Neha B Mullassery

Background: The latent HIV-1 reservoir—a pool of resting memory CD4+ T cells harboring integrated, transcriptionally silent proviral DNA—remains the primary barrier to a functional cure.^6,7 While these cells remain “invisible” to the host immune system under suppressive antiretroviral therapy (ART), they can be reactivated by latency-reversing agents. However, even after reactivation, the host’s natural immune response often fails to clear these cells due to low viral antigen expression and active evasion tactics, such as Nef-mediated MHC-I downregulation.^1,3,5 Recent research has focused on engineering dual-affinity molecules, including single-chain diabodies (scDbs) and bispecific T-cell engagers (BiTEs), to act as synthetic bridges that physically link immune effector cells directly to infected targets.^1,2

Objective: This narrative review explores the mechanisms by which engineered dual-affinity molecules redirect innate and adaptive immune effector cells to identify and eliminate reservoir cells, and examines the clinical implications of translating these protein-engineering strategies into human therapeutic applications.

Search Methods: An online search in the PubMed database was conducted from 2022 to 2026 using keywords including “HIV-1 latent reservoir,” “bispecific antibodies,” “NK cell redirection,” “synNotch T-cells,” and “clinical trials.” The research focused on studies evaluating molecular bridges in vitro, in humanized mouse models, and in Phase I human clinical trials.

Results: Mechanistic studies demonstrate that Env-CD16 scDbs induce potent NK cell degranulation and reduce intact proviral DNA by 40–50% in ex vivo patient samples.¹ To overcome “Env-masking,” TCR-mimic bispecific antibodies were developed to target internal Gag peptides presented by MHC-I, effectively eliminating reservoir cells even at low peptide densities.³ Furthermore, CD8+ T cells engineered with synNotch receptors successfully localized therapeutic secretion to the microenvironment of infected cells, minimizing systemic “off-target” toxicity.² A Phase I clinical trial of the IMC-M113V bispecific protein confirmed these findings, showing that the treatment was well-tolerated and biologically active in humans, evidenced by transient increases in T-cell activation markers.⁴ However, high-potency tetravalent antibodies were shown in murine models to cause significant NK cell depletion, leading to a failure in long-term viral control.⁵

Conclusion: The transition from basic engineering to clinical application confirms that dual-affinity molecules can safely redirect the immune system to target the HIV-1 reservoir.⁴ While Phase I data validates their safety and activity, the risk of effector cell depletion identified in recent in vivo studies underscores that therapeutic success depends not only on the precision of the “kill” but also on preserving the fitness and survival of the immune effector cells themselves.⁵ Future research must prioritize “multi-hit” strategies that incorporate protective modifications to sustain long-term immunological surveillance.

Works cited:

1. Board NL, Yuan Z, Wu F, et al. Bispecific antibodies promote natural killer cell-mediated elimination of HIV-1 reservoir cells. Nat Immunol. 2024;25(3):462-470. doi:10.1038/s41590-023-01741-5.
2. Meng L, Zhao H, Chang S, et al. Engineering of CD8+ T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses. mBio. 2025;16(4):e0383924. doi:10.1128/mbio.03839-24
3. Sengupta S, Board NL, Wu F, et al. TCR-mimic bispecific antibodies to target the HIV-1 reservoir. Proc Natl Acad Sci U S A. 2022;119(15):e2123406119. doi:10.1073/pnas.2123406119
4. Vandekerckhove L, Fox J, Mora-Peris B, et al. Safety and biologic activity of a bispecific T cell receptor targeting HIV Gag in males living with HIV: a first-in-human trial. Nat Commun. Published online January 31, 2026. doi:10.1038/s41467-026-68833-2
5. Sánchez-Gaona, N., Perea, D., Curran, A. et al. NK cell depletion in bispecific antibody therapy is associated with lack of HIV control after ART interruption. Commun Biol 8, 236 (2025). doi:10.1038/s42003-025-07651-6
6. Harper J, Betts MR, Lichterfeld M, et al. Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?. Pathog Immun. 2024;8(2):115-157. Published 2024 Mar 1. doi:10.20411/pai.v8i2.665
7. Kuo HH, Lichterfeld M. Recent progress in understanding HIV reservoirs. Curr Opin HIV AIDS. 2018;13(2):137-142. doi:10.1097/COH.0000000000000441