Mechanisms and Consequences of Reverse Transcription in HIV-1 Cores

点击翻译按钮获取中文摘要

Summary HIV-1 infection results in destruction of T helper cells, leading to immunodeficiency and the disease known as AIDS. Most currently available antiretroviral drugs target the viral reverse transcriptase, integrase, and protease enzymes. These medicines are effective but not curative, and therapy must be adhered to rigorously and permanently. Moreover, HIV-1 constantly evolves and acquires mutations rendering it resistant to therapies. Therefore, ongoing research is needed to develop drugs against new viral and cellular targets. Owing to its multiple functions in infection, the HIV-1 capsid represents an attractive therapeutic target, and potent inhibitors targeting this structure have shown promising results in clinical trials. The capsid, which is an assembled lattice composed of a single viral protein, forms a shell around the viral genome and associated proteins and is essential for efficient reverse transcription, a key early step in HIV-1 infection. Perturbations to the stability of the capsid result in abortive infection, yet the mechanism by which the capsid ensures efficient reverse transcription is unknown. This project will fill this gap by defining the effects of capsid perturbations on HIV-1 reverse transcription in vitro, and vice-versa. Using native viral cores purified from infectious HIV-1 particles, we will employ cutting-edge biophysical techniques together with computational and molecular virology approaches to precisely define the role of the viral capsid in HIV-1 reverse transcription. The project will accomplish the following goals: (1) define the biochemical requirements for reverse transcription in HIV-1 cores; (2) define the structural transitions in the core during reverse transcription; (3) determine the role of capsid pores in nucleotide uptake during reverse transcription; and (4) precisely define the protein-nucleic acid interactions within the core during specific stages of reverse transcription. Collectively, this project will yield a greater understanding of capsid function in HIV-1 infection, thereby informing the mechanism of action of an emerging class of antiviral drugs. Relevance The results of this project will be a greater understanding of the functions of the viral capsid that are critical for HIV-1 infection. This information will inform the development of capsid-targeting antiviral drugs and improve the treatment of HIV-infected persons, thereby improving public health and reducing the spread of HIV-1.