NEWPORT INTERNATIONAL JOURNAL OF SCIENTIFIC AND EXPERIMENTAL SCIENCES

(NIJSES)

Volume 6 Issue 3 Page 130-134, 2025

©NIJSES PUBLICATIONS ONLINE ISSN:2992-5819
Open Access PRINT ISSN:2992-6149 Page | 130

https://doi.org/10.59298/NIJSES/2025/63.130134

Impact of mRNA-Based Immune Modulators Versus Standard ART

on Viral Reservoir Reduction in Treatment-Experienced HIV
Adults: A Review
Odile Patrick Thalia
Faculty of Biological Sciences Kampala International University Uganda

ABSTRACT
Despite the success of standard antiretroviral therapy (ART) in achieving sustained viral suppression among people
living with HIV, the persistence of latent viral reservoirs in resting CD4+ T cells remains a major barrier to cure.
This review examined the emerging role of messenger RNA (mRNA)-based immune modulators as a novel
therapeutic strategy to reduce the HIV reservoir in treatment-experienced adults. Unlike ART, which halts
replication without affecting the latent pool, mRNA-based therapeutics are designed to induce targeted immune
responses, reverse latency, or enhance the clearance of infected cells through the transient expression of
immunostimulatory proteins. Promising preclinical and early-phase clinical studies have shown that mRNA
platforms can enhance HIV-specific T cell responses and delay viral rebound following treatment interruption.
However, evidence of direct reservoir reduction in humans was still limited, and challenges such as immune
exhaustion, delivery logistics, and combination strategy design remained. This article employed a narrative review
methodology, synthesizing findings from peer-reviewed studies published between 2010 and 2025 to compare the
mechanistic and clinical impacts of mRNA-based immune modulators and standard ART. The review concluded that
mRNA immune modulators may complement ART in curative efforts, particularly when used in combination with
latency-reversing agents and immune-enhancing therapies.
Keywords: HIV reservoir, mRNA immune modulators, Antiretroviral therapy, Latency reversal, Treatment-
experienced adults.

INTRODUCTION
Despite the advent and global scale-up of antiretroviral therapy (ART), HIV persists as a chronic infection largely
due to the establishment of latent viral reservoirs that escape immune clearance and pharmacological suppression
[1]. These reservoirs, formed early in infection and residing primarily in resting memory CD4+ T cells, present a
formidable barrier to viral eradication [2, 3]. While ART effectively suppresses plasma viremia to undetectable
levels, it fails to eliminate these latent reservoirs, necessitating lifelong therapy and posing risks of rebound upon
treatment interruption.
Over the past two decades, research efforts have increasingly focused on novel strategies aimed at targeting and
reducing the size and activity of these viral reservoirs. One promising approach involves the use of messenger RNA
(mRNA)-based immune modulators [4, 5]. These modulators utilize synthetic mRNA platforms to transiently
express immunologically active proteins or antigenic sequences designed to stimulate HIV-specific immunity,
enhance immune recognition of infected cells, or reverse latency through immunotherapeutic mechanisms. Their
emergence has coincided with technological advances in mRNA stability, delivery systems (notably lipid
nanoparticles), and immunoengineering, as exemplified in mRNA vaccine development during the COVID-19
pandemic. In contrast, standard ART regimens, while highly effective in suppressing viral replication, do not
influence the latent pool directly, nor do they prime the immune system to recognize and clear latently infected cells
[6, 7]. Therefore, a comparative analysis of mRNA-based immune modulators and standard ART is critical to

