Broadly neutralizing antibodies for HIV prevention: a comprehensive review and future perspectives

Abstract

SUMMARYThe human immunodeficiency virus (HIV) epidemic remains a formidable global health concern, with 39 million people living with the virus and 1.3 million new infections reported in 2022. Despite anti-retroviral therapy's effectiveness in pre-exposure prophylaxis, its global adoption is limited. Broadly neutralizing antibodies (bNAbs) offer an alternative strategy for HIV prevention through passive immunization. Historically, passive immunization has been efficacious in the treatment of various diseases ranging from oncology to infectious diseases. Early clinical trials suggest bNAbs are safe, tolerable, and capable of reducing HIV RNA levels. Although challenges such as bNAb resistance have been noted in phase I trials, ongoing research aims to assess the additive or synergistic benefits of combining multiple bNAbs. Researchers are exploring bispecific and trispecific antibodies, and fragment crystallizable region modifications to augment antibody efficacy and half-life. Moreover, the potential of other antibody isotypes like IgG3 and IgA is under investigation. While promising, the application of bNAbs faces economic and logistical barriers. High manufacturing costs, particularly in resource-limited settings, and logistical challenges like cold-chain requirements pose obstacles. Preliminary studies suggest cost-effectiveness, although this is contingent on various factors like efficacy and distribution. Technological advancements and strategic partnerships may mitigate some challenges, but issues like molecular aggregation remain. The World Health Organization has provided preferred product characteristics for bNAbs, focusing on optimizing their efficacy, safety, and accessibility. The integration of bNAbs in HIV prophylaxis necessitates a multi-faceted approach, considering economic, logistical, and scientific variables. This review comprehensively covers the historical context, current advancements, and future avenues of bNAbs in HIV prevention.

Keywords: HIV; broadly neutralizing antibodies; monoclonal antibodies; prevention.

Fig 1

(A) During the course of infection, the majority of individuals mount a vigorous strain-specific neutralizing immune response; however, only a select fraction progress to generate bNAbs. The development of bNAbs is influenced by a variety of factors, including the presence of non-functional envelope forms and the shedding of gp120, which serve as viral evasion mechanisms. (B) Non-neutralizing antibodies (nnAbs) are antibodies that can bind to viral particles or infected cells but do not exhibit the ability to neutralize the infectivity of the virus. While they may participate in other effector functions like antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis, they are not capable of inhibiting viral entry into host cells. Neutralizing antibodies (nAbs), on the other hand, are capable of directly inhibiting viral infection, typically by binding to specific epitopes on the viral envelope proteins, thereby preventing the virus from entering host cells. bNAbs are a specialized subset of nAbs that can neutralize multiple strains or subtypes of a virus. During the viral replication cycle, various forms of envelope proteins may be produced. Some of these, referred to as non-functional rearranged envelopes, do not facilitate viral entry into host cells and can serve as decoys that distract the immune system. The gp41 stump is a truncated form of the gp41 envelope protein, which is also non-functional in terms of facilitating viral entry but may still be immunogenic. These truncated or rearranged forms can divert the immune response away from generating bNAbs. The HIV-1 envelope spike is a trimer consisting of three gp120 and three gp41 molecules. The shedding of gp120 refers to the dissociation of gp120 from the viral envelope, leaving behind the gp41 protein. This shedding can serve as another evasion mechanism, as it can modulate the surface of the virus and make it more difficult for antibodies to effectively neutralize the virus. The functional envelope (Env) trimer, consisting of three gp120 and three gp41 subunits in a closely packed configuration, is the primary target for neutralizing antibodies, including bNAbs. This trimer undergoes conformational changes to facilitate the fusion of the viral membrane with the host cell membrane, thereby enabling viral entry. bNAbs often target highly conserved regions on this functional Env trimer to neutralize a broad range of viral strains. (C) HIV Env epitopes. bNAbs targeting the major Env epitopes are the V3 glycan, V1V2 glycan, CD4 binding site; fusion peptide, gp41 membrane proximal region (MPER), gp120–41 interface.

Fig 2

Anti-HIV bNAbs and their conserved sites. ^This figure outlines some of the more prominent bNAbs targeting each epitope but is not an exhaustive list. Please refer to publications that provide more in-depth listing of individual bNAbs that have been characterized (12–16, 21, 22). Text in red describes the location of the target site. bNAbs in current clinical development are highlighted in bold blue. #“J” mutations are inserted between the complementarity-determining regions to improve both stability and manufacturability. *Derived from PGT121, contains mutations to increase antibody-dependent cellular cytotoxicity.

