Stability of APOBEC3F in the Presence of the APOBEC3 Antagonist HIV-1 Vif Increases at the Expense of Co-Expressed APOBEC3H Haplotype I

Viruses. 2023 Feb 7;15(2):463. doi: 10.3390/v15020463.

Abstract

The seven human APOBEC3 enzymes (APOBEC3A through H, excluding E) are host restriction factors. Most of the APOBEC3 enzymes can restrict HIV-1 replication with different efficiencies. The HIV-1 Vif protein combats APOBEC3-mediated restriction by inducing ubiquitination and degradation in the proteasome. APOBEC3F and APOBEC3G can hetero-oligomerize, which increases their restriction capacity and resistance to Vif. Here we determined if APOBEC3C, APOBEC3F, or APOBEC3G could hetero-oligomerize with APOBEC3H haplotype I. APOBEC3H haplotype I has a short half-life in cells due to ubiquitination and degradation by host proteins, but is also resistant to Vif. We hypothesized that hetero-oligomerization with APOBEC3H haplotype I may result in less Vif-mediated degradation of the interacting APOBEC3 and stabilize APOBEC3H haplotype I, resulting in more efficient HIV-1 restriction. Although we found that all three APOBEC3s could interact with APOBEC3H haplotype I, only APOBEC3F affected APOBEC3H haplotype I by surprisingly accelerating its proteasomal degradation. However, this increased APOBEC3F levels in cells and virions in the absence or presence of Vif and enabled APOBEC3F-mediated restriction of HIV-1 in the presence of Vif. Altogether, the data suggest that APOBEC3 enzymes can co-regulate each other at the protein level and that they cooperate to ensure HIV-1 inactivation rather than evolution.

Keywords: APOBEC3; HIV-1; restriction factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC Deaminases
  • Aminohydrolases / genetics
  • Cytidine Deaminase
  • Cytoplasm
  • Cytosine Deaminase
  • HIV Seropositivity*
  • HIV-1* / genetics
  • Haplotypes
  • Humans
  • vif Gene Products, Human Immunodeficiency Virus / genetics

Substances

  • APOBEC3A protein, human
  • Cytidine Deaminase
  • vif protein, Human immunodeficiency virus 1
  • vif Gene Products, Human Immunodeficiency Virus
  • APOBEC3F protein, human
  • Cytosine Deaminase
  • APOBEC3 proteins, human
  • APOBEC Deaminases
  • vif protein, Human immunodeficiency virus 2
  • APOBEC3H protein, human
  • Aminohydrolases

Grants and funding