Recent Advances in the Development of Integrase Inhibitors for HIV Treatment

Trivedi, Jay; Mahajan, Dinesh; Jaffe, Russell J.; Acharya, Arpan; Mitra, Debashis; Byrareddy, Siddappa N.

doi:10.1007/s11904-019-00480-3

Cited by 25 publications

(16 citation statements)

References 112 publications

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“…Limitations to this study include that our analysis was restricted to PWH during chronic infection with low baseline CD4 + counts, limiting inference for patients today. Given comorbidity-free life expectancy is increased with early ART administration and rapid viral decline with current regimens that include integrase inhibitors [ 48 , 49 ], investigating whether Gal-9 still predicts NAEs following early modern ART intervention is warranted. Although Gal-9 was not significantly associated with NAEs at baseline, the effect size was notably consistent with our other findings and may be because of its strong link with viremia and immune suppression [ 9 , 12 , 34 ], as well as insufficient plasma for many participants at baseline.…”

Section: Discussionmentioning

confidence: 99%

Plasma galectin-9 as a predictor of adverse non-AIDS events in persons with chronic HIV during suppressive antiretroviral therapy

Premeaux

Moser

McKhann

et al. 2021

Aids

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Background: People with HIV (PWH) on antiretroviral therapy (ART) still experience an increased risk of morbidity and mortality, presumably driven by chronic inflammation, yet predictors of discrete or combinatorial outcomes remain unclear. Galectin-9 (Gal-9), a driver of both inflammatory and immunosuppressive responses, has been associated with HIV disease progression and multimorbidity. Objective: To determine whether plasma Gal-9 levels are associated with the occurrence of specific non-AIDS events (NAEs) in PWH initiating ART. Design: We performed a nested case–control study of PWH enrolled from 2001 to 2009 and evaluated pre-ART (66 cases, 97 controls), a year post-ART (112 cases, 211 controls), and immediately preceding an event (89 cases, 162 controls). Events included myocardial infarction/stroke, malignancy, serious bacterial infection, or death. Methods: Plasma Gal-9 levels were assessed by ELISA. Conditional logistic regression assessed associations with NAEs and Spearman's correlations compared Gal-9 with other previously assessed biomarkers. Results: NAEs occurred at a median of 2.8 years (1.7–4.6) after ART initiation. Higher Gal-9 levels were associated with increased risk of NAEs at year 1 and preevent [odds ratio (OR) per 1 interquartile range = 1.4–1.6; all P < 0.05], specifically myocardial infarction/stroke at year 1 (OR = 1.9; P = 0.029). Gal-9 also correlated with multiple inflammatory and immune activation predictors of NAEs (all timepoints). Conclusion: Elevated Gal-9 levels are predictive of deleterious NAEs, particularly cardiovascular complications. Whether the Gal-9 pathway, potentially binding to its putative ligands, is active in the pathogenesis of these outcomes warrants further investigation to determine if targeting Gal-9 may slow or reverse the risk of NAEs.

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Section: Discussionmentioning

confidence: 99%

Plasma galectin-9 as a predictor of adverse non-AIDS events in persons with chronic HIV during suppressive antiretroviral therapy

Premeaux

Moser

McKhann

et al. 2021

Aids

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“…INSTIs bind to the catalytic core domain of the viral integrase to inhibit binding of the enzyme to the double-stranded DNA of the host. Since no equivalent homologs of integrase are known to exist in humans, INSTIs are generally believed to have limited off-target effects (68). Recent computational work, however, demonstrated that INSTIs could potentially interact with domesticated transposases, such as recombination activating gene 1 (RAG1), which is known to be involved in antibody and T-lymphocyte receptor V(D)J recombination.…”