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, p rovided the
original work is properly cited
understanding the translational potential of mRNA strategies in reservoir targeting, particularly in treatment-
experienced adults who harbor long-standing and possibly more entrenched viral reservoirs. This review synthesizes
the current scientific understanding of mRNA-based immune modulators, evaluates their mechanisms and clinical
applications in comparison to standard ART, and critically assesses their impact on HIV viral reservoir reduction
among treatment-experienced individuals. It also explores future directions, implementation challenges, and the
implications of integrating such strategies into existing therapeutic frameworks.
Mechanisms of HIV Persistence and the Challenge of Viral Reservoirs Page | 131
The persistence of HIV despite ART is largely attributed to the establishment of a latent reservoir, primarily within
resting memory CD4+ T cells, although other cell types, such as macrophages and follicular dendritic cells, may also
contribute [8, 9]. Latency is characterized by the integration of proviral DNA into the host genome without active
transcription, allowing the virus to evade immune detection and ART, both of which target replicating virus.
Standard ART effectively halts replication but lacks any activity against cells harboring transcriptionally silent
provirus [10, 11]. Interruption of ART typically results in rapid viral rebound due to the reactivation of these
latent reservoirs. The magnitude and stability of the latent reservoir are major obstacles to HIV eradication and
cure, and hence have become central targets in curative research.
Approaches to reduce or eliminate the viral reservoir have included latency-reversing agents (LRAs), immune
checkpoint inhibitors, broadly neutralizing antibodies (bNAbs), therapeutic vaccines, and, more recently, mRNA-
based immune modulators. These mRNA-based approaches aim to reprogram the host immune system or enhance
antigen presentation to achieve immune-mediated clearance of reservoir cells.
Standard Antiretroviral Therapy (ART): Achievements and Limitations
ART comprises combinations of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse
transcriptase inhibitors (NNRTIs), protease inhibitors, integrase strand transfer inhibitors (INSTIs), and entry
inhibitors [12]. The principal goal of ART is to achieve and maintain viral suppression, restore immune function,
and prevent disease progression and transmission [13, 14].
Despite its success in transforming HIV into a manageable chronic disease, ART must be taken continuously to
sustain virologic control. Adherence challenges, drug resistance, long-term toxicities, and high healthcare costs
remain persistent concerns, particularly in resource-limited settings. Moreover, ART exerts no effect on the size of
the latent reservoir and provides no immunologic memory or enhanced clearance of infected cells.
Longitudinal studies have demonstrated that even among individuals with sustained virologic suppression for over
a decade, the size of the latent reservoir decreases only minimally over time. Therefore, adjunctive strategies that
can complement ART by directly targeting the reservoir or bolstering immune recognition are urgently needed.
mRNA-Based Immune Modulators: Concept and Mechanism of Action
mRNA-based immune modulators represent a class of therapeutics that utilize in vitro transcribed mRNA to express
antigens or immunostimulatory molecules transiently in host cells [15]. These molecules can include HIV antigens,
cytokines, costimulatory ligands, or chimeric constructs designed to enhance antigen presentation or induce latency
reversal.
Key features of mRNA therapeutics include their non-integrating, non-replicating nature, rapid production
scalability, and the ability to encode virtually any protein of interest [16]. When delivered via lipid nanoparticles
(LNPs), mRNA is taken up by antigen-presenting cells (APCs), translated into protein, and presented via major
histocompatibility complex (MHC) molecules to stimulate adaptive immune responses. Thus, mRNA-based immune
modulators have a dual potential: to expose latent HIV through immune activation and to facilitate the clearance of
infected cells via enhanced immune surveillance [17]. In the context of HIV, mRNA modulators are employed to
either:
i. Boost HIV-specific T cell responses: By encoding HIV Gag, Pol, or Env antigens to prime or expand
cytotoxic T lymphocyte responses.
ii. Reverse latency: By encoding immune-stimulatory cytokines (e.g., IL-15, IFN-α) or transcriptional
activators that trigger latent provirus reactivation.
iii. Induce immunomodulation: Using checkpoint inhibitors (e.g., anti-PD-1) or costimulatory ligands to
reinvigorate exhausted T cells.
Comparative Efficacy: mRNA Modulators Versus Standard ART in Viral Reservoir Reduction
Emerging clinical and preclinical studies have begun to shed light on the efficacy of mRNA-based immune
modulators in targeting the HIV reservoir. In murine and non-human primate models, mRNA-based vaccines
encoding HIV antigens have demonstrated the ability to elicit robust polyfunctional T cell responses, particularly
when combined with adjuvants or immune checkpoint blockade [18, 19]. Notably, mRNA therapeutic platforms have
shown early promise in inducing latency reversal, increasing cell-associated HIV RNA, and enhancing antigen

