mRNA-based vaccine technology for HIV

Abstract

Human immunodeficiency virus (HIV) poses a major health problem around the globe, resulting in hundred-thousands of deaths from AIDS and over a million new infections annually. Although the standard treatment of HIV infection, antiretroviral therapy, has proven effective in preventing HIV transmission, it is unsuitable for worldwide use due to its substantial costs and frequent adverse effects. Besides promoting HIV/AIDS awareness through education, there is hardly an alternative for inhibiting the spread of the disease. One promising approach is the development of an HIV vaccine. Unfortunately, the high variability of envelope proteins from HIV subtypes, their frequency of mutation and the lack of fully understanding the mechanisms of protection against the virus constitute an obstacle for vaccine development. Efforts for developing successful anti-HIV vaccines have been underway for decades now, with little success. Lately, significant progress has been made in adopting the novel mRNA vaccine approach as an anti-HIV strategy. mRNA vaccines received a great thrust during the COVID-19 pandemic. Now, several mRNA-based HIV vaccines are undergoing clinical trials to evaluate their safety and efficacy. This review offers an overview of the pathogenesis and treatment of HIV / AIDS, previous efforts of HIV vaccine development and introduces mRNA vaccines as a promising and potential game changing platform for HIV vaccination.

Keywords: AIDS; HIV; antiretroviral therapy; bNAbs; mRNA.; vaccine.

Figure 1. HIV structure

HIV contains an RNA genome and the enzymes reverse transcriptase, integrase and HIV protease, that are all surrounded by a capsid, matrix proteins and an envelope. Acquired from Alamy (alamy.de website).

Figure 2. HIV replication cycle

After attaching its g120 to the CD4+ receptor and chemokine coreceptor of a host cell (1), viral entry and uncoating takes place (2). The viral enzyme reverse transcriptase turns the viral RNA genome into a cDNA strand (3) which can enter the nucleus in order to be integrated into the DNA-genome of the host cell by action of the viral enzyme integrase (4). Now, biosynthesis of the viral genome can take place creating HIV-RNA strands and viral proteins that can assemble (5) and leave the cell by budding (6) in a next step. Acquired from istockphoto.com.

Figure 3. The course of HIV infection

The diagram shows the changes of CD4 cell count (red) and plasma viral load (blue, amount of HIV detectable in blood) per milliliter in the course of HIV disease. Three stages can be distinguished. 1. The acute phase starts with the eclipse phase, where the virus cannot yet be detected. After this threshold is surpassed, characteristics of this phase are a peak in plasma viral load, while CD4+ cell numbers drop and then partially recover. 2. In the asymptomatic phase, the body relatively manages to keep a set point of viral load with ongoing immune reactions and CD4+ cell depletion. 3. The terminal phase, also called AIDS, is defined by a CD4+ cell drop below 200 cells per µL blood, clinical symptoms become apparent and opportunistic infections lead to a fatal outcome. Reproduced from the reference(distributed under the “Creative Commons CC0 License”)

Figure 4. Epitopes for bNAbs on the HIV-1 envelope glycoprotein Env

The picture shows the most common epitopes on the surface of an Env trimer, that are recognized by different bNAb classes which are specified in the boxes on the right. The CD4-binding site is marked red, V1/V2 blue, V3/Asn322 glycan patch green, gp120/gp41-interface brown and Membrane Proximal External Region (MPER) is represented by the dark grey box. Other surface areas of Env are colored in grey: light grey representing parts belonging to gp120, and dark grey representing parts belonging to gp41. Adapted from the references(distributed under the “Creative Commons Attribution (CC-BY) license”).

Figure 5. Working mechanism of mRNA-based vaccines

An mRNA strand encoding the viral antigen is delivered in a LNP to facilitate cellular uptake. One inside the cell, the mRNA gets translated by the host cell’s replication machinery, so the viral protein the mRNA codes for gets produced. The viral antigen can then be displayed on MHC proteins on the cellular surface or can get secreted into the extracellular matrix, where the viral antigen is accessible for recognition by immune cells. An immune response is generated. Acquired from istockphoto.com.