Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS

M T Boswell; J Nazziwa; K Kuroki; A Palm; S Karlson; F Månsson; A Biague; Z J da Silva; C O Onyango; T I de Silva; A Jaye; H Norrgren; P Medstrand; M Jansson; K Maenaka; S L Rowland-Jones; J Esbjörnsson

doi:10.1093/ve/veac075

Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS

Virus Evol. 2022 Aug 24;8(2):veac075. doi: 10.1093/ve/veac075. eCollection 2022.

Authors

M T Boswell¹, J Nazziwa², K Kuroki³, A Palm², S Karlson², F Månsson², A Biague⁴, Z J da Silva⁴, C O Onyango⁵, T I de Silva^{6

7}, A Jaye⁷, H Norrgren⁸, P Medstrand², M Jansson⁹, K Maenaka³, S L Rowland-Jones^{1

7}, J Esbjörnsson^{1

2}

Affiliations

¹ Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, OX3 7FZ, Oxford, UK.
² Department of Translational Medicine, Lund University, Sölvegatan 17, 223 62, Lund, Sweden.
³ Faculty of Pharmaceutical Sciences and Global Station for Biosurfaces and Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
⁴ National Public Health Laboratory, V94M+HM4, Bissau, Guinea-Bissau.
⁵ US Centres for Disease Control, KEMRI Complex, Mbagathi Road off Mbagathi Way PO Box 606-00621, Kenya.
⁶ Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Beech Hill Rd, S10 2RX, Sheffield, UK.
⁷ Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Atlantic Boulevard, Fajara P. O. Box 273, Banjul, The Gambia.
⁸ Department of Clinical Sciences Lund, Lund University, Sölvegatan 19, 221 84 Lund, Sweden.
⁹ Department of Laboratory Medicine, Lund University, Sölvegatan 19, Sweden.

Abstract

HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 capsid (p26) amino acid polymorphisms are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific T cell responses common in slower progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. In this study we analysed 369 heterochronous HIV-2 p26 sequences from 12 participants with a median age of 30 years at enrolment. CD4% change over time was used to stratify participants into relative faster and slower progressor groups. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10^-3 versus 1.4x10^-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Median virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10^-3 vs. 2.3x10^-3; and nonsynonymous rates: 6.9x10^-4 vs. 2.7x10^-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface. p26 evolutionary rates were associated with progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate HIV-2 p26 may be an attractive therapeutic target.

Keywords: HIV-2; capsid; evolution; p26.