Section: Integrase Strand Transfer Inhibitorsmentioning

confidence: 99%

Interactions of HIV and Antiretroviral Therapy With Neutrophils and Platelets

et al. 2021

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Neutrophils are important components of the innate immune system that mediate pathogen defense by multiple processes including phagocytosis, release of proteolytic enzymes, production of reactive oxygen species, and neutrophil extracellular trap formation. Abnormalities of neutrophil count and function have been described in the setting of HIV infection, with the majority of antiretroviral agents (ARVs), excluding zidovudine, having been reported to correct neutropenia. Questions still remain, however, about their impact on neutrophil function, particularly the possibility of persistent neutrophil activation, which could predispose people living with HIV to chronic inflammatory disorders, even in the presence of virally-suppressive treatment. In this context, the effects of protease inhibitors and integrase strand transfer inhibitors, in particular, on neutrophil function remain poorly understood and deserve further study. Besides mediating hemostatic functions, platelets are increasingly recognized as critical role players in the immune response against infection. In the setting of HIV, these cells have been found to harbor the virus, even in the presence of antiretroviral therapy (ART) potentially promoting viral dissemination. While HIV-infected individuals often present with thrombocytopenia, they have also been reported to have increased platelet activation, as measured by an upregulation of expression of CD62P (P-selectin), CD40 ligand, glycoprotein IV, and RANTES. Despite ART-mediated viral suppression, HIV-infected individuals reportedly have sustained platelet activation and dysfunction. This, in turn, contributes to persistent immune activation and an inflammatory vascular environment, seemingly involving neutrophil-platelet-endothelium interactions that increase the risk for development of comorbidities such as cardiovascular disease (CVD) that has become the leading cause of morbidity and mortality in HIV-infected individuals on treatment, clearly underscoring the importance of unraveling the possible etiologic roles of ARVs. In this context, abacavir and ritonavir-boosted lopinavir and darunavir have all been linked to an increased risk of CVD. This narrative review is therefore focused primarily on the role of neutrophils and platelets in HIV transmission and disease, as well as on the effect of HIV and the most common ARVs on the numbers and functions of these cells, including neutrophil-platelet-endothelial interactions.

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“…This therapeutic cocktail was formulated in a solvent mixture of 10% ethanol, 30% polyethylene glycol 400, and 60% Phosal 50 PG for administration to HIV-infected mice via oral gavage. An integrase strand transfer inhibitor (raltegravir) [ 22 ] and an attachment inhibitor (BMS-663068, 20 mg/kg b.w.) [ 23 ] were also included as a daily ART regimen.…”

Section: Concept Of Sechmentioning

confidence: 99%

Selective elimination of host cells harboring replication-competent human immunodeficiency virus reservoirs: a promising therapeutic strategy for HIV cure

Zaongo¹,

Ma²,

Song³

et al. 2021

Chinese Medical Journal

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Many seminal advances have been made in human immunodeficiency virus (HIV)/AIDS research over the past four decades. Treatment strategies, such as gene therapy and immunotherapy, are yielding promising results to effectively control HIV infection. Despite this, a cure for HIV/AIDS is not envisioned in the near future. A recently published academic study has raised awareness regarding a promising alternative therapeutic option for HIV/AIDS, referred to as “selective elimination of host cells capable of producing HIV” (SECH). Similar to the “shock and kill strategy,” the SECH approach requires the simultaneous administration of drugs targeting key mechanisms in specific cells to efficiently eliminate HIV replication-competent cellular reservoirs. Herein, we comprehensively review the specific mechanisms targeted by the SECH strategy. Briefly, the suggested cocktail of drugs should contain (i) latency reversal agents to promote the latency reversal process in replication-competent reservoir cells, (ii) pro-apoptotic and anti-autophagy drugs to induce death of infected cells through various pathways, and finally (iii) drugs that eliminate new cycles of infection by prevention of HIV attachment to host cells, and by HIV integrase inhibitor drugs. Finally, we discuss three major challenges that are likely to restrict the application of the SECH strategy in HIV/AIDS patients.

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Recent Advances in the Development of Integrase Inhibitors for HIV Treatment

Cited by 25 publications

References 112 publications

Plasma galectin-9 as a predictor of adverse non-AIDS events in persons with chronic HIV during suppressive antiretroviral therapy

Plasma galectin-9 as a predictor of adverse non-AIDS events in persons with chronic HIV during suppressive antiretroviral therapy

Interactions of HIV and Antiretroviral Therapy With Neutrophils and Platelets

Selective elimination of host cells harboring replication-competent human immunodeficiency virus reservoirs: a promising therapeutic strategy for HIV cure

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