Rotten to the core: antivirals targeting the HIV-1 capsid core

Abstract

The capsid core of HIV-1 is a large macromolecular assembly that surrounds the viral genome and is an essential component of the infectious virus. In addition to its multiple roles throughout the viral life cycle, the capsid interacts with multiple host factors. Owing to its indispensable nature, the HIV-1 capsid has been the target of numerous antiretrovirals, though most capsid-targeting molecules have not had clinical success until recently. Lenacapavir, a long-acting drug that targets the HIV-1 capsid, is currently undergoing phase 2/3 clinical trials, making it the most successful capsid inhibitor to-date. In this review, we detail the role of the HIV-1 capsid protein in the virus life cycle, categorize antiviral compounds based on their targeting of five sites within the HIV-1 capsid, and discuss their molecular interactions and mechanisms of action. The diverse range of inhibition mechanisms provides insight into possible new strategies for designing novel HIV-1 drugs and furthers our understanding of HIV-1 biology. Graphical Abstract

HIV Capsid Protein Genetic Diversity Across HIV-1 Variants and Impact on New Capsid-Inhibitor Lenacapavir

“…The high conservation of p24 also makes it an attractive target for antiretrovirals ( Chen, 2016 ; Novikova et al, 2019 ; McFadden et al, 2021 ; Saito and Yamashita, 2021 ; Dvory-Sobol et al, 2022 ; Margot et al, 2022 ). Many capsid-targeting molecules that aim to block HIV-1 infection through different mechanisms of action have been developed ( Thenin-Houssier and Valente, 2016 ; Carnes et al, 2018 ; Cevik and Orkin, 2019 ; Bester et al, 2020 ; Dvory-Sobol et al, 2022 ).…”

“…Finally, we identified the substitutions affecting the capsid assembly ( Lingappa et al, 2014 ), HIV uncoating ( Hulme et al, 2015 ), infectivity ( Yamashita et al, 2007 ; Koh et al, 2013 ), molecule binding ( Qi et al, 2008 ; Ylinen et al, 2009 ; McFadden et al, 2021 ; Saito and Yamashita, 2021 ), and lenacapavir key capsid-interaction sites and described resistance-associated mutations ( Bester et al, 2020 ; Link et al, 2020 ; Sun et al, 2021 ) according to the bibliography.…”

“…Since the capsid’s stability and integrity are critical to the normal viral replication cycle and infectivity, the HIV capsid is an exciting target for the design of new ARVs ( Rihn et al, 2013 ; Chen, 2016 ; Jacques et al, 2016 ; Novikova et al, 2019 ; McFadden et al, 2021 ; Saito and Yamashita, 2021 ). Furthermore, p24 can induce cellular immune responses [ Los Alamos National Laboratory (LANL), 2021a ] and has been included in some vaccine strategies ( Larijani et al, 2018 , 2021a , b ).…”

“…Among the numerous molecules that targeted the capsid, lenacapavir seems the most promising to date ( Yant et al, 2019 ; Dvory-Sobol et al, 2022 ; Margot et al, 2022 ). Capsid-targeting molecules bind to different sites in p24, aiming to alter the capsid stability and morphology, interfering in the assembly or disassembly processes, or competing with host factors resulting in the suppression of viral infectivity ( Li et al, 2013 ; McFadden et al, 2021 ).…”

“…This descriptive study on p24 diversity across secondary structure elements in a large p24 sequence set from different HIV-1 variants reports differences and variant-specific markers in p24 across HIV-1 groups (M, O, N, and P) and group M variants. We also report the proportion of substitutions per variant in p24 residues affecting the capsid assembly ( Lingappa et al, 2014 ), HIV uncoating ( Hulme et al, 2015 ), infectivity ( Yamashita et al, 2007 ; Koh et al, 2013 ), molecule binding ( Qi et al, 2008 ; Ylinen et al, 2009 ; McFadden et al, 2021 ; Saito and Yamashita, 2021 ), and the new CA-inhibitor lenacapavir key capsid-interaction sites and described resistance mutations ( Bester et al, 2020 ; Link et al, 2020 ; Sun et al, 2021 ), according to the bibliography.…”