Immunoinformatic-driven design and evaluation of multi-epitope mRNA vaccine targeting HIV-1 gp120

Muhammad Zeeshan Ahmed^1,2Tazeen Rao³Zeeshan Mutahir²Sarfraz Ahmed⁴Najeeb Ullah^3*Suvash Chandra Ojha^5*

• ¹Department of Biochemistry, Bahauddin Zakariya University, Multan, Pakistan
• ²School of Biochemistry and Biotechnology, University of the Punjab Lahore Pakistan, Lahore, Pakistan
• ³Department of Biochemistry, Bahauddin Zakariya University, Multan 60800, Pakistan, Multan, Punjab, Pakistan
• ⁴Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
• ⁵Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China, Luzhou, Sichuan Province, China

HIV presents a global health crisis, causing significant AIDS-related deaths and over one million new infections annually. The curbing of HIV is an intricate and continuously evolving domain, marked by numerous challenges, including drug resistance and the absence of a significant cure or vaccine because of its mutating ability and diverse antigens in its envelope, prompting research for functional cures and long-term remission strategies. The endeavor to devise an HIV vaccine capable of eliciting robust and broadly cross-reactive humoral and cellular immune responses is a formidable undertaking, primarily due to the pronounced genetic heterogeneity of HIV-1, the variances observed in virus subtypes (clades) across distinct geographic regions, and the polymorphic nature of HLA. The viral envelope protein (gp120) selectively interacts with CD4 and chemokine receptors on the surface of target cells. It serves as the key initiator in the intricate viral entry into host cells, rendering it a compelling candidate for vaccine development. This study used bioinformatic tools to design a safe, hypoallergenic, and non-toxic mRNA HIV-1 vaccine by assembling immunogenic B-and T-cell epitopes from the gp120 protein.We identified antigenic, non-toxic, and non-allergic B-cell epitopes and T-cell epitopes. For designing the mRNA vaccine against HIV-1 gp120, we assembled the epitopes with 5′ m7G cap, 5′ UTR, Kozak sequence, signal peptide, RpfE adjuvant at N-terminal and MITD adjuvant, stop codon, 3′ UTR, and 120-nucleotide long poly(A) tail at the C-terminal with immunogenic robustness linkers. The mRNA vaccine is translated into a protein-based vaccine by the host body's ribosomes. Their comprehensive computational findings, including physicochemical, structural, and 3D refinement analyses, substantiated the stability and quality of the translated vaccine. Molecular docking and simulation revealed a strong and stable binding affinity of vaccine immunization with immune cells' pattern recognition receptors (TLR4). Immune simulations demonstrated a potent primary immune response characterized by gradual increase in immunoglobulins and a corresponding decline in antigen concentration. This bioinformatics-driven study presents a promising HIV-1 mRNA vaccine candidate, underscoring the need for further experimental validation through preclinical and clinical trials. At the same time, its methodologies hold the potential for addressing other challenging infectious diseases, thereby impacting vaccinology broadly.