Role of Implementation Science: Linking Fundamental Discovery Science and Innovation Science to Ending the HIV Epidemic at the Community Level.

BACKGROUND: During the past 4 decades, substantial progress has been made in the development of strategies for HIV prevention, treatment, and care resulting from observational science, discovery and innovation science, and implementation science. Building on these fundamental discoveries, innovation science has led to novel, safe, and effective modalities for HIV treatment and prevention, including combination antiretroviral therapy and treatment as prevention and pre-exposure prophylaxis, respectively. SETTING: In the United States and globally, there remains a major challenge in the optimal implementation of the strategies that we already have in the areas of HIV prevention, diagnosis, treatment, and care. METHODS: Implementation science will be essential to the successful achievement of ending the global HIV epidemic by translating evidence-based interventions, resulting from discovery and innovation science, into real-world practice. Strategies are needed that integrate and implement the biomedical tools currently available within the social and structural contexts and across all stages of the HIV prevention and care continuum. Several of the latest methodologies and analytical approaches that are being actively pursued, as well as the research challenges and opportunities to conducting implementation science in the context of both the global and domestic responses to HIV, are the focus of this special supplement to the Journal of AIDS. CONCLUSIONS: Knowledge resulting from implementation science will be critical to define and refine the approaches to successfully bring HIV prevention and treatment interventions to scale and achieve the goal of ending the HIV epidemic in the United States and worldwide.

HIV-AIDS: much accomplished, much to do.

As a result of decades of research-driven breakthroughs in basic and clinical science and recent advances in the broad-scale implementation of interventions for the prevention and treatment of infection with HIV, a turning point has been reached in the global HIV-AIDS pandemic. To end the pandemic and achieve the goal of an AIDS-free generation, researchers and clinicians must follow the dual pathway of optimizing the implementation of existing prevention and treatment interventions and discovering with basic and clinical research new and effective tools in both of these arenas.

Preventing HIV transmission through antiretroviral treatment-mediated virologic suppression: aspects of an emerging scientific agenda.

PURPOSE OF REVIEW: This review describes important aspects of the research agenda that have emerged as a result of the recent findings of the HIV transmission study in sero-discordant couples conducted by the National Institute of Allergy and Infectious Disease (NIAID)-supported HIV Prevention Trials Network (HPTN) and referred to as HPTN 052. RECENT FINDINGS: The HPTN 052 study provided strong evidence that antiretroviral treatment (ART), given to HIV-infected partners with the purpose of achieving and maintaining full virologic suppression, could prevent linked HIV transmission in sero-discordant couples. These findings have implications in all future combination prevention strategies. SUMMARY: The HPTN 052 study demonstrated that sustained virus suppression, below detectable levels, can prevent HIV transmission in sero-discordant couples. As a result of this study, we have now identified ART as a key component for all combination prevention strategies. Additionally, this study demonstrates that HIV testing is the single door of entry for individualized HIV treatment and prevention. The challenge now is to create a robust, seamless linkage and retention system so that the vision of HIV treatment as prevention can be realized. Such a system will maximize both the treatment and the prevention benefits of ART. The research agenda outlined here describes the need to extend this finding to areas of implementation science, such as the development of simpler, easier to use point-of-care assays for virus load, and improved, better tolerated, more durable combinations and formulations of antiretroviral drugs.

Thirty years of HIV and AIDS: future challenges and opportunities.

As the third decade since AIDS was first recognized comes to an end, extraordinary advances have occurred in the understanding, treatment, and prevention of HIV infection and AIDS. As a result of these successes, it is now time to focus on future challenges. Paramount among these is reaching the goal of truly controlling and ultimately ending the HIV and AIDS pandemic. To that end, AIDS researchers and public health personnel worldwide are aggressively pursuing 3 key areas of scientific research. Given the availability of highly effective therapeutic regimens for HIV infection, the first challenge is efficiently identifying a maximum number of HIV-infected persons through voluntary HIV testing and initiating antiretroviral therapy (ART). Second, scientists are trying to develop a cure for HIV infection, which would alleviate the need for lifelong ART. Finally, preventing new cases of HIV infection, which currently number approximately 2.6 million per year globally, is critical to any attempt to end this pandemic. This article addresses each of these challenges and provides directions for the future.

Rethinking prevention of HIV type 1 infection.

Research on the prevention of human immunodeficiency virus (HIV)-1 infection is at a critical juncture. Major methodological challenges to performing prevention trials have emerged, and one after another promising biomedical interventions have failed to reduce the incidence of HIV-1 infection. Nevertheless, there is growing optimism that progress can be achieved in the near term. Mathematical modeling indicates that 2 new strategies, "test and treat" and preexposure prophylaxis, could have a major impact on the incidence of HIV-1 infection. Will our hopes be justified? We review the potential strengths and limitations of these antiretroviral "treatment as prevention" strategies and outline other new options for reducing the incidence of HIV-1 infection in the near term. By maximizing the potential of existing interventions, developing other effective strategies, and combining them in an optimal manner, we have the opportunity to bring the HIV-1 epidemic under control.

A way forward: the National HIV/AIDS Strategy and reducing HIV incidence in the United States.

