AIDSWEEKLY Plus, Monday, 16 December 1996
Daniel J. DeNoon, Senior Editor

The finding, reported by University of Southern California researcher Angeline Douvas and colleagues, could be of great importance in the development of an HIV vaccine.

It also hints that an unknown retrovirus may play a role in the autoimmune syndrome known as mixed connective tissue disease (MCTD).

"The current findings provide further evidence that individuals unexposed to HIV-1 may develop immunologic resistance by alternative mechanisms, possibly including molecular mimicry or exposure to as-yet-unidentified retroviruses," Douvas et al. wrote in the journal AIDS Research and Human Retroviruses ("Neutralization of HIV Type 1 Infectivity by Serum Antibodies from a Subset of Autoimmune Patients with Mixed Connective Tissue Disease," AIDS Res Hum Retrovirus, 1996;12(16):1509-17).

Another, unexpected finding reported by Douvas et al. is that the anti-IgG immunoglobulin known as rheumatoid factor, or RF, was found in all of the MCTD sera that neutralized HIV. RF was detected in less than 30 percent of MCTD sera.

RF can be found in the sera of patients with rheumatic disorders, as well as in patients with chronic bacterial, parasitic, and viral infections. In viral infections, RF can cause antibodies to form infectious, rather than neutralized, immune complexes with the virus. But additional RF makes these complexes highly vulnerable to neutralization in vitro.

"One therapeutic implication is that RF may enhance the neutralizing potency of antibodies used in passive immunotherapy," Douvas et al. proposed. "High titers of circulating RF early in infection may also absorb and prevent immune complexes carrying infectious virions from seeding lymph nodes. Alternative strategies for reducing sequestration of virus in lymph nodes may include the use of RF-blocking agents."

Douvas et al. noted that MCTD is characterized by autoantibodies that attack important nuclear regulatory molecules. These include the U1-U6 small nuclear ribonucleoprotein (snRNP) splicing complexes.

MCTD patients exhibit symptoms common to systemic lupus erythematosus (SLE), scleroderma, and polymyositis. They also exhibit immune dysfunction as well as a number of symptoms seen in patients with HIV disease: arthritis, lymphadenopathy, vasculitis, myositis, and Sjogren's syndrome.

The distinctive antiself antibody seen in MCTD is the anti-RNP antibody specific for the U1 snRNP particle. Because the HIV-1 gp120/gp41 complex is homologous to the 70K protein of U1 snRNP, anti-RNP antibodies cross-react with HIV-1 surface proteins.

Douvas et al. noted that a key 70K epitope is homologous to a dominant B- and T-cell epitope in the third variable (V3) loop of HIV-1 gp120. They therefore tested the ability of anti-RNP sera to inhibit in vitro HIV-1 infection.

"Of nine sera tested, five were 70-99 percent effective in neutralizing one or more HIV-1 strains," they reported. "One serum was >99 percent effective in neutralizing HIV-1[MN], and 86 and 77 percent effective against the primary isolates HIV- 1CO and HIV-1[JR-FL], respectively."

When tested against the HIV-1[JR-FL] clinical isolate, the mean neutralizing activity of the anti-RNP sera was 3.9 times greater than that of the commercial pooled neutralizing sera from HIV(+) donors (HIVIG, North American Biologicals Inc., Miami, Florida) used in passive immunotherapy of HIV infection.

Preliminary studies of T-cell cross-reactivity showed that peripheral blood mononuclear cells (PBMCs) from four of eight MCTD patients proliferated in response to gp120, while PBMCs from 14 of 18 patients with HIV-1 infection proliferated in response to 70K.

"Thus MCTD, which involves both B- and T-cell reactivity to self epitopes homologous to HIV-1, may elucidate new strategies for generating protective immunity to this virus," Douvas et al. concluded.

The corresponding author for this study is Angeline Douvas, Division of Hematology/Oncology, Department of Medicine, University of Southern California, 2011 Zonal Avenue, HMR-711, Los Angeles, California 90033.

This study was supported in part by the Plum Foundation.

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