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, p rovided the
original work is properly cited
presentation without widespread T cell activation or systemic toxicity. In one study, mRNA encoding HIV Env
protein delivered via LNPs in SIV-infected macaques led to a measurable reduction in the reservoir size, particularly
when administered following ART-mediated viral suppression.
In contrast, standard ART, while effective in halting viral replication, does not reduce the size of the latent reservoir.
Studies involving analytical treatment interruptions (ATIs) consistently show rapid rebound in patients maintained
only on ART, irrespective of duration or viral suppression history. Importantly, recent pilot clinical trials involving
treatment-experienced HIV-positive adults have tested mRNA vaccine candidates in combination with ART. Page | 132
Preliminary findings suggest that mRNA immunization enhances the breadth and magnitude of HIV-specific
immune responses, and in some cases, delays time to viral rebound post-ART cessation, suggesting an indirect
impact on reservoir activity or structure. However, quantitative reductions in the size of the inducible reservoir have
not yet been definitively established in large-scale human trials. The lack of standardized assays to measure reservoir
size and the heterogeneity in participant immune history pose additional challenges in comparing outcomes between
ART and mRNA-based approaches.
Safety, Immunogenicity, and Implementation Considerations
Safety remains a paramount concern with any novel therapeutic platform. To date, mRNA-based
immunotherapeutics have demonstrated favorable safety profiles in oncology and infectious disease contexts,
including in therapeutic vaccines for cancer and prophylactic SARS-CoV-2 vaccines. Transient local and systemic
reactogenicity is the most common side effect, typically resolving within days. In the context of HIV, mRNA
strategies must be tailored to avoid overstimulation of the immune system, which may risk immune exhaustion or
systemic inflammation [20]. Precision delivery systems, targeted antigen selection, and dose optimization are
essential to maximizing therapeutic benefit while minimizing adverse effects.
From an implementation standpoint, the rapid scalability and flexibility of mRNA manufacturing offer a distinct
advantage over protein- or viral vector-based immunotherapies. However, cold-chain requirements, cost of
formulation, and the need for repeated dosing remain practical barriers, particularly in low-resource settings.
Furthermore, the immunologic history of treatment-experienced individuals, many of whom have undergone
multiple ART regimens and harbor exhausted or senescent T cells, may limit the effectiveness of mRNA immune
modulation. Thus, patient stratification based on immunophenotyping and reservoir characterization may be
required to optimize therapeutic outcomes.
Future Directions and Combination Strategies
While current evidence supports the immunogenic potential of mRNA-based immune modulators, it is increasingly
clear that a multipronged approach will be required to achieve meaningful reductions in the HIV reservoir. Strategies
that combine mRNA immunotherapy with latency-reversing agents (LRAs) to induce viral expression, broadly
neutralizing antibodies (bNAbs) to block new infection and enhance clearance, immune checkpoint inhibitors to
restore T cell function, and gene-editing tools like CRISPR to excise proviral DNA are actively under investigation.
Additionally, therapeutic timing (e.g., during ART suppression vs. treatment interruption), personalized
immunotherapeutic design, and iterative booster regimens may influence the efficacy of mRNA interventions. The
