Pathogenesisinvolvement in disease

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Whereas animal retroviruses have been known for a long time to cause a variety of diseases, including benign and malignant neoplasms, anemias, wasting syndromes, neurological disease and immunodeficiency states, the role of retroviruses as human pathogens has only been substantiated during the last 15 years. HTLV-I is etiologically associated with adult T cell leukemia (ATL) and tropical spastic paraparesis (see below). Although HTLV-II was originally isolated from patients with a T cell variant of hairy cell leukemia, its role in human disease has not been established. The two human lentiviruses HIV-1 and HIV-2 cause the acquired immune deficiency syndrome (AIDS). Foamy or spuma retroviruses are commonly found in several simian species, chimpanzees, cats, cattle and hamsters. There is no known association with disease in these animals. Infection of humans can occur through contact with animals but is not passed on and proposed associations with human disease have not been substantiated.

The following examples of diseases caused by retroviruses are meant to illustrate some of the mechanisms by which retroviruses cause disease.

Immunodeficiency diseases/wasting/anemias

A number of retroviruses are known to cause immunodeficiency states. The closest analog to human AIDS is the disease caused in macaques by a number of simian lentiviruses. Simian lentiviruses have been found in several species (Table 1). SIVA(,M, SIVMN, SIVsm do not cause disease in their natural host but are pathogenic when inoculated into other monkey species. SIVm.,c is pathogenic to macaques which, however, are not its natural host. SIVSM, SIVmac and HIV-2 are highly related and a simian virus from this group may be the ancestor of HIV-2 in humans and SIVmac in captive macaques.

Many other species also contain lentiviruses. A wasting disease in sheep with some features of human AIDS is caused by visna virus. In goats and sheep caprine arthritis encephalitis virus (CAEV) causes arthritis, pneumonia and meningoencephalitis, and an infectious anemia in horses is due to equine infectious anemia virus (FIAV). A common feature of all lentiviral infections is the chronic, protracted course of the disease which affects many organ systems and the long latency of the virus in the infected host. During the early and late stages of HIV infection virus turnover is very high with 109-10"' virions produced and cleared, and a corresponding number of CD4+ T cells destroyed each day. This massive destruction of immune effector cells as a direct result of viral infection probably accounts for most of the damage to the immune system. In addition, immune mechanisms may contribute. Circulating immune complexes may play a role in the glomerulonephritis of equine infectious anemia and the thrombocytopenia purpura of AIDS patients. The phagocytosis and hemolysis of erythrocytes coated with viral antigen, antiviral antibody and complement is at the root of equine infectious anemia and an inflammatory response is responsible for lesions in the lungs and joints of animals infected with visna virus and CAEV. A T cell response to HIV-l-infected T cells may be involved in the destruction of this group of cells.

Some members of a subgroup of oncoviruses, D-type viruses, cause an immunodeficiency state in macaques which was referred to as SAIDS (simian acquired immunodeficiency syndrome). Five viral serotypes belonging to this group are known and have been termed SRV-1-5 (for simian retroviruses).

SRV-3 is also known as Mason-Pfizer monkey virus (MPMV).

In cats and mice, defective forms of feline leukemia virus (FeLV) and MLV have been shown to cause immunodeficiency disease with some features similar to human AIDS. These defective forms have small deletions and insertions in env (FeLV) or large deletions in env and pol (MLV) and are therefore replication defective, i.e. they require the presence of intact helper viruses in order to propagate their genome and package it into infectious particles. The diseases induced by these defective viruses differ in some respects from human or simian AIDS: the murine disease is accompanied by a rapidly progressive B cell hyperplasia and this and the immunosuppression may be T cell dependent. Exactly why these defective viruses are pathogenic is only incompletely understood. There is evidence that minor changes in the envelope gene may affect post-translational processing of the envelope protein core.

