Role of CD8<sup>+</sup>T Cells in the Selection of HIV-1 Immune Escape Mutations

Arcia, David; Acevedo-Sáenz, Liliana; Rugeles, Marı́a Teresa; Velilla, Paula A.

doi:10.1089/vim.2016.0095

Cited by 14 publications

(13 citation statements)

References 91 publications

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“…The cells infected with the escape variant, I W , have reduced susceptibility to cytotoxic T cells (by applying a factor χ<1 to the killing rate). This variant also infects target cells at a lower rate constant (b W <b V ), as escape can often incur a fitness penalty [46][47][48].…”

Section: Plos Computational Biologymentioning

confidence: 99%

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

et al. 2021

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Immunomodulatory drugs could contribute to a functional cure for Human Immunodeficiency Virus (HIV). Interleukin-15 (IL-15) promotes expansion and activation of CD8+ T cell and natural killer (NK) cell populations. In one study, an IL-15 superagonist, N-803, suppressed Simian Immunodeficiency Virus (SIV) in non-human primates (NHPs) who had received prior SIV vaccination. However, viral suppression attenuated with continued N-803 treatment, partially returning after long treatment interruption. While there is evidence of concurrent drug tolerance, immune regulation, and viral escape, the relative contributions of these mechanisms to the observed viral dynamics have not been quantified. Here, we utilize mathematical models of N-803 treatment in SIV-infected macaques to estimate contributions of these three key mechanisms to treatment outcomes: 1) drug tolerance, 2) immune regulation, and 3) viral escape. We calibrated our model to viral and lymphocyte responses from the above-mentioned NHP study. Our models track CD8+ T cell and NK cell populations with N-803-dependent proliferation and activation, as well as viral dynamics in response to these immune cell populations. We compared mathematical models with different combinations of the three key mechanisms based on Akaike Information Criterion and important qualitative features of the NHP data. Two minimal models were capable of reproducing the observed SIV response to N-803. In both models, immune regulation strongly reduced cytotoxic cell activation to enable viral rebound. Either long-term drug tolerance or viral escape (or some combination thereof) could account for changes to viral dynamics across long breaks in N-803 treatment. Theoretical explorations with the models showed that less-frequent N-803 dosing and concurrent immune regulation blockade (e.g. PD-L1 inhibition) may improve N-803 efficacy. However, N-803 may need to be combined with other immune therapies to countermand viral escape from the CD8+ T cell response. Our mechanistic model will inform such therapy design and guide future studies.

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Section: Plos Computational Biologymentioning

confidence: 99%

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

et al. 2021

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“…During acute/early infection, immune escape mutations are selected by immune responses, allowing mutant viruses to evade immune selection pressure. These individual mutations can significantly reduce the replicative fitness of HIV-1 (14)(15)(16)(17)(18)(19). The reduced viral fitness and lowered viral loads can lead to long-term HIV-1 control and a decreased probability of transmission to new hosts (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Accumulated mutations by 6 months of infection collectively render transmitted/founder HIV-1 significantly less fit

Wang

Liu²,

Zuo

et al. 2020

Journal of Infection

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Objective: Viral fitness plays an important role in HIV-1 evolution, transmission and pathogenesis. However, how mutations accumulated during early infection affect viral fitness has not been well studied. Methods:We generated paired infectious molecular clones (IMCs) for transmitted/founder (T/F) and 6-month (6-mo) viruses post infection from 10 infected individuals to investigate the impact of accumulated mutations on viral fitness by comparing 6-mo viruses to their cognate T/F viruses. Results:We found that all ten 6-mo viruses were less fit than their cognate T/F viruses. Moreover, the fitness losses of the 6-mo viruses correlated with the decrease in viral loads from the peak of viremia. Conclusion:These results show that the mutations accumulated during half a year post infection collectively reduce viral fitness and thereby contribute to lowering viral loads.

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“…The cells infected with the escape variant, I , have reduced susceptibility to cytotoxic T cells (by applying a factor <1 to the killing rate). This variant also infects target cells at a lower rate constant ( < ), as escape can often incur a fitness penalty [46][47][48].…”

Section: Methods Mathematical Modelmentioning

confidence: 99%

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

Cody

Ellis

O’Connor

et al. 2020

Preprint

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Immunomodulatory drugs could contribute to a functional cure for Human Immunodeficiency Virus (HIV). Interleukin-15 (IL-15) promotes expansion and activation of CD8+ T cell and natural killer (NK) cell populations. In one study, an IL-15 superagonist, N-803, suppressed Simian Immunodeficiency Virus (SIV) in non-human primates (NHPs) who had received prior SIV vaccination. However, viral suppression attenuated with continued N-803 treatment, partially returning after long treatment interruption. While there is evidence of concurrent drug tolerance, immune regulation, and viral escape, the relative contributions of these mechanisms to the observed viral dynamics have not been quantified. Here, we utilize mathematical models of N- 803 treatment in SIV-infected macaques to estimate contributions of these three key mechanisms to treatment outcomes: 1) drug tolerance, 2) immune regulation, and 3) viral escape. We calibrated our model to viral and lymphocyte responses from the above-mentioned NHP study. Our models track CD8+ T cell and NK cell populations with N-803-dependent proliferation and activation, as well as viral dynamics in response to these immune cell populations. We compared mathematical models with different combinations of the three key mechanisms based on Akaike Information Criterion and important qualitative features of the NHP data. Two minimal models were capable of reproducing the observed SIV response to N-803. In both models, immune regulation strongly reduced cytotoxic cell activation to enable viral rebound. Either long-term drug tolerance or viral escape (or some combination thereof) could account for changes to viral dynamics across long breaks in N-803 treatment. Theoretical explorations with the models showed that less-frequent N-803 dosing and concurrent immune regulation blockade (e.g. PD-L1 inhibition) may improve N-803 efficacy. However, N-803 may need to be combined with other immune therapies to countermand viral escape from the CD8+ T cell response. Our mechanistic model will inform such therapy design and guide future studies.

show abstract

Role of CD8⁺T Cells in the Selection of HIV-1 Immune Escape Mutations

Cited by 14 publications

References 91 publications

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

Accumulated mutations by 6 months of infection collectively render transmitted/founder HIV-1 significantly less fit

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

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Role of CD8+T Cells in the Selection of HIV-1 Immune Escape Mutations

Cited by 14 publications

References 91 publications

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

Accumulated mutations by 6 months of infection collectively render transmitted/founder HIV-1 significantly less fit

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

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Role of CD8⁺T Cells in the Selection of HIV-1 Immune Escape Mutations