use of mRNA platforms to deliver personalized neoantigens derived from an individual’s own proviral sequences
represents a novel frontier in HIV immunotherapy [21].
Ongoing clinical trials are expected to clarify the role of mRNA immune modulators in cure-oriented strategies and
whether they can be effectively integrated into ART-free remission protocols.
CONCLUSION
The persistent challenge of HIV viral reservoirs necessitates innovative therapeutic strategies beyond standard
ART. mRNA-based immune modulators represent a promising and versatile class of interventions capable of
enhancing host immune responses, reversing latency, and potentially reducing the size and stability of the latent
reservoir. Unlike ART, which solely suppresses viral replication, mRNA therapeutics offer an active immunologic
approach to target the reservoir directly. Preclinical data and early-phase clinical trials suggest that mRNA immune
modulators can boost HIV-specific immunity and delay viral rebound post-ART, although definitive evidence of
quantitative reservoir reduction remains limited. Importantly, these strategies are generally safe, customizable, and
scalable, offering significant advantages in the evolving landscape of HIV cure research. However, several challenges
persist, including immune exhaustion in treatment-experienced populations, the need for improved reservoir
measurement techniques, and logistical issues in delivery and cost. Future efforts will likely focus on combination
regimens that integrate mRNA-based strategies with other immunologic and gene-based tools. While standard ART
remains the cornerstone of HIV treatment, mRNA-based immune modulators represent a compelling adjunctive
strategy with the potential to shift the paradigm from lifelong viral suppression to functional cure or durable
remission.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, p rovided the
original work is properly cited
 REFERENCES
1. Mr.S.R.P., -, Dr.A.A.: Nanostructured Lipid Carriers in HIV Therapy: Unlocking the Future of Long-Acting
and Targeted Antiretroviral Delivery. IJSAT - International Journal on Science and Technology. 16, (2025).
https://doi.org/10.71097/IJSAT.V16.I2.5597
2. Alum, E.U., Ugwu, O.P.C., Obeagu, E.I., Aja, P.M.: Reducing HIV Infection Rate in Women: A Catalyst to
reducing HIV Infection pervasiveness in Africa. (2023). https://doi.org/10.58538/IJIAR/2048
3. Li, K., Zhang, Q.: Eliminating the HIV tissue reservoir: current strategies and challenges. Infect Dis. 56, Page | 133
165–182 (2024).
https://doi.org/10.1080/23744235.2023.2298450;REQUESTEDJOURNAL:JOURNAL:INFD20
4. Wang, Y., Zhang, Z., Luo, J., Han, X., Wei, Y., Wei, X.: mRNA vaccine: a potential therapeutic strategy.
Molecular Cancer 2021 20:1. 20, 1–23 (2021). https://doi.org/10.1186/S12943-021-01311-Z
5. Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C., Thakur, A.: Opportunities and Challenges in the Delivery
of mRNA-Based Vaccines. Pharmaceutics 2020, Vol. 12, Page 102. 12, 102 (2020).
https://doi.org/10.3390/PHARMACEUTICS12020102
6. Alum, E. U., Uti, D. E., Ugwu, O. P., Alum, B. N. Toward a cure - Advancing HIV/AIDs treatment modalities
beyond antiretroviral therapy: A Review. Medicine (Baltimore). 2024 Jul 5;103(27):e38768. doi:
10.1097/MD.0000000000038768.
7. Taye, M.A.: Drug Washout and Viral Rebound: Modeling HIV Reactivation Under ART Discontinuation.
(2025)
8. Chen, J., Zhou, T., Zhang, Y., Luo, S., Chen, H., Chen, D., Li, C., Li, W.: The reservoir of latent HIV. Front
Cell Infect Microbiol. 12, 945956 (2022). https://doi.org/10.3389/FCIMB.2022.945956/XML
9. Mzingwane, M.L., Tiemessen, C.T.: Mechanisms of HIV persistence in HIV reservoirs. Rev Med Virol. 27,
