Modelling HIV dynamics with cell-to-cell transmission and CTL response

In most HIV models, the emergence of backward bifurcation means that the control for basic reproduction number less than one is no longer effective for HIV treatment. In this paper, we study an HIV model with CTL response and cell-to-cell transmission by using the dynamical approach. The local and global stability of equilibria is investigated, the relations of subcritical Hopf bifurcation and supercritical bifurcation points are revealed, especially, the so-called new type bifurcation is also found with two Hopf bifurcation curves meeting at the same Bogdanov-Takens bifurcation point. Forward and backward bifurcation, Hopf bifurcation, saddle-node bifurcation, Bogdanov-Takens bifurcation are investigated analytically and numerically. Two limit cycles are also found numerically, which indicates that the complex behavior of HIV dynamics. Interestingly, the role of cell-to-cell interaction is fully uncovered, it may cause the oscillations to disappear and keep the so-called new type bifurcation persist. Finally, some conclusions and discussions are also given.

HIV-1 Mutants that Escape the Cytotoxic T-Lymphocytes are Defective in Viral DNA Integration

ABSTRACTHIV-1 replication is durably controlled in certain untreated HIV-1-infected individuals expressing particular human leukocyte antigens (HLA). These HLAs tag infected cells for elimination by presenting specific viral epitopes to CD8+ cytotoxic T-lymphocytes (CTL). In individuals expressing HLA-B27, CTLs primarily target the capsid protein (CA)-derived KK10 epitope. Selection of CA mutation R264K helps HIV-1 escape the CTL response but severely diminishes virus infectivity. Here we report that the R264K mutation-associated infectivity defect arises primarily from impaired viral DNA integration. Strikingly, selection of the compensatory CA mutation S173A or depletion of host cyclophilin A largely rescues the R264K-associated integration and infectivity defects. Collectively, our study reveals novel mechanistic insights into the fitness defect incurred by an HIV-1 variant escaping a CA-directed CTL response.

The correlation between antiviral drug, immune response and HIV viral load

Developing antiviral drugs is an exigent task since viruses mutate to overcome the effect of antiviral drugs. As a result, the efficacy of most antiviral drugs is short-lived. To include this effect, we modify the Neumann and Dahari model. Considering the fact that the efficacy of the antiviral drug varies in time, the differential equations introduced in the previous model systems are rewritten to study the correlation between the viral load and antiviral drug. The effect of antiviral drug that either prevents infection or stops the production of a virus is explored. First, the efficacy of the drug is considered to decreases monotonously as time progresses. In this case, our result depicts that when the efficacy of the drug is low, the viral load decreases and increases back in time revealing the effect of the antiviral drugs is short-lived. On the other hand, for the antiviral drug with high efficacy, the viral load as well as the number of infected cells monotonously decreases while the number of uninfected cells increases. The dependence of the critical drug efficacy on time is also explored. Moreover, the correlation between viral load, the antiviral drug, and CTL response is also explored. In this case, not only the dependence for the basic reproduction ratio on the model parameters is explored but also we analyze the critical drug efficacy as a function of time. We show that the term related to the basic reproduction ratio increases when the CTL response step up. A simple analytically solvable mathematical model is also presented to analyze the correlation between viral load and antiviral drugs.PACS numbersValid PACS appear here

The effect of basal core promoter and pre-core mutations on HBV replication and persistence in mice

The appearance of the BCP or Pre-C mutations, which reduce or abolish HBeAg production, could increase HBV replication. The remove of the HBeAg often lead to a vigorous immune response, which has an important role in HBV related fulminant outcome. In this study, BCP mutations and Pre-C mutations were separately introduced by site-directed mutagenesis in the same genetic background of an HBV infectious clone, to determine the effect of these mutations per se on replication. BCP and Pre-C mutations increased HBV replication both in vitro and in vivo. HBV could persist in mice injected with wild type HBV infectious clone for about 7 weeks. However, HBV could persist about 5 weeks in mice injected with BCP HBV infectious clone, and 3 weeks only in mice injected with Pre-C HBV infectious clone. HBV related CD8+ CTL response in BCP HBV infectious clone injected mice only slightly increased, but significantly increased in Pre-C HBV infectious clone injected mice compared with that in wild type HBV infectious clone injected mice. The population of Tregs significantly increased in liver but not in spleen of mice injected with Pre-C HBV infectious clone. In summary, we demonstrate that HBeAg plays an important role in suppressing the CTL response, which is related with increasing the frequency of Tregs in mouse. Lack of HBeAg expression leads to the partial loss of immune tolerance.

Exploratory open-label clinical study to determine the S-588410 cancer peptide vaccine-induced tumor-infiltrating lymphocytes and changes in the tumor microenvironment in esophageal cancer patients

Cancer vaccines induce cancer-specific T-cells capable of eradicating cancer cells. The impact of cancer peptide vaccines (CPV) on the tumor microenvironment (TME) remains unclear. S-588410 is a CPV comprising five human leukocyte antigen (HLA)-A*24:02-restricted peptides derived from five cancer testis antigens, DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1, which are overexpressed in esophageal cancer. This exploratory study investigated the immunologic mechanism of action of subcutaneous S-588410 emulsified with MONTANIDE ISA51VG adjuvant (median: 5 doses) by analyzing the expression of immune-related molecules, cytotoxic T-lymphocyte (CTL) response and T-lymphocytes bearing peptide-specific T-cell receptor (TCR) sequencing in tumor tissue or blood samples from 15 participants with HLA-A*24:02-positive esophageal cancer. Densities of CD8+, CD8+ Granzyme B+, CD8+ programmed death-1-positive (PD-1+) and programmed death-ligand 1-positive (PD-L1+) cells were higher in post- versus pre-vaccination tumor tissue. CTL response was induced in all patients for at least one of five peptides. The same sequences of peptide-specific TCRs were identified in post-vaccination T-lymphocytes derived from both tumor tissue and blood, suggesting that functional peptide-specific CTLs infiltrate tumor tissue after vaccination. Twelve (80%) participants had treatment-related adverse events (AEs). Injection site reaction was the most frequently reported AE (grade 1, n = 1; grade 2, n = 11). In conclusion, S-588410 induces a tumor immune response in esophageal cancer. Induction of CD8+ PD-1+ tumor-infiltrating lymphocytes and PD-L1 expression in the TME by vaccination suggests S-588410 in combination with anti-PD-(L)1 antibodies may offer a clinically useful therapy. Trial registration UMIN-CTR registration identifier: UMIN000023324.