Variants in Host Viral Replication Cycle Genes Are Associated With Heterosexual HIV-1 Acquisition in Africans

Bigham, Abigail W. PhD*; Mackelprang, Romel D. PhD; Celum, Connie MD†,‡,§; Bruyn, Guy De MD; Beima-Sofie, Kristin PhD; John-Stewart, Grace MPH, MD, PhD†,‡,§; Ronald, Allan MD; Mugo, Nelly R. MD, MPH, MMed†,#; Buckingham, Kati BS**; Bamshad, Michael J. MD**,††; Mullins, James I. PhD¶,‡‡; McElrath, M. J. MD, PhD¶,§§; Lingappa, Jairam R. MD, PhD†,§,**

JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0000000000000113
Basic and Translational Science
Abstract

Objective: We evaluated genetic variants in 51 candidate genes encoding proteins that interact with HIV-1 during the virus life cycle for association with HIV-1 outcomes in an African cohort.

Methods: Using a nested case–control study within a cohort of heterosexual HIV-1–serodiscordant couples, we genotyped 475 haplotype-tagging single-nucleotide polymorphisms (tagSNPs) and 18 SNPs previously associated with HIV-1 transmission and/or progression (candidate SNPs) in 51 host genes. We used logistic and Cox proportional hazard regression with adjustment for sex, age, and population stratification to detect SNP associations with HIV-1 acquisition, plasma HIV-1 set point, and a composite measure of HIV-1 disease progression. Significant thresholds for tagSNP, but not candidate SNP, associations were subjected to Bonferroni correction for multiple testing.

Results: We evaluated 491 HIV-1–infected and 335 HIV-1–uninfected individuals for 493 SNPs, 459 of which passed quality control filters. Candidate SNP PPIA rs8177826 and tagSNP SMARCB1 rs6003904 were significantly associated with HIV-1 acquisition risk (odds ratio = 0.14, P = 0.03, and odds ratio = 2.11, Pcorr = 0.01, respectively). Furthermore, the TT genotype for CCR5 rs1799988 was associated with a mean 0.2 log10 copies per milliliter lower plasma HIV-1 RNA set point (P = 0.04). We also identified significant associations with HIV-1 disease progression for variants in FUT2 and MBL2.

Conclusions: Using a targeted gene approach, we identified variants in host genes whose protein products interact with HIV-1 during the virus replication cycle and were associated with HIV-1 outcomes in this African cohort.

Author Information

*Department of Anthropology, University of Michigan, Ann Arbor, MI;

Departments of Global Health;

Epidemiology;

§Medicine, University of Washington, Seattle, WA;

Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa;

Department of Medicine, University of Manitoba, Winnipeg, Canada;

#Department of Obstetrics and Gynaecology, University of Nairobi, Nairobi, Kenya;

Departments of **Pediatrics;

††Genome Sciences;

‡‡Laboratory Medicine, University of Washington, Seattle, WA; and

§§Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Correspondence to: Abigail W. Bigham, PhD, Department of Anthropology, University of Michigan, 101 West Hall, 1085 S University Avenue, Ann Arbor, MI 48109 (e-mail: awbigham@umich.edu).

A.W.B. and R.D.M. performed the analysis, A.W.B., R.D.M., and J.R.L. wrote the manuscript. J.R.L. conceived of the experiments. M.J.B. and K.B. provided materials and reagents. K.B.S., C.C., G.D.B., G.J.S., M.J.M., J.I.M., N.R.M., and A.R. assisted with sample collection.

Presented at the Keystone Symposia: HIV Evolution, Genomics and Pathogenesis, March 20-25, 2011, British Columbia, Canada.

J.R.L. is a scientific board member of Prosetta AntiViral Inc. G.J.S. receives royalties from UpToDate. M.J.B. receives royalties from textbook publication.

Supported by the Bill and Melinda Gates Foundation (grants 26469 and 41185), National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (R21 grant AI073115), and the University of Washington Center for AIDS Research, an NIH funded program (P30 AI027757). A.W.B. was supported by a training fellowship from the NIH/National Human Genome Research Institute. R.D.M. was supported by the University of Washington STD/AIDS Research Training Program (T32AI007140) from the NIH, US Public Health Service.

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Received January 03, 2014

Accepted January 03, 2014

© 2014 by Lippincott Williams & Wilkins