Advances toward Curing HIV-1 Infection in Tissue Reservoirs

Abstract

A disease of more than 39.6 million people worldwide, HIV-1 infection has no curative therapy. To date, one man has achieved a sterile cure, with millions more hoping to avoid the potential pitfalls of lifelong antiretroviral therapy and other HIV-related disorders, including neurocognitive decline. Recent developments in immunotherapies and gene therapies provide renewed hope in advancing efforts toward a sterilizing or functional cure. On the horizon is research concentrated in multiple separate but potentially complementary domains: vaccine research, viral transcript editing, T-cell effector response targeting including checkpoint inhibitors, and gene editing. Here, we review the concept of targeting the HIV-1 tissue reservoirs, with an emphasis on the central nervous system, and describe relevant new work in functional cure research and strategies for HIV-1 eradication.

Trial registration: ClinicalTrials.gov NCT03367754 NCT03239899.

Keywords: CRISPR/Cas9; HIV-1; brain; checkpoint inhibitors; functional cure; latency; reservoir.

FIG 1

Summary of types of HIV reservoirs. (A and B) There are several anatomical compartments (A) that are populated by HIV-infected cells (B). (C) The integrated provirus contained within these cells may be transcriptionally silent (latent), transcriptionally active and capable of producing infectious virions (persistent), or transcriptionally active but replication defective due to mutations or deletions in the HIV genome, leading to translation of specific viral proteins for which an open reading frame remains intact.

FIG 2

Summary of immune checkpoint receptor interactions and gene editing strategies. (1) Coinhibitory checkpoint molecules such as PD-1, CTLA-4, TIGIT, Tim-3, LAG3, BTLA-4, CD160, and 2B4 are upregulated on T cells during HIV infection and negatively regulate T-cell proliferation and effector function when bound to their cognate ligands. In contrast, the costimulatory molecules CD28, CD226, and GITR enhance T-cell activation when ligated in conjunction with TCR-mediated stimulation. Checkpoint inhibitors that block binding of the indicated molecule to its target to enhance immune function are indicated in blue boxes, while the agonist TRX518, which mimics the interaction of GITR with its ligand, is indicated in yellow. Other potential HIV cure strategies include (2a) editing of the host CCR5 gene to generate resistance to HIV infection or (2b) deletion or indel-mediated transcriptional silencing of the HIV provirus by the CRISPR/Cas9 system, (3a) posttranscriptional silencing of HIV gene expression by antisense oligonucleotides complementary to viral mRNA or novel compounds, and (3b) inhibition of Tat-mediated LTR transactivation by small-molecule inhibitors identified by high-throughput screening.