Abstract
BackgroundAny strategy for curing HIV infection must include a method to eliminate viral-infected cells. Based on our earlier proof-of-principle results targeting HIV-1 infected cells with radiolabeled antibody (mAb) to gp41 viral antigen, we embarked on identifying a suitable candidate mAb for preclinical development.Methodology/Principal FindingsAmong the several human mAbs to gp41 tested, mAb 2556 was found to have high affinity, reactivity with multimeric forms of gp41 present on both the surface of virus particles and cells expressing HIV-1 Env, and recognition of a highly conserved epitope of gp41 shared by all HIV-1 subtypes. Also, mAb 2556 was the best in competition with HIV-1+ serum antibodies, which is an extremely important consideration for efficacy in the treatment of HIV patients. When radiolabeled with alpha-emitting radionuclide 213-Bismuth (213Bi) - 213Bi-2556 efficiently and specifically killed ACH-2 human lymphocytes chronically infected with HIV-1, and HIV-1 infected human peripheral blood mononuclear cells (hPBMCs). The number of binding sites for 213Bi-2556 on the surface of the infected cells was >106. The in vivo experiments were performed in two HIV-1 mouse models – splenic and intraperitoneal. In both models, the decrease in HIV-1 infected hPBMCs from the spleens and peritoneum, respectively, was dose-dependent with the most pronounced killing of hPBMCs observed in the 100 µCi 213Bi-2556 group (P = 0.01). Measurement of the blood platelet counts and gross pathology of the treated mice demonstrated the lack of toxicity for 213Bi-2556.Conclusions/SignificanceWe describe the preclinical development of a novel radiolabeled mAb reagent that could potentially be part of an HIV eradication strategy that is ready for translation into the clinic as the next step in its development. As viral antigens are very different from “self” human antigens - this approach promises high selectivity, increased efficacy and low toxicity, especially in comparison to immunotoxins.
Highlights
Any strategy for curing HIV infection must include a method to eliminate viral-infected cells
Based on our encouraging proof-of-principle results targeting HIV-1 infected cells in vitro and in vivo with radiolabeled monoclonal antibodies (mAbs) 246D to gp41 viral antigen [14], we embarked on identifying the best candidate mAb for a preclinical development
The best mAb to use for RIT is a mAb that binds to the immunodominant domain of gp41 which is displayed on infected cells
Summary
Any strategy for curing HIV infection must include a method to eliminate viral-infected cells This basic fact has been recognized for almost two decades. Despite the success of HAART (highly active antiretroviral therapy) in effectively reducing the viral burden of HIV to essentially undetectable levels, the occurrence of viral blips and the rebound of virus levels upon cessation of treatment suggests a long-lived reservoir of latently infected cells [1,2]. HIV-1 latency is believed to represent a major obstacle to achieving a curative AIDS therapy. This becomes even more paramount as the HIV/AIDS population ages due to the success of HAART. Based on our earlier proof-of-principle results targeting HIV-1 infected cells with radiolabeled antibody (mAb) to gp viral antigen, we embarked on identifying a suitable candidate mAb for preclinical development
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