e1924 (2017). https://doi.org/10.1002/RMV.1924
10. Sadowski, I., Hashemi, F.B.: Strategies to eradicate HIV from infected patients: elimination of latent provirus
reservoirs. Cellular and Molecular Life Sciences 2019 76:18. 76, 3583–3600 (2019).
https://doi.org/10.1007/S00018-019-03156-8
11. Schwarzer, R., Gramatica, A., Greene, W.C.: Reduce and Control: A Combinatorial Strategy for Achieving
Sustained HIV Remissions in the Absence of Antiretroviral Therapy. Viruses 2020, Vol. 12, Page 188. 12,
188 (2020). https://doi.org/10.3390/V12020188
12. Foka, F.E.T., Mufhandu, H.T.: Current ARTs, Virologic Failure, and Implications for AIDS Management: A
Systematic Review. Viruses 2023, Vol. 15, Page 1732. 15, 1732 (2023). https://doi.org/10.3390/V15081732
13. Madu, C.V., Aloh, H.E., Ugwu, O.P.C., Obeagu, E.I., Uti, D.E., Egba, S.I., et al. The price of progress:
Assessing the financial costs of HIV/AIDS management in East Africa. Medicine (Baltimore). 2025 May
2;104(18):e42300. doi: 10.1097/MD.0000000000042300.
14. Ezenwaji, C.O., Alum, E.U. & Ugwu, O.PC. Bridging the gap: telemedicine as a solution for HIV care
inequities in rural and vulnerable communities. Int J Equity Health 24, 205 (2025).
https://doi.org/10.1186/s12939-025-02584-2
15. Sahin, U., Karikó, K., Türeci, Ö.: mRNA-based therapeutics — developing a new class of drugs. Nature
Reviews Drug Discovery 2014 13:10. 13, 759–780 (2014). https://doi.org/10.1038/nrd4278
16. Esteban, I., Pastor-Quiñones, C., Usero, L., Plana, M., García, F., Leal, L.: In the Era of mRNA Vaccines, Is
There Any Hope for HIV Functional Cure? Viruses 2021, Vol. 13, Page 501. 13, 501 (2021).
https://doi.org/10.3390/V13030501
17. Prakash, S., Kumar, M.: The Hidden Enemy Within: Uncovering the Secrets of HIV Tissues Reservoirs and
Current mRNA Vaccine Development. Curr HIV Res. 22, 73–81 (2024).
https://doi.org/10.2174/011570162X301593240409072840/CITE/REFWORKS
18. Valentin, A., Bergamaschi, C., Rosati, M., Angel, M., Burns, R., Agarwal, M., Gergen, J., Petsch, B.,
Oostvogels, L., Loeliger, E., Chew, K.W., Deeks, S.G., Mullins, J.I., Pavlakis, G.N., Felber, B.K.: Comparative
immunogenicity of an mRNA/LNP and a DNA vaccine targeting HIV gag conserved elements in macaques.
Front Immunol. 13, 945706 (2022). https://doi.org/10.3389/FIMMU.2022.945706/XML
19. Zhang, Y., Jin, S., Zuo, Z., Liu, S., Xu, J., Yang, C., Wan, P., Xun, L., Luo, M., Yang, F., Chen, W., Song, Z., Qi,
J.: Rational Design and Immunological Mechanisms of Circular RNA-Based Vaccines: Emerging Frontiers
in Combating Pathogen Infection. Vaccines (Basel). 13, 563 (2025).
https://doi.org/10.3390/VACCINES13060563/S1
20. Linares-Fernández, S., Lacroix, C., Exposito, J.Y., Verrier, B.: Tailoring mRNA Vaccine to Balance
Innate/Adaptive Immune Response. Trends Mol Med. 26, 311–323 (2020).

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, p rovided the
original work is properly cited
 https://doi.org/10.1016/J.MOLMED.2019.10.002/ATTACHMENT/ADB91320-EC2C-411A-9032-
275CE59A919E/MMC1.MP4
21. Floudas, C.S., Sarkizova, S., Ceccarelli, M., Zheng, W.: Leveraging mRNA technology for antigen based
immuno-oncology therapies. J Immunother Cancer. 13, e010569 (2025). https://doi.org/10.1136/JITC-
2024-010569

Page | 134

CITE AS: Odile Patrick Thalia (2025). Impact of mRNA-Based Immune Modulators Versus Standard
ART on Viral Reservoir Reduction in Treatment-Experienced HIV Adults: A Review. NEWPORT
INTERNATIONAL JOURNAL OF SCIENTIFIC AND EXPERIMENTAL SCIENCES 6(3):130-134
https://doi.org/10.59298/NIJSES/2025/63.130134

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, p rovided the
original work is properly cited