Aug 2026· Biomolecules· Vol 16, pp. 1221· 0 citations· 178 references
TL;DR
This review highlights promising protein-based HIV entry inhibitors that have demonstrated efficacy in preclinical studies, and discusses ongoing efforts to optimize their valency, avidity, specificity, serum half-life, effector functions, and production platforms to improve their therapeutic potential and economic feasibility.
Abstract
Human immunodeficiency virus (HIV) is an enveloped virus with a remarkable capacity for genetic diversification, enabling rapid escape from host immune responses and therapeutic interventions. Despite extensive global efforts, the development of an effective vaccine has remained elusive owing to the virus’s high genetic variability and antigenic diversity. Consequently, considerable effort has been directed toward the development of therapeutic agents targeting viral entry, reverse transcriptase, integrase, protease, and more recently, capsid. Although antiretroviral therapy (ART) remains the cornerstone of HIV treatment, it is associated with challenges including drug resistance, adverse side effects, and limitations in access and affordability. Targeting viral entry offers distinct advantages by blocking infection at the earliest stage of the viral life cycle and enabling the neutralization of free virions, as well as Fc-mediated elimination of HIV-infected cells in some cases. This review highlights promising protein-based HIV entry inhibitors that have demonstrated efficacy in preclinical studies, and discusses ongoing efforts to optimize their valency, avidity, specificity, serum half-life, effector functions, and production platforms to improve their therapeutic potential and economic feasibility.
Antiretroviral therapy (ART) has proven effective in suppressing HIV-1 replication, but further development of HIV-1 inhibitors is continually driven by the challenge of drug resistance and viral adaptation. The HIV-1 capsid is a promising target for treatment due to its high sequence conservation as well as its crucial role in the viral life cycle. Recently, we have developed a novel capsid-targeting biologic that prevents HIV-1 replication by efficient degradation of newly synthesized capsid. Here, we have investigated the sensitivity to viral escape as well as the breadth of this biologic against HIV-1 subtypes. The capsid-targeting biologic efficiently blocked replication of different primary HIV-1 isolates, and continuous exposure of these viruses to the biologic resulted in viral breakthrough of two out of ten primary HIV-1 isolates tested. Notably, the breakthrough variants did not have amino acid changes in the nanobody epitope but primarily in the matrix region. The breakthrough variants remained sensitive to the biologic albeit to a lesser extent. In the absence of the biologic, breakthrough variants showed increased replication kinetics when compared to their parental virus, suggesting that adaption to the biologic is likely due to the increased viral production and that the target area of the biologic is too conserved for actual escape. This is further underscored by the broad specificity of the biologic as importantly the biologic blocked infection of different HIV-1 subtypes that occur worldwide (A, B, C, D, CRF01_AE, CRF02_AG). These results demonstrate the broad neutralization potential of anti-capsid biologics with a high barrier to resistance, making capsid-targeting inhibitors important for novel antiretroviral drug strategies worldwide.
F. M. Stel, E. Zijlstra-Willems, Ad C. van Nuenen et al.· International Journal of Mol...· 0 citations
Human immunodeficiency virus type 1 remains a major global health challenge, with persistent transmission despite advances in antiretroviral therapy and preventive interventions. The viral envelope glycoproteins gp120 and gp41, organized as trimeric spikes on the virion surface, mediated host cell entry and represented the principal targets of neutralizing antibodies; however, extensive glycan shielding, conformational masking, and genetic variability historically hindered vaccine development. The purpose of this review was to critically evaluate current progress in mRNA vaccine platforms encoding HIV 1 envelope glycoproteins and to examine their potential to overcome longstanding immunological barriers. A structured narrative synthesis of recent preclinical and early clinical studies, integrated with advances in structural biology and molecular engineering, was undertaken to assess emerging evidence. Accumulating data indicated that mRNA platforms permitted precise encoding of stabilized envelope trimers, germline targeting constructs, and mosaic immunogens, resulting in improved antigen expression and enhanced induction of neutralizing antibody precursors in animal models and early human trials. Nevertheless, induction of broadly neutralizing antibodies with sufficient breadth and durability remained elusive. mRNA-based approaches provided unprecedented flexibility and translational promise for HIV vaccine design, yet required iterative immunogen optimization and rigorous clinical evaluation to achieve meaningful protective efficacy.
Keywords: HIV 1, mRNA vaccine, Envelope glycoprotein, Broadly neutralizing antibodies, Structural vaccinology.
