Study of the protective efficacy of CombiMab-2 against human immunodeficiency virus type 1 in mice humanised with CD4⁺ T-lymphocytes

Abstract

INTRODUCTION. Despite existing treatment methods, complete eradication of human immunodeficiency virus (HIV) infection remains an unattainable goal due to the high variability of HIV type 1 (HIV-1). HIV infection necessitates life-long administration of antiretroviral medicinal products, which cause serious adverse drug reactions. The development of gene therapy products based on adeno-associated virus (AAV) vectors encoding broadly neutralising antibodies represents a promising direction for creating long-term therapies capable of countering a wide range of viral variants.AIM. This study aimed to evaluate the protective efficacy of CombiMab-2, a medicinal product consisting of a combination of three AAV vectors (AAV9-VRC07-523, AAV9-10-1074, and AAV9-PGDM1400) encoding broadly neutralising antibodies against HIV-1, in a humanised mouse model.MATERIALS AND METHODS. The study used an HIV infection model based on immunodeficient B-NDG mice humanised with human CD4+ lymphocytes (1.5×107 cells per animal) from a leukoconcentrate of a healthy donor. The experiment used two groups of mice, including a control group (3 animals) receiving saline solution and an experimental group (5 animals) receiving CombiMab-2. The medicinal product was administered into different muscles as three separate components six weeks prior to infection. The CCR5-tropic HIV-1 strain was obtained by transfecting HEK293FT cells with the pNL4-3(AD8) plasmid encoding the full-length virus. The authors monitored viral loads in the plasma of animals by reverse transcription polymerase chain reaction and CD4+ lymphocyte counts in the peripheral blood of animals by flow cytometry for four weeks after infection.RESULTS. Six weeks after CombiMab-2 administration, the levels of broadly neutralising antibodies in the serum of humanised mice ranged from 0.17 μg/mL to 4.0 μg/mL. In the control group, the viral load reached 105 copies/mL one week after HIV-1 infection and continued to rise over the next three weeks. In the treatment group, infection developed only in one mouse, which had the lowest antibody titre before infection. No viral load was detected in the remaining mice of the treatment group, which indicated that the medicinal product was effective if serum concentrations of broadly neutralising antibodies reached 0.5 μg/mL or higher.CONCLUSIONS. The tested medicinal product based on three AAV vectors (AAV9-VRC07-523, AAV9-10-1074, and AAV9-PGDM1400) exhibits protective activity against HIV-1 in humanised mice. The presented data allow the authors to consider CombiMab-2 as a promising antiviral agent that can serve as a basis for further pharmaceutical development.

Keywords

• humanised mice
• human immunodeficiency virus type 1
• hiv-1
• cd4+ t-lymphocytes
• adenoassociated virus
• aav vector
• gene therapy
• broadly neutralising antibodies
• protective efficacy
• antiviral activity