A Review of Block and Lock Strategies to Cure HIV

Human Immunodeficiency Virus (HIV) is a virus that targets the human immune system. In the HIV life cycle, the virus fuses with the host cell, reverse transcribes the viral RNA into DNA, integrates the viral and host DNA together, transcribes the integrated DNA, and then produces viral particles and proteins that exit the host cell to create a new viral cell. When the immune system becomes infected with HIV, some cells continue with the viral replication actively, but others become dormant after the integration phase. This is known as HIV latency. While HIV is no longer a fatal disease, but more a chronic infection due to treatment with antiretroviral drug therapy (ART), it is not a curable disease. ART is able to suppress the virus to barely detectable levels but is unable to target latent cells. The block and lock strategy aims to silence the virus within infected cells and thus, permanently cure HIV. This involves two key steps: blocking HIV transcription or replication, and locking the virus in a state of latency, where it cannot be reactivated even after stopping ART. There are many avenues of research targeting both viral and host factors and the interaction between them. To understand more about the block and lock strategies we’re explaining, it is important to understand the HIV genome and HIV transcription and the factors within it that are targeted. The HIV genome consists of nine major genes with two long terminal repeats (LTRs), the 5′ LTR and the 3′ LTR, on either side. Transcription begins at the 5′ LTR, which contains three key regions: the U3 (Unique 3′) region with promoter and enhancer elements, the R (Repeat) region containing the transcription start site and Trans-Activation Response (TAR) element, and the U5 (Unique 5′) region, which helps regulate reverse transcription and RNA processing. Viral particles like Trans-activation of transcription (Tat) recruit a host of cellular transcription factors and the RNA polymerase II enzyme to initiate transcription. Viral transcription produces RNA transcripts which are spliced and processed outside the nucleus to create new viral particles and proteins that are essential to create a new HIV cell. Most block and lock strategies attempt to target either viral or host cellular transcription factors to disrupt HIV’s replication cycle and over time push it into permanent latency.