Cat and Mouse: HIV Transcription in Latency, Immune Evasion and Cure/Remission Strategies

Abstract

There is broad scientific and societal consensus that finding a cure for HIV infection must be pursued. The major barrier to achieving a cure for HIV/AIDS is the capacity of the HIV virus to avoid both immune surveillance and current antiretroviral therapy (ART) by rapidly establishing latently infected cell populations, termed latent reservoirs. Here, we provide an overview of the rapidly evolving field of HIV cure/remission research, highlighting recent progress and ongoing challenges in the understanding of HIV reservoirs, the role of HIV transcription in latency and immune evasion. We review the major approaches towards a cure that are currently being explored and further argue that small molecules that inhibit HIV transcription, and therefore uncouple HIV gene expression from signals sent by the host immune response, might be a particularly promising approach to attain a cure or remission. We emphasize that a better understanding of the game of “cat and mouse” between the host immune system and the HIV virus is a crucial knowledge gap to be filled in both cure and vaccine research.

The chromatin landscape at the HIV-1 provirus integration site determines viral expression

“…The latent reservoir is the major hurdle for curing HIV and hence the main target for cure strategies ( 7 , 71 ). The extensively studied ‘shock-and-kill’ strategy aims to reactivate latent provirus followed by killing of reactivated cells by viral cytopathic effects or immune clearance ( 72 , 73 ).…”

“…Moreover, reactivation of latent provirus is influenced by the site of integration indicating that a combination of multiple LRAs would be required ( 43 ). More recently, a strategy called ‘block-and-lock’ was proposed, that aims to permanently lock HIV provirus in a silent state unable to resume viral replication upon cART interruption ( 7 , 71 ). This latent state may be maintained by blocking HIV transcription with an inhibitor of trans-activator of transcription (Tat) ( 77–79 ).…”

Immune Control of HIV

“…Though the activated CD4 + T cells infected by HIV-1 have a very short half-life (t 1/2 of ~1 day) and die of one of the many proposed cell death pathways, if HIV-1 stochastically infects activated CD4 + T cells that are in the process of transitioning into memory phenotype [194], a sufficient window of time may be available for completion of the early events of virus replication culminating in the establishment of the provirus. The transition into memory phenotype causes sequestration of host transcription factors that are essential for virus gene expression from the provirus, and the resulting transcriptionally-silent provirus [195] may further be subjected to certain epigenetic modifications that sustain the latent phenotype [158, 196].…”

Advances in Developing CAR T-Cell Therapy for HIV Cure

“…All the cell types bearing the CD4 and its co-receptor (CCR5 or CXCR4) can be infected and become HIV latent reservoirs, including monocytes, macrophages, and dendritic cells (2). The HIV reservoir can exist in various compartments, such as peripheral blood, lymph nodes, the central nervous system, gut-associated lymphoid tissue (GALT), the genital tract, and any other tissues that contain HIV-infected cells (3). This latency does not express virus under the suppression of cART, but it can cause virus rebound once the therapy is interrupted (4).…”