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.
Bibliographical noteFunding Information:
We thank Brett Anderson and Matthew Jarvis for comments, Kate Lauer for technical assistance, and Bruce Torbett for support. The following reagents were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: anti-human APO-BEC3G C-terminal polyclonal antibody (pAb 10201) from Dr. Jaisri Lingappa, pCH058. c/2960 (cat# 11856) from Dr. John Kappes and Dr. Christina Ochsenbauer, pRHGA (cat#12421) from Dr. Beatrice Hahn, HIV-1 Z3618M T/F (cat# 13262) and Z3618F Z3618F (SGA 11) infectious molecular clones (cat# 13263) from Dr. Eric Hunter, and SIVmac239 SpX from Dr. Ronald C. Desrosiers. This work was supported by NIAID R37 AI064046 and NCI R21 CA206309 (to R.S.H.) and a Collaborative Development Project sub-award from NIGMS 2U54GM103368 and NIAID R21 AI138793 (to D.E.). Funding for the Partners in Prevention HSV/HIV Transmission Study was provided by the Bill and Melinda Gates Foundation, Grant # 26469. C.M.R. received salary support from NIAID T32-AI83196 and a University of Minnesota Doctoral Dissertation Fellowship, A. Z.C. from University of Minnesota Medical Scientist Training Program (NCI F30 CA200432) and NIGMS T32 GM008244, J.W. from a University of Minnesota Graduate School Interdisciplinary Doctoral Fellowship, J.L.M. from NSF Graduate Research Fellowship, D.J.S. from University of Minnesota Craniofacial Research Training (Min-nCResT) program (NIH T90DE022732), and G.J.S. from NSF Graduate Research Fellowship. R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of the Howard Hughes Medical Institute.