HIV-1 capsid variability: viral exploitation and evasion of capsid-binding molecules

Abstract

The HIV-1 capsid, a conical shell encasing viral nucleoprotein complexes, is involved in multiple post-entry processes during viral replication. Many host factors can directly bind to the HIV-1 capsid protein (CA) and either promote or prevent HIV-1 infection. The viral capsid is currently being explored as a novel target for therapeutic interventions. In the past few decades, significant progress has been made in our understanding of the capsid–host interactions and mechanisms of action of capsid-targeting antivirals. At the same time, a large number of different viral capsids, which derive from many HIV-1 mutants, naturally occurring variants, or diverse lentiviruses, have been characterized for their interactions with capsid-binding molecules in great detail utilizing various experimental techniques. This review provides an overview of how sequence variation in CA influences phenotypic properties of HIV-1. We will focus on sequence differences that alter capsid–host interactions and give a brief account of drug resistant mutations in CA and their mutational effects on viral phenotypes. Increased knowledge of the sequence-function relationship of CA helps us deepen our understanding of the adaptive potential of the viral capsid.

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

“…Since p24 genetic variability can impact on viral replication cycle at different stages, we analyzed the conservation percentage in these p24 positions affecting the capsid assembly ( Lingappa et al, 2014 ), HIV uncoating ( Hulme et al, 2015 ), infectivity ( Yamashita et al, 2007 ; Koh et al, 2013 ), and molecule binding ( Qi et al, 2008 ; Ylinen et al, 2009 ; Saito and Yamashita, 2021 ).…”

“…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 ).…”

“…Since sequence variation in p24 can influence the phenotypic properties of HIV-1 and its interactions with host factors and ARVs, a deep knowledge of p24 variability across circulating variants and the identification of highly conserved HIV epitopes could help for a more rational design of p24-based diagnostic tests, ARV, and vaccines, which, ideally, should be directed to highly conserved p24 sites across all HIV-1 variants (groups, subtypes, sub-sub types, and recombinants) ( Ferrari et al, 2000 ; Hatziioannou et al, 2004 ; Thenin-Houssier and Valente, 2016 ; Saito and Yamashita, 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.…”

“…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.…”