Alphavirus-specific cytotoxic T lymphocytes recognize a cross-reactive epitope from the capsid protein and can eliminate virus from persistently infected macrophages.

Persistent alphavirus infections in synovial and neural tissues are believed to be associated with chronic arthritis and encephalitis, respectively, and represent likely targets for CD8+ alphabeta cytotoxic T lymphocytes (CTL). Here we show that the capsid protein is a dominant target for alphavirus-specific CTL in BALB/c mice and that capsid-specific CTL from these mice recognize an H-2Kd restricted epitope, QYSGGRFTI. This epitope lies in the highly conserved region of the capsid protein, and QYSGGRFTI-specific CTL were cross reactive across a range of Old World alphaviruses. In vivo the acute primary viraemia of these highly cytopathic viruses was unaffected by QYSGGRFTI-specific CTL. However, in vitro these CTL were able to completely clear virus from macrophages persistently and productively infected with the arthrogenic alphavirus Ross River virus.

Antibody-dependent enhancement and persistence in macrophages of an arbovirus associated with arthritis.

Ross River virus (RRV) is the aetiological agent of epidemic polyarthritis (EPA) a predominantly rheumatic disease afflicting up to 5000 Australians annually. We show here for the first time that macrophages can be productively infected by RRV. Subneutralizing titres of anti-RRV IgG (but not IgM) also showed classical antibody-dependent enhancement (ADE) of RRV infection in macrophage and monocyte cell lines. No correlation between development of EPA and the pre-existence of ADE titres was apparent, nor could sera raised against a related arbovirus, Barmah Forest, enhance RRV infection. Tumour necrosis factor-alpha, implicated in the immunopathogenesis of rheumatoid arthritis, was not secreted by RRV-infected monocytes or macrophages. Macrophage cell lines infected with RRV were, however, capable of producing virus for over 50 days. RRV-induced arthritis may therefore be due to the persistent productive infection of macrophages, perhaps established by a brief period of ADE early in infection.

Analysis of functional epitopes on the dengue 2 envelope (E) protein using monoclonal IgM antibodies.

Forty-two hybridomas secreting IgM antibody against dengue virus were derived from spleen cells of dengue 2 infected mice. Antibody from 27 of these recognised the E protein of this virus. Of the 22 antibodies which neutralised dengue 2, only two cross-reacted with other flaviviruses. These 22 antibodies recognised three discrete domains on dengue virions. Competitive binding studies with IgG monoclonal antibodies suggested that two of the three domains were recognised by both IgG and IgM antibodies and that there were two additional domains which may be recognised exclusively by either IgG or IgM antibodies. IgM antibodies reacting with domains recognised by IgG antibodies that enhanced infection of susceptible cells by dengue 2, had no enhancing properties. None of the IgM antibodies activated the serum complement system after reacting with dengue 2 virions.

Visual recovery in combined central retinal artery and central retinal vein occlusion.

We observed two patients who had combined central retinal artery occlusion and central retinal vein occlusion with severely reduced visual acuity and characteristic retinal changes. Over the course of several months, visual acuity and ophthalmoscopic appearance returned to normal. Both patients had a transient visual loss before their occlusive events and a mild nonconcurrent central retinal vein occlusion in their fellow eye. There was no evidence of inflammatory, vascular, or myeloproliferative disease.