Biotech Values

[jazzbeerman]

follow up- new Duke study/search:

They've actually recently started looking for more potential broadly neutralizing HIV antibodies in folks with autoimmune disease, as described here-

http://htc.medicine.duke.edu/modules/trials/index.php?id=13

1. Purpose of the study- This is a cross-sectional study that analyzes the sera of subjects in order to answer two clinical questions. First, we will assay the antibody profiles of subjects with autoimmune diseases to determine if there is cross-reactivity with the HIV epitopes 2G12, 1b12, 2F5 and 4E10, in addition to analyzing B and T cells to assess patterns that contribute to autoimmunity and autoantibody reactivity. The second goal of the study is to assess the prevalence of HIV infection in a cross-sectional cohort of subjects with autoimmune disease.

2. Background & significance – After twenty years of study, the HIV epidemic continues to rage world-wide. Now over 40 million people are infected and an estimated 100 million will be infected by the year 2010 (1). A safe and effective HIV vaccine is desperately needed. HIV vaccines have proven extremely difficult to develop. One of the most urgent problems to solve is to induce antibodies that broadly neutralize HIV of all subtypes. To date, 4 human monoclonal antibodies that broadly neutralize HIV, termed 2G12, 1b12, 2F5 and 4E10, have been made from HIV infected subjects (2-4). Anti-2G12 targets a carbohydrate determinate on HIV envelope protein gp120. Anti-1b12 binds to an epitope on the CD4 binding site, and anti-2F5 and anti-4E10 recognize membrane-proximal epitopes of the envelope protein gp41 near the surface of the virion.

A conundrum has developed with the observation that while multiple envelope immunogens express these epitopes on the surface of the envelope trimer, after injection into animals or man, the epitopes are not immunogenic. Moreover, most patients who are infected with HIV do not routinely make antibodies to these targets. Thus a major effort is to learn how to induce broadly reactive neutralizing antibodies against HIV by immunizing with these epitopes.

Recently we have turned our studies to examine abnormalities in the host that may prevent a robust humoral immune response to these conserved HIV epitopes. We have speculated that a critical host factor could be that the 2G12, 1b12, 2F5 and 4E10 epitopes are also self-antigens. Consequently, if host B cells generate antibodies against these HIV epitopes, they are immediately deleted because the antibodies are autoreactive. Supporting evidence for this hypothesis from our group has shown that antibodies raised against 1b12, 2F5 and 4E10 have potent cross-reactivity for autoantigens including double stranded DNA, Ro, phospholipids, centromere B, topoisomerase and histones.

The association between autoimmune disease and infection with human immunodeficiency virus (HIV) has evolved over the past two decades. Initial observations described spontaneous improvement in conditions including systemic lupus erythematosus (SLE) in patients that developed AIDS as a consequence of HIV infection. Since the advent of highly-effective anti-retroviral therapy, new-onset autoimmune diseases or relapse of previous autoimmune diagnoses have been observed after recovery of CD4+ T cell counts. Although it is consistent with the known pathophysiology of autoimmune disease that a reduction in immune function, whether by therapeutic intervention or retroviral infection, should decrease disease activity, little has been reported on the overall prevalence of HIV infection in patients with autoimmunity. In fact, relatively few cases of systemic lupus erythematosus, the prototypical systemic autoimmune syndrome, have been described in the literature. Moreover, there are no reports of HIV prevalence among cohorts of subjects with defined autoimmune disease. More recently, the sense has grown that subjects with autoimmune disease experience less HIV burden than would be expected of the general population.

These clinical and laboratory observations have led to an exciting postulate that perhaps patients with autoimmune disease are protected from HIV infection due to their intrinsic loss of self-tolerance. Whatever the defect in central and/or peripheral tolerance that leads to the emergence of autoimmune disease may also permit these patients to generate neutralizing (auto-)antibodies against the HIV epitopes described above. To investigate this proposition, we plan to assess for the prevalence of HIV infection in the cohort of autoimmune disease-afflicted patients cared for in the Duke Rheumatology Clinic (particularly, the Duke Lupus Clinic and Duke Scleroderma Research Center). In addition, we will examine the reactivity of sera from subjects with autoimmune diseases including SLE, systemic sclerosis, Antiphospholipid antibody syndrome, and Sjogren’s syndrome. Serum reactivity will be analyzed for a broad panel of autoantigens (centromere, topoisomerase, extractable nuclear antigens (Smith, ribonucleoprotein, Ro, and La), double-stranded DNA, cardiolipin (phospholipids), histones) and the HIV epitopes (2G12, 1b12, 2F5 and 4E10). In addition, all subjects will be tested for HIV infection with HIV PCR. These results will be compared with those obtained from a healthy control group (n=100). As part of the protocol, separated B cells will be sent to Dr. James Robinson of Tulane University for manufacture of hybridomas. This technique will generate B cells that make antibodies targeting various HIV envelope antigens. Dr. Robinson will use the hybridomas to sequence interesting B cell DNA for analysis of immunoglobulin gene structure.




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