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Genetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1

Diako Ebrahimi1, Christopher M Richards1, Michael A Carpenter1,2

  • 1Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA.

Nature Communications
|October 10, 2018
PubMed

Insights

Human APOBEC3H (A3H) splice variant 200 (SV200) is highly antiviral against HIV-1, but HIV-1 protease degrades it. This mechanism, prevalent in Africa, counters A3H

Area of Science:

  • Immunology
  • Genetics
  • Virology

Background:

  • Human APOBEC3H (A3H) is a DNA deaminase that restricts HIV-1.
  • Seven A3H haplotypes and four splice variants (SV) exist with varied antiviral activities.
  • The genetic basis for A3H variant expression and function is not fully understood.

Purpose of the Study:

  • To investigate the genetic and mechanistic basis for differential expression and function of A3H splice variants.
  • To understand the role of A3H SV200 in HIV-1 restriction, particularly in sub-Saharan African populations.

Main Methods:

  • Combined bioinformatic and experimental analysis.
  • mRNA splicing analysis.
  • HIV-1 restriction assays.
  • Protease cleavage assays.

Main Results:

  • SV200 expression is specific to A3H haplotype II, found predominantly in sub-Saharan Africa.
  • An ancient intronic deletion [del(ctc)] in haplotype II drives SV200 mRNA splicing.
  • SV200 exhibits at least fourfold greater HIV-1 restriction than other A3H variants.
  • HIV-1 protease cleaves SV200 into a less restrictive isoform, acting as a counter-defense.

Conclusions:

  • Differential A3H splicing and function are driven by genetic variations like intronic deletions.
  • HIV-1 employs protease cleavage as a counter-defense against potent A3H variants, particularly SV200.
  • This protease-based evasion mechanism is prevalent in >80% of sub-Saharan African populations, impacting HIV-1 restriction.

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