Genetic and Mechanistic Basis for APOBEC3H Alternative Splicing, Retrovirus Restriction, and Counteraction by HIV-1 Protease

Nat Commun. 2018 Oct 8;9(1):4137. doi: 10.1038/s41467-018-06594-3.

Abstract

Human APOBEC3H (A3H) is a single-stranded DNA cytosine deaminase that inhibits HIV-1. Seven haplotypes (I-VII) and four splice variants (SV154/182/183/200) with differing antiviral activities and geographic distributions have been described, but the genetic and mechanistic basis for variant expression and function remains unclear. Using a combined bioinformatic/experimental analysis, we find that SV200 expression is specific to haplotype II, which is primarily found in sub-Saharan Africa. The underlying genetic mechanism for differential mRNA splicing is an ancient intronic deletion [del(ctc)] within A3H haplotype II sequence. We show that SV200 is at least fourfold more HIV-1 restrictive than other A3H splice variants. To counteract this elevated antiviral activity, HIV-1 protease cleaves SV200 into a shorter, less restrictive isoform. Our analyses indicate that, in addition to Vif-mediated degradation, HIV-1 may use protease as a counter-defense mechanism against A3H in >80% of sub-Saharan African populations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Alternative Splicing / immunology*
  • Amino Acid Sequence
  • Aminohydrolases / genetics
  • Aminohydrolases / immunology*
  • Aminohydrolases / metabolism
  • Base Sequence
  • HEK293 Cells
  • HIV Protease / immunology*
  • HIV Protease / metabolism
  • HIV-1 / immunology*
  • HIV-1 / metabolism
  • Haplotypes / genetics
  • Haplotypes / immunology*
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / immunology
  • Isoenzymes / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Polymorphism, Single Nucleotide / immunology
  • Sequence Homology, Amino Acid
  • Sequence Homology, Nucleic Acid
  • Virus Replication / immunology
  • vif Gene Products, Human Immunodeficiency Virus / immunology
  • vif Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Isoenzymes
  • vif Gene Products, Human Immunodeficiency Virus
  • vif protein, Human immunodeficiency virus 1
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1
  • APOBEC3H protein, human
  • Aminohydrolases