Reviews & Analysis

Synthetic lethality describes a situation in which defects in either one of two genes are not detrimental, but combining defects in the two genes is lethal. The targeting of BRCA-deficient tumors by PARP inhibitors is the first clinical example utilizing the principle of synthetic lethality to treat cancer. Despite the promise of this approach, a number of resistance mechanisms have been identified, and this Perspective describes these mechanisms and their clinical relevance.

There is much interest in the applications of pluripotent stem cells for regenerative medicine. In this Perspective, the authors discuss the factors that might contribute to the potential risk of tumorigenicity from pluripotent stem cell therapies. They also outline recent developments in techniques that allow the sorting of tumorigenic species from nontumorigenic cells and offer a viewpoint into the future hurdles for moving pluripotent stem cell–based therapies from bench to bedside.

Persistence of hepatitis C virus contributes to chronic infection, which can lead to liver fibrosis and even liver cancer. Different factors, such as host genetics and immunity and viral immune evasion strategies, account for the outcome of the infection and the patient response to antivirals. This Perspective discusses how the interaction of these factors modulates viral immunity and how they might be used to identify the key targets to mount an effective immune response that will clear the virus and improve drug response.

Autism spectrum disorders (ASDs) are a clinically heterogeneous group of neurodevelopmental disorders characterized by social and communication deficits and repetitive behaviors. In a subset of individuals with ASD, mutations in genes involved in synaptic function have been identified, and this Perspective discusses the evidence from mouse models of ASD that synaptic deficits can be ameliorated in the mature brain. The authors also suggest a strategy for designing more informative clinical trials for ASD therapies that stratify patients according to their specific synaptic mutations.

Rapid and effective host responses keep herpes simplex virus-2 (HSV-2) at bay, preventing genital mucosa lesions. However, periodic shedding and frequent reactivation of the latent virus allow for silent transmission, posing a challenge to virus elimination. The rapid clearance of HSV-2 in the genital mucosa by resident and virus-specific immune cells that persist in the mucosa suggests new ways to harness the immune system to develop effective therapies.

Malaria's death toll has been reduced as a result of global efforts over the last decade. Yet the rise of drug resistance and the plateauing of funding are still obstacles to eradicating the disease and reducing malaria burden. This review brings up the goals and challenges faced by researchers and the public health workforce and a way forward to effectively control and eliminate malaria.

There is renewed enthusiasm in developing an HIV vaccine and in understanding the requirements to elicit broadly neutralizing HIV-specific antibodies. In May 2012, a workshop convened researchers to discuss the interplay of CD4⁺ T cell and antibody responses to help identify key questions and areas of research that can inform future vaccine development. This Perspective summarizes the discussion of three main topics on the role of CD4⁺ T cells in HIV vaccine design.

The term 'mesenchymal stem cells' is widely used, yet the capabilities and characteristics of these postnatal bone marrow stem cells still warrant further examination. A further understanding and clarification of the true potential of these mesenchymal stem cells is crucial for their appropriate exploitation in the clinic.