Neoplasia

Ever since P. Rous demonstrated in 1911 that cell-free tumor filtrates could transmit a chicken sarcoma, the list of animal tumors caused by retroviruses has continued to grow. Several pathogenic mechanisms have been elucidated over the last 20 years. Retroviruses can cause tumors by transducing oncogenes, i.e. cellular genes involved in the control of cell proliferation and differentiation. Cellular oncogenes, often in a mutated form, can be 'picked up' by retroviruses and become part of recombinant retroviral genomes. Oncogene-carrying retroviruses are usually replication defective since the foreign gene interferes with the normal retroviral life cycle and requires the presence of intact 'helper viruses' to package the oncogene-containing viral genome into viral particles. Other examples include Avian sarcoma virus (fps, yes oncogenes), feline sarcoma viruses (fes, fms, sis), avian erythroblastosis virus (erbA, erbB), murine sarcoma virus (mos, Ha-ras, Ki-ras), simian sarcoma virus (sis). In this situation the transduced oncogenes are under the control of viral promoters and enhancers and these viruses tend to cause rapidly appearing and progressing tumors.

However, retroviruses need not transduce host genes to cause neoplasia. In the case of avian leukosis virus viral integration occurs in the vicinity of the cellular oncogene c-myc and places this oncogene under the control of the retroviral 3' LTR. Mouse mammary tumor virus integrates preferentially in two genomic loci, termed int-1 and int-2, and affects expression of these genes which resemble fibroblast growth factor. In the case of murine leukemia virus the situation is more complex: minimal differences between the U3 regions of different virus strains (presence or absence of certain tandem direct repeats) seem to be important for leukemogenicity and tissue tropism, most likely by affecting the enhancer function of the viral LTR. An increased enhancer activity may affect the expression of cellular genes in whose vicinity the virus has integrated. Feline leukemia virus may use several of these mechanisms - in some cases integration near the c-myc locus and/or recombinant viruses carrying the cellular c-myc gene have been observed.

The only human neoplasia associated with a retrovirus is adult T cell leukemia (AIL) caused by HTLV-I. Although the majority of ATL cases are associated with HTLV-I, the existence of rare cases of HTLV-I-negative ATL, the long latency period between infection and the emergence of ATL, and the low proportion of seropositive individuals developing ATL indicate that other events may be involved. The oncogenic role of HTLV-I is related to the viral transactivating Tax protein, which, as outlined above, activates a number of cellular genes and may thus create a pool of proliferating cells. These cells are more prone to further genetic changes which may constitute the actual transforming event. The recently described inhibitory effect of Tax on the repair enzyme polymerase I may contribute to the likelihood of genetic 'accidents'.

Neurological disease

In humans, HTLV-I is etiologically associated with tropical spastic paraparesis (TSP/HAM), but TSP can occur in the absence of HTLV-I infection. The presence of large numbers of activated (HTLV-I infected and uninfected) T cells may play a role in disease development. However, the precise role of HTLV-I in the pathogenesis of this disease is nor yet understood. Among lentiviruses both HIV and visna virus cause CNS lesions characterized by inflammatory and degenerative changes. For both viruses, macrophages and microglia seem to be important virus reservoirs in the CNS. A temperature-sensitive mutant of MLV also causes a neurological disease and this may be due to minor sequence changes in the envelope protein which interfere with the normal processing of the envelope in the endoplasmic reticulum and Golgi apparatus of neural cells.

Autoimmune disease

In addition to the 'autoimmune' mechanisms found in immunodeficiency and wasting disorders discussed earlier, murine leukemia viruses are thought to exacerbate the autoimmune disease of (NZB > NZW)F1 mice that resembles human systemic lupus erythematosus (SLE), as well as the necrotizing arthritis and glomerulonephritis of SL/Ni mice. Retroviral particles have been observed in animal models of autoimmune diabetes, and a new endogenous avian leukosis virus gene locus has been found in obese chicken with spontaneous autoimmune thyroiditis. However, the pathogenic role of retroviruses in these diseases remains to be established.

See also: Acquired immune deficiency syndrome (AIDS); Antigenic variation; Human immunodeficiency viruses; Leukemia; Superantigens.

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