Modeling the effects of a Shock-and-Kill Treatment for HIV: Latency-Reversing Agents and Natural Killer Cells

Despite the substantial success of combination antiretroviral therapy (ART) in suppressing HIV replication, achieving a complete cure remains challenging due to the persistence of viral reservoirs. The use of latency-reversing agents (LRAs) combined with natural killer (NK) cells in a "shock-and-kill" strategy has been experimentally confirmed as an effective approach to reducing reservoirs. Here, we utilized an HIV infection mathematical model that incorporates both 'virus-cell' and 'cell-cell' infection modes to assess the dynamic synergy of ART, LRAs, and NK cells. Model calibration was performed using experimental viral load data from HIV-1-infected humanized mice, employing Bayesian inference and an affine-invariant ensemble Markov Chain Monte Carlo (MCMC) sampling algorithm. Our findings validate the established understanding of HIV pathogenesis: post-treatment viral rebound is significantly influenced by the size of the viral reservoir, and 'cell-cell' transmission accounts for more than half of infections. Our findings also highlight the crucial role of natural killer (NK) cell-mediated immune responses in influencing interindividual variability in therapeutic responses to HIV. Comparative analysis of therapeutic strategies reveals that tripartite regimens combining ART with LRAs and NK cells demonstrate enhanced antiviral efficacy and accelerated treatment timelines. There is a key parameter region of the tripartite regimens therapy that will lead to an HIV cure. These insights collectively reinforce the immunotherapeutic potential of NK cells modulation and provide a mechanistic basis for optimizing combination therapies in eradication strategies.