Review of Current Cell-Penetrating Antibody Developments for HIV-1 Therapy

Abstract

The discovery of highly active antiretroviral therapy (HAART) in 1996 has significantly reduced the global mortality and morbidity caused by the acquired immunodeficiency syndrome (AIDS). However, the therapeutic strategy of HAART that targets multiple viral proteins may render off-target toxicity and more importantly results in drug-resistant escape mutants. These have been the main challenges for HAART and refinement of this therapeutic strategy is urgently needed. Antibody-mediated treatments are emerging therapeutic modalities for various diseases. Most therapeutic antibodies have been approved by Food and Drug Administration (FDA) mainly for targeting cancers. Previous studies have also demonstrated the promising effect of therapeutic antibodies against HIV-1, but there are several limitations in this therapy, particularly when the viral targets are intracellular proteins. The conventional antibodies do not cross the cell membrane, hence, the pathogenic intracellular proteins cannot be targeted with this classical therapeutic approach. Over the years, the advancement of antibody engineering has permitted the therapeutic antibodies to comprehensively target both extra- and intra-cellular proteins in various infections and diseases. This review aims to update on the current progress in the development of antibody-based treatment against intracellular targets in HIV-1 infection. We also attempt to highlight the challenges and limitations in the development of antibody-based therapeutic modalities against HIV-1.

Antibody Structure and Function: The Basis for Engineering Therapeutics

“…Because naturally occurring Abs are optimized to be secreted from the cell, intrabodies require special alterations, including: The use of single-chain antibodies (scFvs); modification of immunoglobulin VL domains for hyperstability [597]; selection of antibodies resistant to the more reducing intracellular environment [598]; expression as a fusion protein stable as intracellular proteins [599]; or the use of virus-like particles [600]. Several preclinical studies have demonstrated favorable results, including tumor growth inhibition and downregulation of viral envelope proteins, when such therapy candidates were used against inflammation [601], HIV [602], and hepatitis [603,604], respectively. The major challenge associated with these molecules is the absence of effective in vivo methods that can deliver the genetic material encoding the intrabody to live target cells [605].…”

Beyond bNAbs: Uses, Risks, and Opportunities for Therapeutic Application of Non-Neutralising Antibodies in Viral Infection

“…As many viruses, such as HIV and influenza virus, also increase cell membrane permeability, scFv and transbody-based intracellular therapy strategies could possibly be developed for these infections [ 38 ]. The landscape of potential cell-penetrating antibody therapies in HIV has already been reviewed, with multiple potential viral targets across different stages of the viral lifecycle [ 41 ]. These include integration, targeting integrase by sFv-IN, or translation and assembly with scFvs or single domain antibodies against viral components Tat, Nef, Rev and Vif, as well as p24, all developed [ 41 ].…”

“…The landscape of potential cell-penetrating antibody therapies in HIV has already been reviewed, with multiple potential viral targets across different stages of the viral lifecycle [ 41 ]. These include integration, targeting integrase by sFv-IN, or translation and assembly with scFvs or single domain antibodies against viral components Tat, Nef, Rev and Vif, as well as p24, all developed [ 41 ]. Such cell-penetrating antibodies appear more effective than small molecule inhibitors.…”

Antibody-Mediated Therapy against HIV/AIDS: Where Are We Standing Now?

“…To solve this problem, conventional antibodies can be conjugated with cell penetrating peptides (CPPs) derived from various sources to enter the cell cytoplasm [ 88 ]. Antibodies in smaller format such as Fabs, scFvs, and sdAbs (with Fc removal) have also been constructed for this purpose [ 57 , 89 , 90 ]. These antibodies have targeted various intracellular proteins including capsid [ 91 ], integrase [ 92 ], and other accessory proteins such as Nef [ 93 ], Vif [ 94 ], Tat [ 95 ], and Rev [ 96 ].…”