Quantifying the inhibitory efficacy of HIV-1 therapeutic interfering particles at a single CD4 T-cell resolution

Abstract

Efficient control of HIV-1 infection relies on highly active antiretroviral therapy (HAART). However, this therapy is not curative and requires continuous drug administration. Application of HIV-1 defective interfering particles (DIPs), engineered with ablations in key viral protein expressions (e.g., Tat, Rev, Vpu, and Env), suggests a therapeutic potential transforming them into Therapeutic Interfering Particles (TIPs). A recent animal HIV model study in non-human primates reports a substantial reduction in viral load after a single intravenous injection of TIPs. In contrast, human clinical trials demonstrate no beneficial effect of defective interfering particles (DIPs) in people living with HIV-1. This discrepancy highlights the importance of further investigation of HIV-TIP interactions. A quantitative view of intracellular replication for HIV-1 in the presence of TIPs is still missing. Here, we develop a high-resolution mathematical model to study various aspects of the interference of a specific engineered TIP-2 particle characterized by a 2.5-kb deletion in the HIV pol-vpr region with HIV-1 replication within infected CD4+ T cells. We define the conditions in terms of the number of homozygous HIV-1 virions and TIP-2 particles that enable the reduction of the wild-type virus replication number to the value of about one. The deterministic model predicts that at a ratio of 1 HIV-1 to 10 TIP-2 particles, the infected cell still produces some viruses, although in a minor quantity, i.e., about two virions per cycle. Pre-activation of the interferon type I (IFN-I) system results in a complete block of HIV-1 production by TIP-2 co-infected cells. Overall, the modelling results suggest that to improve the effectiveness of TIPs in reducing HIV infection, their combination with other types of antiviral protection should be considered. Our results can be used in the development of combination therapy aimed at treating HIV-1 infection.

This research was funded by the Russian Science Foundation (Grant Number 23-11-00116) (deterministic model development, calibration, and simulations presented in Sections Section 1, Section 2.1, Section 2.2, Section 2.3, Section 3.1, Section 3.2 and Section 4). A.M. is also supported by Grant PID2022-141395OB-I00 funded by MICIU/AEI/10.13039/501100011033 and ERDF/EU, the 2021 SGR 00176 grant from the Departament de Recerca i Universitats de la Generalitat de Catalunya, and "Unidad de Excelencia María de Maeztu" CEX2024-001431-M, funded by MICIU/AEI/10.13039/501100011033. The study was partly supported by the Moscow Center of Fundamental and Applied Mathematics at INM RAS (Agreement with the Ministry of Education and Science of the Russian Federation No. 075-15-2025-347) (stochastic model development and numerical simulations presented in Section 2.4, Section 3.4, Section 3.5, Section 3.6, Section 3.7 and Section 3.8).