damage to the target tissues of maedi visna virus (MVV), in this case usually the lungs, udder, central nervous system (CNS), lymph nodes and joints.

Which Cells are Infected by the Virus?

Maedi visna virus (MVV) infects the sheep for life, i.e. it is not cleared by the immune system of the host despite all best attempts.  When MVV infects a sheep, it invades mature activated macrophages located near the mucosal surfaces, e.g. digestive or respiratory tract or the conjunctiva of the eye.  The virus then hides out in the bone marrow in the monocyte/macrophage precursor cells and so is a source of continued viral infection. When these cells are recruited to fight other disease agents, they bring the virus with them to the target organs, i.e. lung, udder, CNS, lymph nodes and joints. 

The virus also infects the epithelial cells of the lung, mammary gland and choroid plexus of the ventricles of the brain, and endothelial cells and fibroblast-like cells of the CNS and lung.  Although it is likely that these cells are not important for virus replication, they are important in the pathogenesis of disease. It is the proliferation of inflammatory cells in the lungs, brain, spinal cord, mammary glands and joints that results in disease.  Lymphadenopathy (enlargement of the lymph nodes) and pathologic changes to the heart, kidneys, eyes and liver also occurs. 

Inflammation and Level of Disease

The level of inflammation and disease varies from animal to animal. Rarely, lambs infected initially through the ingestion of infected colostrum may clear the virus after 6 months and be antibody negative after 8 months – suggesting that either they cleared the infection, or the infection has become occult (hidden).  Other animals may be “rapid progressors”, i.e. develop evidence of disease quite quickly; or are long-term non-progressors (LTNP), i.e. never develop disease; or they develop clinical disease and death 6 months to 8 years after infection.  Genetics likely plays a role in this.

Antibody Response and the Virus

The initial virus infection produces a neutralizing antibody response within a few weeks up to 6 to 8 months after infection (we can measure this antibody) but it does not appear effective in killing virus which is mostly intracellular (inside the cell) at this point.  It also does not appear to be protective against repeated viral infection, which likely occurs in heavily infected flocks. It has been suggested that some antibodies may actually enhance entry of the virus into the cell. So level of antibody in a sheep does not indicate protection against further infection and may actually indicate the opposite. After the initial infection, the virus then enters a phase of restricted replication and latency, i.e. sort of goes dormant.

How the Viral Infection Causes Damage to the Target Tissues

Immature infected monocytes in the bone marrow are the reservoir of the virus.  These cells contain the proviral DNA. No viral messenger RNA (the type of nucleic acid that transcribes the provirus DNA back to the virus RNA) or protein is produced by these cells and so no virus replication occurs within the bone marrow.  Eventually though, these infected monocytes migrate from the bone marrow to target organs (e.g. lungs, udder) where they mature to macrophages and become activated, expressing the provirus – like a “Trojan Horse”.   The presence of the foreign virus is now detected by the immune system, causing immune cells (T lymphocyte cells)to flood in - causing inflammation and damage as they try to kill the virus and the infected cells. This damage releases virus from the macrophages, thus attracting more inflammatory cells.  As the repeated rounds of inflammation damages the tissues– pathology occurs. This damage may accumulate causing signs of disease in the sheep, e.g. pneumonia or mastitis as more and more the the healthy tissue of the targe organs is damaged by this fight within the immune system. 

Why Don't the Antibodies Kill the Virus?

Retroviruses such as MVV frequently undergo antigenic variation or drift within the host and it is thought this aids in avoiding the effects of neutralization by antibodies.  While generally the strain that initial infects the sheep is the dominant strain later isolated from the same sheep, it has been shown that different strains may be present in the blood versus colostrum or that more than one strain can even be isolated from the blood.  Some strains are more virulent for specific organs, e.g. CNS versus lungs. As mentioned previously, the virus also spends quite a bit of time hiding out in monocyte cells and can't be detected by the immune system. For these reasons, there is little "free" virus found in animals - most of the virus is present as provirus. 

An excellent diagram of the origin of the different types of cells of the immune system here