Antiretroviral Drug Discovery Targeting the HIV-1 Nef Virulence Factor

Abstract

While antiretroviral drugs have transformed the lives of HIV-infected individuals, chronic treatment is required to prevent rebound from viral reservoir cells. People living with HIV also are at higher risk for cardiovascular and neurocognitive complications, as well as cancer. Finding a cure for HIV-1 infection is therefore an essential goal of current AIDS research. This review is focused on the discovery of pharmacological inhibitors of the HIV-1 Nef accessory protein. Nef is well known to enhance HIV-1 infectivity and replication, and to promote immune escape of HIV-infected cells by preventing cell surface MHC-I display of HIV-1 antigens. Recent progress shows that Nef inhibitors not only suppress HIV-1 replication, but also restore sufficient MHC-I to the surface of infected cells to trigger a cytotoxic T lymphocyte response. Combining Nef inhibitors with latency reversal agents and therapeutic vaccines may provide a path to clearance of viral reservoirs.

Keywords: AIDS; HIV-1; MHC-I; Nef; Nef inhibitor; antiretroviral; latent viral reservoir.

Figure 1

Chemical structures of direct binding HIV-1 Nef inhibitors. Initial studies describing the discovery of these compounds are referenced in parentheses. A comparison of their antiretroviral activities is presented in Table 1 [29,31,32,38,40].

Figure 2

Medicinal chemistry optimization of B9. First-generation B9 analogs replaced the diazene linker with one- or two-carbon bonds; a non-azo analog with a 2-carbon linker is shown. These analogs retained Nef binding and antiretroviral activity and demonstrated oral bioavailability [37]. B9 and these non-azo analogs also restored sufficient MHC-I surface expression in primary CD4+ T cells to trigger a CTL response in vitro [36]. Subsequent analogs maintained the hydroxypyrazole core, which is essential for Nef interaction and antiretroviral activity, while diversifying substituents around the core as exemplified by analog FC-7976. This analog bound recombinant Nef by SPR with a K_D value in the 0.1 nM range and inhibited HIV-1 replication in donor PBMCs with an IC₅₀ value of 0.7 µM [39]. Also shown is a related benzimidazole analog, FC-7097, which disrupted Nef homodimer formation by X-ray crystallography. See main text for details.