In July 2010, the Obama Administration released a National HIV/AIDS Strategy for the United States to refocus national attention on responding to the domestic HIV epidemic. The goals of the strategy are to reduce HIV incidence; to increase access to care and optimize health outcomes among people living with HIV; and to reduce HIV-related disparities. The strategy identifies a small number of action steps that will align efforts across federal, state, local, and tribal levels of government, and maximally impact the domestic HIV epidemic. In this article, we outline key programmatic and research issues that must be addressed to accomplish the prevention goals of the National HIV/AIDS Strategy.

Fighting HIV/AIDS in Washington, D.C.

Washington, D.C., is the capital of the United States and is a major center for public health and health policy expertise. Yet the District of Columbia has an HIV prevalence rate among adults of 3 percent, on par with some sub-Saharan African countries. To date, the local public health response has not controlled the epidemic. The ways in which that response has been galvanized in recent years--through collaboration among the capital's public health agencies, community and faith organizations, and research institutions--may be instructive to other jurisdictions combating HIV/AIDS.

HIV vaccine development: Lessons from the past, informing the future.

In September 2007, a clinical trial (STEP trial) evaluating the candidate HIV vaccine MRK Ad5 HIV-1 gag/pol/nef from Merck & Co Inc was halted at the first interim analysis because the vaccine demonstrated no positive impact on virus acquisition or virus load following infection. Additionally, there was an increased rate of HIV infection in vaccinees who had prior immunity to adenovirus type 5 (Ad5) and/or were circumcised. This failure of the vaccine, as well as the apparent harm caused to some study participants, generated a massive pessimism regarding HIV vaccine development. Concerns regarding the future of HIV vaccine research led to a summit convened by the NIAID in March 2008 to provide new directions in HIV vaccine research. A shift in emphasis focused on three areas: discovery research, animal models and clinical research. In each of these areas, notable new activities have occurred: a wealth of information has emerged from the STEP trial, promising results have been reported on assay development for markers of vaccine-induced immune function, and evaluations of promising new experimental vaccines have occurred in nonhuman primates. Overall, the progress in the field of HIV vaccine research since September 2007 has reinforced the need for a balanced approach between basic vaccine discovery and development, as well as the importance of addressing questions in nonhuman primate studies and clinical trials. This article discusses how past product failures have invigorated the field of HIV vaccine research by addressing critical questions and suggesting additional possible approaches to follow. As a result of the insight gained, a new sense of optimism exists in the field of HIV vaccine research.

Cataloguing the HIV type 1 human protein interaction network.

Although many interactions between HIV-1 and human proteins have been reported in the scientific literature, no publicly accessible source for efficiently reviewing this information was available. Therefore, a project was initiated in an attempt to catalogue all published interactions between HIV-1 and human proteins. HIV-related articles in PubMed were used to develop a database containing names, Entrez GeneIDs, and RefSeq protein accession numbers of interacting proteins. Furthermore, brief descriptions of the interactions, PubMed identification numbers of articles describing the interactions, and keywords for searching the interactions were incorporated. Over 100,000 articles were reviewed, resulting in the identification of 1448 human proteins that interact with HIV-1 comprising 2589 unique HIV-1-to-human protein interactions. Preliminary analysis of the extracted data indicates 32% were direct physical interactions (e.g., binding) and 68% were indirect interactions (e.g., upregulation through activation of signaling pathways). Interestingly, 37% of human proteins in the database were found to interact with more than one HIV-1 protein. For example, the signaling protein mitogen-activated protein kinase 1 has a surprising range of interactions with 10 different HIV-1 proteins. Moreover, large numbers of interactions were published for the HIV-1 regulatory protein Tat and envelope proteins: 30% and 33% of total interactions identified, respectively. The database is accessible at http://www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions/ and is cross-linked to other National Center for Biotechnology Information databases and programs via Entrez Gene. This database represents a unique and continuously updated scientific resource for understanding HIV-1 replication and pathogenesis to assist in accelerating the development of effective therapeutic and vaccine interventions.

HIV vaccine research: the way forward.

The need to broaden research directed at answering fundamental questions in HIV vaccine discovery through laboratory, nonhuman primate (NHP), and clinical research has recently been emphasized. In addition, the importance of attracting and retaining young researchers, developing better NHP models, and more closely linking NHP and clinical research is being stressed. In an era of a level budget for biomedical research at the U.S. National Institutes of Health (NIH), HIV/AIDS vaccine research efforts will need to be carefully prioritized such that resources to energize HIV vaccine discovery can be identified. This article summarizes progress and challenges in HIV vaccine research, the priorities arising from a recent summit at NIAID, and the actions needed, some already under way, to address those priorities.

Defining and solving the essential protein-protein interactions in HIV infection.

The structure determination of macromolecular complexes is entering a new era. The methods of optical microscopy, electron microscopy, X-ray crystallography, and nuclear magnetic resonance increasingly are being combined in hybrid method approaches to achieve an integrated view of macromolecular complexes that span from cellular context to atomic detail. A particularly important application of these hybrid method approaches is the structural analysis of the Human Immunodeficiency Virus (HIV) proteins with their cellular binding partners. High resolution structure determination of essential HIV - host cell protein complexes and correlative analysis of these complexes in the live cell can serve as critical guides in the design of a broad, new class of therapeutics that function by disrupting such complexes. Here, with the hope of stimulating some discussion, we will briefly review some of the literature in the context of what could be done to further apply structural methods to HIV research. We have chosen to focus our attention on certain aspects of the HIV replication cycle where we think that structural information would contribute substantially to the development of new therapeutic and vaccine targets for HIV.