High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients
Abstract
:1. Introduction
2. Results
2.1. Phenotypic Susceptibility of Viral Isolates to INIs and BSS-730A
2.2. Curve Slope and Instantaneous Inhibitory Potential (IIP)
2.3. Antiviral Activity of BSS-730A and RAL Are Synergic
2.4. Analysis of Genotypic Drug Resistance
3. Discussion
4. Materials and Methods
4.1. Ethics
4.2. Cells, Plasmids, and Drugs
4.3. Patient Data
4.4. Virus Stocks and Titration
4.5. Drug Susceptibility Assays
4.6. Instantaneous Inhibitory Potential (IIP)
4.7. Drug Combination Assays
4.8. DNA Extraction, PCR Amplification and Sequencing
4.9. Phylogenetic Analysis
4.10. Analysis of Genotypic Drug Resistance
4.11. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Parameter a | RAL-Naive Isolates [Mean Values (95% CI)] (n = 14) | RAL-Experienced Isolates [Mean Values (95% CI)] (n = 3) | p-Value b |
---|---|---|---|
RALTEGRAVIR | |||
IC50 (nM) | 2.692 (1.351, 4.032) | 78.178 (−195.1, 351.5) | 0.0294 |
Fold-change IC50 | 1.681 (0.803, 2.559) | 29.043 (−72.491, 130.578) | 0.1393 |
IC90 (nM) | 19.998 (7.463, 32.533) | 236.169 (−242.727, 715,065) | 0.0324 |
Fold-change IC90 | 1.066 (0.401, 1.731) | 11.809 (−12.138, 35.757) | 0.0393 |
Hill slope | 1.44 (0.922, 1.952) | 1.95 (−1.952, 5.846) | 0.9529 |
DOLUTEGRAVIR | |||
IC50 (nM) | 2.778 (2.037, 3.518) | 14.467 (−24.96, 53.89) | 0.0059 |
Fold-change IC50 | 0.970 (0.688, 1.253) | 5.208 (−8.985, 19.401) | 0.0071 |
IC90 (nM) | 16.264 (11.307, 21.221) | 89.460 (−70.462, 249,383) | 0.0132 |
Fold-change IC90 | 1.607 (1.099, 2.116) | 5.501 (−4.332, 15.334) | 0.1464 |
Hill slope | 1.64 (0.925, 2.352) | 1.22 (0.276, 2.162) | 0.6765 |
BICTEGRAVIR | |||
IC50 (nM) | 2.595 (1.707, 3.483) | 8.322 (−14.37, 31.01) | 0.3618 |
Fold-change IC50 | 0.735 (0.458, 1.013) | 3.207 (−5.537, 11.951) | 0.3536 |
IC90 (nM) | 30.493 (17.248, 43.738) | 156.100 (−312.135, 624.335) | 0.1485 |
Fold-change IC90 | 2.375 (1.322, 3.427) | 5.119 (−10.236, 20.474) | 0.7821 |
Hill slope | 1.03 (0.840, 1.228) | 1.14 (−0.488, 2.773) | 0.5912 |
BSS-730A | |||
IC50 (nM) | 18.101 (13.37, 22.84) | 15.667 (7.61, 23.65) | 0.6044 |
Fold-change IC50 | 0.993 (0.710, 1.277) | 0.865 (0.425, 1.306) | 0.8161 |
IC90 (nM) | 46.549 (31.850, 61.247) | 42.974 (−0.975, 86.924) | 0.9529 |
Fold-change IC90 | 0.957 (0.607, 1.308) | 0.903 (−0.021, 1.827) | >0.9999 |
Hill slope | 2.87 (2.087, 3.651) | 2.58 (0.581, 4.579) | >0.9999 |
Drug Combination (Combination Ratio) | CI Values at Inhibition of 1: | CIwt-Values 3 | |||
---|---|---|---|---|---|
50% | 75% | 90% | 95% | ||
RAL + BSS-730A (1:1) | 0.24265 | 0.17127 | 0.18068 | 0.19165 | 0.19 |
++++ 2 | ++++ | ++++ | ++++ | ++++ | |
RAL + BSS-730A (1:3) | 0.17775 | 0.16790 | 0.18613 | 0.20118 | 0.15 |
++++ | ++++ | ++++ | ++++ | ++++ | |
RAL + BSS-730A (3:1) | 0.09422 | 0.05240 | 0.06646 | 0.08334 | 0.07 |
+++++ | +++++ | +++++ | +++++ | +++++ |
Patient (Isolate) | Major Resistance Mutations | Accessory Resistance Mutations | Predicted Susceptibility * | ||
---|---|---|---|---|---|
RAL | DTG | BIC ** | |||
10PTHSJIG | E92Q | T97A | Resistant | Intermediate | Sensitive |
15PTHSJIG | None | I84V | Sensitive | Sensitive | Sensitive |
15PTHCEC | E92A, Q148K | I84V | Resistant | Resistant | Sensitive |
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Bártolo, I.; Moranguinho, I.; Gonçalves, P.; Diniz, A.R.; Borrego, P.; Martin, F.; Figueiredo, I.; Gomes, P.; Gonçalves, F.; Alves, A.J.S.; et al. High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients. Int. J. Mol. Sci. 2022, 23, 14300. https://doi.org/10.3390/ijms232214300
Bártolo I, Moranguinho I, Gonçalves P, Diniz AR, Borrego P, Martin F, Figueiredo I, Gomes P, Gonçalves F, Alves AJS, et al. High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients. International Journal of Molecular Sciences. 2022; 23(22):14300. https://doi.org/10.3390/ijms232214300
Chicago/Turabian StyleBártolo, Inês, Inês Moranguinho, Paloma Gonçalves, Ana Rita Diniz, Pedro Borrego, Francisco Martin, Inês Figueiredo, Perpétua Gomes, Fátima Gonçalves, Américo J. S. Alves, and et al. 2022. "High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients" International Journal of Molecular Sciences 23, no. 22: 14300. https://doi.org/10.3390/ijms232214300