Targeting Immune Checkpoint Molecules to Eliminate Latent HIV

Abstract

The advent of antiretroviral therapy (ART) has seen a dramatic decrease in the morbidity and mortality of individuals infected with human immunodeficiency virus (HIV). However, ART is not curative and HIV persists in treated individuals within a pool of infected CD4+ memory T cells. The targeting and elimination of these cells, termed the latent HIV reservoir, may be essential in establishing a cure for HIV. Current HIV reservoir research is focused on identifying cells that harbor latent, replication-competent, HIV provirus using specific cell surface markers. Recently, studies have turned to immune checkpoint (IC) molecules, such as programmed cell death protein 1 (PD-1). IC molecules are regulators of the immune system and have previously been linked to HIV infection. Furthermore, cells isolated from treated individuals co-expressing PD-1 alongside other IC molecules are enriched for HIV DNA. Administration of a IC blocking antibodies resulted in an increase of cell-associated HIV RNA within an individual, indicating the potential for this therapeutic to be utilized as a latency reversing agent. IC inhibitors could target CD4+ T cells expressing IC molecules and possibly enhance HIV transcription, allowing for the elimination of these cells by either ART or the immune system. However, treatment with IC inhibitors has been associated with toxicities such as immune-related adverse events and therefore future studies should proceed with caution.

HIV Reservoir Decay and CD4 Recovery Associated With High CD8 Counts in Immune Restored Patients on Long-Term ART

“…To examine the viral reservoir decay dynamics of the three groups, we assessed levels of cell-associated HIV DNA (17,18), HIV specific antibodies (19,20), and PD-1 expression on CD4 T-cells (21)(22)(23)(24) in this study.…”

Advances toward Curing HIV-1 Infection in Tissue Reservoirs

“…During chronic viral infections, including HIV infection, upregulation of inhibitory checkpoint molecules on immune cells contributes to T-cell exhaustion characterized by loss of effector functions and failure to proliferate in response to antigen (67). Checkpoint molecules are enriched on the surface of HIV-infected CD4 ϩ T cells in ART-treated individuals, and the number of cells expressing these molecules is tightly correlated with the size of the T-cell viral reservoir (68)(69)(70).…”

Measuring the Success of HIV-1 Cure Strategies

“…One such method utilizes the relatively new discovery that exhausted CD4 T cells expressing immune checkpoint (IC) makers such as PD1 and CTLA-4, are a major reservoir of replication competent provirus (Banga et al, 2016;Fromentin et al, 2016;Castellano et al, 2017;McGary et al, 2017). IC markers are inhibitory receptors expressed by T cells in response to chronic viral infection to attenuate their effector function and limit tissue damage associated with long term immune activation (Boyer and Palmer, 2018). Cells expressing these markers, that are enriched in latent provirus, could therefore be specifically targeted for drug delivery or clearance using PD1, CTLA-4, or PD-L1 antibodies (Pantaleo and Levy, 2016;Gay et al, 2017a;Boyer and Palmer, 2018).…”

“…IC markers are inhibitory receptors expressed by T cells in response to chronic viral infection to attenuate their effector function and limit tissue damage associated with long term immune activation (Boyer and Palmer, 2018). Cells expressing these markers, that are enriched in latent provirus, could therefore be specifically targeted for drug delivery or clearance using PD1, CTLA-4, or PD-L1 antibodies (Pantaleo and Levy, 2016;Gay et al, 2017a;Boyer and Palmer, 2018). To this end, several studies have demonstrated that IC blockade can inhibit the establishment of latency in vitro and aid latency reversal in vivo, revealing its potential as an HIV-1 therapeutic (McManamy et al, 2014;Gay et al, 2017a;Evans et al, 2018;Fromentin et al, 2019;van der Sluis et al, 2020).…”