Unknown authors· IDOSR Journal of Scientific...· 0 citations
Herpes simplex virus (HSV) remains a pervasive global health concern and has the ability to challenge current therapeutic strategies because of its frequent recurrence and drug resistance. This research aimed to disrupt the critical interaction between the viral glycoprotein gD and the host cell receptor of herpes simplex virus, thereby blocking viral infection as a novel antiviral approach. An HVEM-derived native peptide NP (KEACGELTGTVCEP) targeting HSV was rationally designed, with no cytotoxicity and approximately 50% antiviral protection in vitro. Through computational residue scanning, docking and molecular dynamic simulation, seven modified variations of peptides were created to increase the potency and stability, which revealed that the modified peptide F4 with improved binding affinity docking. In vitro tests indicated its dose-dependent antiviral activity, and 60.58% protection at 250 µg/ml was achieved without toxicity. Although relatively less effective than Acyclovir, F4 (RQACGELTGTVCEP) has promising therapeutic potential. This integrated approach highlights the viability of Optimized HVEM-derived peptides as promising candidates with demonstrated antiviral efficacy, offering a strong foundation for future anti-HSV drug development.
Sanskruti Shrenik Patil, R. Garge, Anantha Padmanabha Aithal et al.· Amino Acids· 0 citations
Given its pivotal role in the viral life cycle, blocking integrase (IN) through IN strand transfer inhibitors (INSTIs) represented a breakthrough in the treatment of HIV infection, establishing these antiretroviral regimens as first‐line options against AIDS. However, the onset of drug‐resistant strains has challenged the efficacy of INSTIs, demanding new efforts in the search for therapeutic tools that work through alternative modes of action. In this context, the discovery of allosteric IN inhibitors (ALLINIs) has highlighted new opportunities to target IN beyond its active site, enhancing antiviral efficacy and the genetic barrier to resistance. Extensive drug discovery campaigns have resulted in the development of effective ALLINIs with both in vitro and in vivo efficacy, two of which are advancing in clinical trials as next‐generation therapeutic tools. Nevertheless, advancements in structural biology have critically aided in elucidating the underlying effects of ALLINIs, highlighting a complex, multimodal mode of action that ultimately yields defects in virion maturation. This review focuses on ALLINIs, providing a comprehensive overview of major drug discovery efforts devoted to this field, with an emphasis on the medicinal chemistry and structural biology findings that have revealed unprecedented opportunities for developing innovative and effective anti‐HIV drugs.
Francesco Saccoliti, E. Patacchini, Emanuele Cara et al.· ChemMedChem· 0 citations
The development of effective treatment strategies for human immunodeficiency virus (HIV) infection is a major achievement. Antiretroviral drugs inhibit key steps in the viral replication cycle and consist of six mechanistic classes: HIV entry inhibitors, reverse-transcriptase inhibitors (both nucleosides and nonnucleosides), capsid inhibitors, integrase inhibitors, and protease inhibitors. Antiretroviral therapy (ART) suppresses viral replication, thereby enhancing immune function, decreasing morbidity and mortality, and preventing viral transmission. Consequently, ART is recommended for all persons with HIV infection. On the basis of randomized clinical trials, the Food and Drug Administration has approved 36 antiretroviral drugs for the treatment of HIV infection since 1987; of these, 28 are currently available in the United States, and combination ART regimens are used. Initial preferred ART regimens are potent, convenient, and unlikely to cause side effects and consist of an HIV integrase inhibitor with a high barrier to resistance combined with one or two nucleoside reverse-transcriptase inhibitors. In the majority of patients using current ART regimens, viral replication is durably suppressed below detectable levels. Patients receiving ART are monitored for virologic response over time, and if virologic failure occurs, the next regimen is selected on the basis of treatment history and the results of drug-resistance testing; often, antiretroviral drugs from new classes are administered. Today, the life expectancy of someone with HIV infection who consistently takes ART approaches that of the general population.
Roy M Gulick· New England Journal of Medic...· 3 citations
Human immunodeficiency virus (HIV) infection remains a major global health challenge despite the success of antiretroviral therapy, largely due to the persistence of viral reservoirs and chronic immune dysregulation. Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication during viral infection, operating at the interface between viral and host cellular pathways. Depending on their cellular origin and molecular cargo, EVs can exert context-dependent effects, with studies suggesting roles in both viral dissemination and persistence, as well as in the modulation of antiviral immune responses. This review examines the molecular mechanisms through which EVs have been proposed to contribute to HIV infection, focusing on host-virus interactions, immune regulation, chronic inflammation, and viral latency. We further discuss emerging therapeutic strategies targeting EV biology, including approaches aimed at modulating EV biogenesis and cargo composition, as well as the development of engineered EVs as platforms for drug delivery, gene editing, and immune modulation. Overall, this study highlights the emerging roles of EVs in HIV infection, emphasizing both their potential relevance and the limitations that currently complicate the interpretation of EV-associated effects.
Flora Salzano, Nicoletta Capuano, F. Giordano et al.· FEMS Microbiology Reviews· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
