| 1. |
- Adriaensen, Wim, et al.
(författare)
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Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients.
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8, s. 1943-
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Tidskriftsartikel (refereegranskat)abstract
- Patients with visceral leishmaniasis (VL)-human immunodeficiency virus (HIV) coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients respond poorly to conventional VL treatment and play an important role in parasite transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic drugs, new interventions that target host immunity may offer an effective alternative. In this review, we first summarize current views on how VL immunopathology is significantly affected by HIV coinfection. We then review current clinical and promising preclinical immunomodulatory interventions in the field of VL and discuss how these may operate in the context of a concurrent HIV infection. Caveats are formulated as these interventions may unpredictably impact the delicate balance between boosting of beneficial VL-specific responses and deleterious immune activation/hyperinflammation, activation of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to prioritize a target molecule and a more detailed account of the immunological status induced by the coinfection as well as surrogate markers of cure and protection are still required. We do, however, argue that virologically suppressed VL patients with a recovered immune system, in whom effective antiretroviral therapy alone is not able to restore protective immunity, can be considered a relevant target group for an immunomodulatory intervention. Finally, we provide perspectives on the translation of novel theories on synergistic immune cell cross-talk into an effective treatment strategy for VL-HIV-coinfected patients.
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| 2. |
- Elinder, Malin, et al.
(författare)
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Inhibition of HIV-1 by non-nucleoside reverse transcriptase inhibitors via an induced fit mechanism : Importance of slow dissociation and relaxation rates for antiviral efficacy
- 2010
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 80:8, s. 1133-1140
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Tidskriftsartikel (refereegranskat)abstract
- The importance of slow dissociation of non-nucleoside reverse transcriptase inhibitors (NNRTIs) for antiviral effect has been investigated. The kinetic characteristics of a series of NNRTIs interacting with wild type and drug resistant variants of HIV-1 RT (EC 2.7.7.49) were analyzed by SPR biosensor technology. The antiviral effect was determined in MT-4 and peripheral blood mononuclear cells. Due to extremely slow dissociation rates and a complex interaction mechanism, rate constants could not be quantified. Instead, interaction characteristics were qualitatively analyzed using simulated sensorgrams. The simplest model describing these interactions adequately was an induced fit mechanism, i.e. a mechanism involving the formation of an initial enzyme-inhibitor complex subsequently transformed into a more stable complex. Differences in rates of dissociation from the initial complex and rates of relaxation from the induced complex explained (1) the differences in the amounts of formed complex, (2) the stability of the complex and (3) the antiviral efficacies of the compounds. The effect of NNRTI binding site mutations also correlated with these kinetic characteristics. MIV-170 was the most effective inhibitor of wild type and mutant HIV-1 in cell culture, a property that was associated with the formation of the largest amount of complex and the slowest relaxation and dissociation rates. This study supports the hypothesis that the efficacy of anti-HIV drugs is dependent on slow dissociation from the target, thereby maximizing the duration of the inhibitory effect. It also illustrates the strength of simulating interaction data for qualitative analysis of tight-binding drugs and the importance of resolving the kinetic mechanism of drug-target interactions.
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| 3. |
- Elinder, Malin, et al.
(författare)
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MIV-170 : A novel NNRTI exhibiting tight binding to HIV-1 reverse transcriptase (RT)
- 2008
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Ingår i: Antiviral Research. - : Elsevier BV. - 0166-3542.
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Konferensbidrag (refereegranskat)abstract
- The NNRTI MIV-170 has been found to be a very efficient inhibitor of wtHIV and HIV mutant strains resistant to the NNRTIs used in the clinic. To better understand the interaction between MIV-170 and HIV-1 the details of this have been studied by different methods. The kinetics of the interaction between MIV-170 and HIV-1 RT was analysed using a biosensor assay. The association and dissociation rates were determined using immobilized wtRT or RT mutants and MIV-170 as analyte. The results demonstrated that MIV-170 had both a faster association and a slower dissociation rate than efavirenz, nevirapine and delavirdine, thus exhibiting a higher affinity than these compounds. The strength of the interaction between the NNRTIs and RT and RT mutants in the biosensor assay was compared to the reversibility of inhibition in cell culture experiments. In these experiments virus and infected cells were incubated with MIV-170 and other NNRTIs for various times and after removal of the compounds the remaining infectivity was assayed. X-ray analysis of the binding of MIV-170 to HIV-1 RT displayed extensive interactions, not only between the compound and the lining amino acids but also between these residues, turning the binding cavity into a rigid entity and explaining the tight binding in the biosensor assay and the inactivation of HIV.
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| 4. |
- Heyndrickx, Leo, et al.
(författare)
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Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an adjuvant. Methods: Based on in vitro neutralizing activity in serum, patients with bNAbs were selected for cloning of their HIV-1 Env. Seven stable soluble trimeric gp140 proteins were generated from sequences derived from four adults and two children infected with either clade A or B HIV-1. From one of the clade A Envs both the monomeric and trimeric Env were produced for comparison. Rabbits were immunized with soluble gp120 or trimeric gp140 proteins in combination with the adjuvant dimethyl dioctadecyl ammonium/trehalose dibehenate (CAF01). Env binding in rabbit immune serum was determined using ELISAs based on gp120-IIIB protein. Neutralizing activity of IgG purified from rabbit immune sera was measured with the pseudovirus-TZMbl assay and a PBMC-based neutralization assay for selected experiments. Results: It was initially established that gp140 trimers induce better antibody responses over gp120 monomers and that the adjuvant CAF01 was necessary for such strong responses. Gp140 trimers, based on HIV-1 variants from patients with bNAbs, were able to elicit both gp120(IIIB) specific IgG and NAbs to Tier 1 viruses of different subtypes. Potency of NAbs closely correlated with titers, and an gp120-binding IgG titer above a threshold of 100,000 was predictive of neutralization capability. Finally, peptide inhibition experiments showed that a large fraction of the neutralizing IgG was directed against the gp120 V3 region. Conclusions: Our results indicate that the strategy of reverse immunology based on selected Env sequences is promising when immunogens are delivered as stabilized trimers in CAF01 adjuvant and that the rabbit is a valuable model for HIV vaccine studies.
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| 5. |
- Visciano, Maria Luisa, et al.
(författare)
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Characterization of humoral responses to soluble trimeric HIV gp140 from a clade A Ugandan field isolate
- 2013
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 11:165
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Tidskriftsartikel (refereegranskat)abstract
- Trimeric soluble forms of HIV gp140 envelope glycoproteins represent one of the closest molecular structures compared to native spikes present on intact virus particles. Trimeric soluble gp140 have been generated by several groups and such molecules have been shown to induce antibodies with neutralizing activity against homologous and heterologous viruses. In the present study, we generated a recombinant trimeric soluble gp140, derived from a previously identified Ugandan A-clade HIV field isolate (gp140(94UG018)). Antibodies elicited in immunized rabbits show a broad binding pattern to HIV envelopes of different clades. An epitope mapping analysis reveals that, on average, the binding is mostly focused on the C1, C2, V3, V5 and C5 regions. Immune sera show neutralization activity to Tier 1 isolates of different clades, demonstrating cross clade neutralizing activity which needs to be further broadened by possible structural modifications of the clade A gp140(94UG018). Our results provide a rationale for the design and evaluation of immunogens and the clade A gp140(94UG018) shows promising characteristics for potential involvement in an effective HIV vaccine with broad activity.
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