In the Era of mRNA Vaccines, Is There Any Hope for HIV Functional Cure?

Abstract

Over 36 million people worldwide are infected with HIV. Antiretroviral therapy (ART) has proven to be highly effective to prevent HIV-1 transmission, clinical progression and death. Despite this success, the number of HIV-1 infected individuals continues increasing and ART should be taken for life. Therefore, there are two main priorities: the development of preventive vaccines to protect from HIV acquisition and achieve an efficient control of HIV infection in the absence of ART (functional cure). In this sense, in the last few years, there has been a broad interest in new and innovative approaches such as mRNA-based vaccines. RNA-based immunogens represent a promising alternative to conventional vaccines because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. Some mRNA-based vaccines platforms against infectious diseases have demonstrated encouraging results in animal models and humans. However, their application is still limited because the instability and inefficient in vivo delivery of mRNA. Immunogens, design, immunogenicity, chemical modifications on the molecule or the vaccine delivery methods are all crucial interventions for improvement. In this review we, will present the current knowledge and challenges in this research field. mRNA vaccines hold great promises as part of a combined strategy, for achieving HIV functional cure.

Keywords: HIV; infectious diseases; mRNA; vaccines.

Figure 1

Milestones in RNA vaccines: steps and milestones in the development, application, and clinical use of mRNA-based vaccines. APC, antigen-presenting cell; DC, dendritic cells; NPs; nanoparticles; LNP, lipid nanoparticle; MVA, Modified Vaccinia Ankara. References for each time point: 1 [5], 2 [16], 3 [17], 4 [13], 5 [15], 6 [18], 7 [19], 8 [20].

Figure 2

Types of mRNA vaccines. (1a) conventional or non-replicating (NRM) construct includes an opening frame encoding the gene of interest (GOI), 5′ and 3′ untranslated regions (UTRs), and a terminal poly(A). (1b) The self-amplifying mRNA (SAM) construct encodes replicative components to direct intracellular mRNA self-amplification and abundant protein expression. (2) Both structures required a delivery system, usually by endocytosis, for cellular uptake. Once the vaccine with its carrier is internalized (3), the mRNA is transported through the endosomal route and is released to the cytosol (4). NMR are immediately translated by ribosomes to produce the protein of interest. (5) SAM can also be translated by ribosomes to develop replicase machinery essential for self-amplification. (6) SAM mRNA constructs are translated to produce the protein of interest. (7) The expressed protein is generated in different ways: secreted, trans-membrane, or intracellular. (8) Protein processing for MHC presentation. (9) Peptide-MHC presentation and adaptive and innate immune responses after protein of interest detection. Figure adapted from [26,27].