Fig 3

Antibody structure. (A) bNAbs predominantly adhere to the classical immunoglobulin structure, consisting of two heavy chains and two light chains arranged in a “Y” shape. The fragment antigen-binding (Fab) regions, at the arms of the Y, contain the variable domains of both the heavy and light chains, which confer the antigen-binding specificity. The fragment crystallizable (Fc) region forms the stem of the Y and is responsible for engaging effector functions through interactions with Fc receptors on immune cells. (B) Bispecific antibodies are engineered molecules designed to simultaneously bind to two different epitopes or antigens. There are several formats for bispecific antibodies, but a common design features two different Fab arms attached to a single Fc region. The Fab of one of the two bNAbs is engineered in a cross-Fab fashion before combining with another bNAb. Each Fab arm is engineered to recognize a different antigen, enabling the antibody to bridge two distinct molecular targets. (C) Trispecific antibodies take the concept of bispecific antibodies a step further by possessing the ability to bind to three different epitopes or antigens. The trispecific bNAb combines three Fabs. These are complex, multi-domain molecules, and their structures can vary. One common design includes an Fc region with three different Fab arms extending from it. Each Fab arm contains a unique variable region, allowing the antibody to interact with three different targets simultaneously.

Fig 4

Effector functions. Antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent phagocytosis (ADP), and complement-dependent cytotoxicity (CDC) represent three distinct yet interrelated mechanisms that function to enhance the immune system’s capacity to identify and eliminate pathogenic or aberrant cells. ADCC is facilitated predominantly through the interaction between the Fc portion of antibodies and Fc receptors found on the surface of effector cells, macrophages, and natural killer (NK) cells. Upon antibody binding to a target antigen on a pathogenic or aberrant cell, Fc receptors on NK cells engage with the Fc region of the antibody, triggering a signaling cascade that results in the release of cytotoxic granules from the NK cell. These granules contain perforin and granzymes that induce apoptosis in the target cell, thus effectuating its elimination. ADP operates through a similar mechanism involving Fc receptors, but the primary effector cells are phagocytes, including macrophages, monocytes, and granulocytes. Here, the binding of antibodies to the target cell facilitates its engulfment and subsequent degradation within the phagocyte. Unlike ADCC, which involves the extracellular release of cytotoxic molecules, ADP accomplishes target cell elimination via internalization and lysosomal degradation. CDC, on the other hand, does not rely on cellular effector mechanisms but instead utilizes a series of serum proteins known as complements. Following antibody attachment to an antigenic target on a cell, the complement cascade is activated, culminating in the formation of the membrane attack complex (MAC). This complex disrupts the target cell membrane, leading to cell lysis. While ADCC and ADP utilize cellular effector mechanisms that depend on Fc receptor-mediated interactions, CDC employs a non-cellular approach, leveraging the complement system to achieve targeted cell lysis. Each of these pathways offers a unique strategy for the immune system to neutralize and remove cells that are pathogenic or display aberrant behavior, thereby contributing to the maintenance of physiological homeostasis.

Fig 5

Applying artificial intelligence (AI) and deep learning to novel research and design of bNAbs in silico. Shown are current in silico research and design projects that use AI and deep learning algorithms to develop potential new bNAbs. The interplay between bNAbs and advancements in AI and computational techniques presents a burgeoning area of research with transformative potential for immunology and infectious disease management. AI and computational techniques have significantly accelerated the discovery, optimization, and characterization of bNAbs. Machine learning algorithms can sift through vast data sets to identify probable bNAb candidates, perform in silico mutagenesis to enhance their potency, and predict their pharmacokinetic and pharmacodynamic profiles. Molecular dynamics simulations offer insights into the binding kinetics between bNAbs and their target epitopes, facilitating rational design and optimization. Moreover, AI-driven analytics can integrate multi-omic data to uncover novel biological pathways and mechanisms underlying the generation and function of bNAbs, enabling a deeper understanding of host-virus interactions and immune responses. Computational models can also simulate the evolutionary trajectories of both viruses and antibodies, providing valuable information for the design of bNAbs that can neutralize emerging viral variants. [Projects include AlphaFold (329, 330), DeepSequence (331), optimal bNab design with Intefer Programming (332, 333), GlycoMinestruct (334, 335), and system serology with regularized random forests (336)].