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Combinatorial approaches to the prevention and treatment of HIV-1 infection.

ABSTRACT: The discovery of the human immunodeficiency virus type 1 (HIV-1) in 1982 soon led to the identification and development of antiviral compounds to be used in treatment strategies for infected patients. Early in the epidemic, drug monotherapies frequently led to treatment failures because the virus quickly developed resistance to the single drug. Following the advent of highly active antiretroviral therapy (HAART) in 1995, dramatic improvements in HIV-1-infected patient health and survival were realized as more refined combination therapies resulted in reductions in viral loads and increases in CD4+ T-cell counts. In the absence of an effective vaccine, prevention of HIV-1 infection has also gained traction as an approach to curbing the pandemic. The development of compounds as safe and effective microbicides has intensified and has focused on blocking the transmission of HIV-1 during all forms of sexual intercourse. Initial preclinical investigations and clinical trials of microbicides focused on single compounds effective against HIV-1. However, the remarkable successes achieved using combination therapy to treat systemic HIV-1 infection have subsequently stimulated the study and development of combination microbicides that will simultaneously inhibit multiple aspects of the HIV-1 transmission process by targeting incoming viral particles, virus-infected cells, and cells susceptible to HIV-1 infection. This review focuses on existing and developing combination therapies, covering preclinical development, in vitro and in vivo efficacy studies, and subsequent clinical trials. The shift in focus within the microbicide development field from single compounds to combination approaches is also explored.

SUBMITTER: Pirrone V

PROVIDER: S-EPMC3088245 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Combinatorial approaches to the prevention and treatment of HIV-1 infection.

Pirrone Vanessa V Thakkar Nina N Jacobson Jeffrey M JM Wigdahl Brian B Krebs Fred C FC

Antimicrobial agents and chemotherapy 20110222 5

The discovery of the human immunodeficiency virus type 1 (HIV-1) in 1982 soon led to the identification and development of antiviral compounds to be used in treatment strategies for infected patients. Early in the epidemic, drug monotherapies frequently led to treatment failures because the virus quickly developed resistance to the single drug. Following the advent of highly active antiretroviral therapy (HAART) in 1995, dramatic improvements in HIV-1-infected patient health and survival were re ...[more]

PMID: 21343462

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Project description:IntroductionThe REGAL (RSV Evidence - A Geographical Archive of the Literature) series has provided a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This seventh and final publication covers the past, present and future approaches to the prevention and treatment of RSV infection among infants and children.MethodsA systematic review was undertaken of publications between January 1, 1995 and December 31, 2017 across PubMed, Embase and The Cochrane Library. Studies reporting data on the effectiveness and tolerability of prophylactic and therapeutic agents for RSV infection were included. Study quality and strength of evidence (SOE) were graded using recognized criteria. A further nonsystematic search of the published literature and Clinicaltrials.gov on antiviral therapies and RSV vaccines currently in development was also undertaken.ResultsThe systematic review identified 1441 studies of which 161 were included. Management of RSV remains centered around prophylaxis with the monoclonal antibody palivizumab, which has proven effective in reducing RSV hospitalization (RSVH) in preterm infants < 36 weeks' gestational age (72% reduction), children with bronchopulmonary dysplasia (65% reduction), and infants with hemodynamically significant congenital heart disease (53% reduction) (high SOE). Palivizumab has also shown to be effective in reducing recurrent wheezing following RSVH (high SOE). Treatment of RSV with ribavirin has conflicting success (moderate SOE). Antibodies with increased potency and extended half-life are currently entering phase 3 trials. There are approximately 15 RSV vaccines in clinical development targeting the infant directly or indirectly via the mother.ConclusionPalivizumab remains the only product licensed for RSV prophylaxis, and only available for high-risk infants. For the general population, there are several promising vaccines and monoclonal antibodies in various stages of clinical development, with the aim to significantly reduce the global healthcare impact of this common viral infection.FundingAbbVie.

Project description:Attenuated viruses have numerous applications, in particular in the context of live viral vaccines. However, purposefully designing attenuated viruses remains challenging, in particular if the attenuation is meant to be resistant to rapid evolutionary recovery. Here we develop and analyze a new attenuation method, promoter ablation, using an established viral model, bacteriophage T7. Ablation of promoters of the two most highly expressed T7 proteins (scaffold and capsid) led to major reductions in transcript abundance of the affected genes, with the effect of the double knockout approximately additive of the effects of single knockouts. Fitness reduction was moderate and also approximately additive; fitness recovery on extended adaptation was partial and did not restore the promoters. The fitness effect of promoter knockouts combined with a previously tested codon deoptimization of the capsid gene was less than additive, as anticipated from their competing mechanisms of action. In one design, the engineering created an unintended consequence that led to further attenuation, the effect of which was studied and understood in hindsight. Overall, the mechanisms and effects of genome engineering on attenuation behaved in a predictable manner. Therefore, this work suggests that the rational design of viral attenuation methods is becoming feasible. IMPORTANCE Live viral vaccines rely on attenuated viruses that can successfully infect their host but have reduced fitness or virulence. Such attenuated viruses were originally developed through trial and error, typically by adaptation of the wild-type virus to novel conditions. That method was haphazard, with no way of controlling the degree of attenuation or the number of attenuating mutations or preventing evolutionary reversion. Synthetic biology now enables rational design and engineering of viral attenuation, but rational design must be informed by biological principles to achieve stable, quantitative attenuation. This work shows that in a model system for viral attenuation, bacteriophage T7, attenuation can be obtained from rational design principles, and multiple different attenuation approaches can be combined for enhanced overall effect.

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Combinatorial approaches to the prevention and treatment of HIV-1 infection.

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Combinatorial approaches to the prevention and treatment of HIV-1 infection.

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