title: Genome-Wide Analyses Reveal Gene Influence on HIV Disease Progression and HIV-1C Acquisition in Southern Africa.
abstract: Sub-Saharan Africans infected with HIV-1C make up the largest AIDS patient population in the world and exhibit large heterogeneity in disease progression before initiating antiretroviral therapy. To identify host variants associated with HIV disease progression, we performed genome-wide association studies on a total of 556 treatment-naive HIV-infected individuals in Botswana. We characterized the pattern of HIV disease progression using a novel functional principal component analysis, which can better capture longitudinal CD4 and viral load (VL) trajectories. Two single-nucleotide polymorphisms (SNPs) near HCG22 (chr6, peak variant rs2535307, combined p = 3.72 × 10-7, minor allele as risky allele) and CCNG1 (chr5, peak variant kgp22385164, combined p = 1.88 × 10-6, minor allele as risky allele) were significantly associated with CD4 and VL dynamics. Inspection of SNPs in these gene regions in a third Botswana cohort (using GWATCH) also revealed a strong association of HCG22 with HIV-1C acquisition, suggesting that this region is associated with infection as well as disease progression. Our study uncovered two genetic regions that are significant and have specific effects on HIV-1C acquisition or progression in sub-Saharan Africans, and the result suggested new potential targets for AIDS prevention and treatment. In addition, our results also indicate the possibility of using genetic markers as HIV disease progression indicators in sub-Saharan Africans to prioritize fast progressors for antiretroviral treatment.
authors.affiliation: 1 Harvard T.H. Chan School of Public Health AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health , Boston, Massachusetts.|2 Botswana Harvard AIDS Institute , Gaborone, Botswana .
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.affiliation: 3 Department of Biomedical Informatics, Harvard Medical School , Boston, Massachusetts.
authors.forename: Denis
authors.initials: D
authors.lastname: Agniel
authors.affiliation: 4 Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University , St. Petersburg, Russia .
authors.forename: Andrey
authors.initials: A
authors.lastname: Shevchenko
authors.affiliation: 4 Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University , St. Petersburg, Russia .|5 Department of Mathematics, St. Petersburg Electrotechnical University , St Petersburg, Russia .
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Malov
authors.affiliation: 4 Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University , St. Petersburg, Russia .
authors.forename: Anton
authors.initials: A
authors.lastname: Svitin
authors.affiliation: 4 Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University , St. Petersburg, Russia .
authors.forename: Nikolay
authors.initials: N
authors.lastname: Cherkasov
authors.affiliation: 6 Department of Dietetics and Nutrition, Robert Stempel College of Public Health & Social Work, Florida International University , Miami, Florida.
authors.forename: Marianna K
authors.initials: MK
authors.lastname: Baum
authors.affiliation: 6 Department of Dietetics and Nutrition, Robert Stempel College of Public Health & Social Work, Florida International University , Miami, Florida.
authors.forename: Adriana
authors.initials: A
authors.lastname: Campa
authors.affiliation: 1 Harvard T.H. Chan School of Public Health AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health , Boston, Massachusetts.|2 Botswana Harvard AIDS Institute , Gaborone, Botswana .
authors.forename: Simani
authors.initials: S
authors.lastname: Gaseitsiwe
authors.affiliation: 1 Harvard T.H. Chan School of Public Health AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health , Boston, Massachusetts.|2 Botswana Harvard AIDS Institute , Gaborone, Botswana .
authors.forename: Hermann
authors.initials: H
authors.lastname: Bussmann
authors.affiliation: 1 Harvard T.H. Chan School of Public Health AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health , Boston, Massachusetts.|2 Botswana Harvard AIDS Institute , Gaborone, Botswana .
authors.forename: Joseph
authors.initials: J
authors.lastname: Makhema
authors.affiliation: 1 Harvard T.H. Chan School of Public Health AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health , Boston, Massachusetts.|2 Botswana Harvard AIDS Institute , Gaborone, Botswana .
authors.forename: Richard
authors.initials: R
authors.lastname: Marlink
authors.affiliation: 1 Harvard T.H. Chan School of Public Health AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health , Boston, Massachusetts.|2 Botswana Harvard AIDS Institute , Gaborone, Botswana .
authors.forename: Vladimir
authors.initials: V
authors.lastname: Novitsky
authors.affiliation: 1 Harvard T.H. Chan School of Public Health AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health , Boston, Massachusetts.
authors.forename: Tun-Hou
authors.initials: TH
authors.lastname: Lee
authors.affiliation: 7 Department of Biostatistics, Harvard T.H. Chan School of Public Health , Boston, Massachusetts.
authors.forename: Tianxi
authors.initials: T
authors.lastname: Cai
authors.affiliation: 4 Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University , St. Petersburg, Russia .|8 Oceanographic Center, Nova Southeastern University , Ft. Lauderdale, Florida.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Brien
authors.affiliation: 1 Harvard T.H. Chan School of Public Health AIDS Initiative, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health , Boston, Massachusetts.|2 Botswana Harvard AIDS Institute , Gaborone, Botswana .
authors.forename: M
authors.initials: M
authors.lastname: Essex
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001902:Botswana; D018791:CD4 Lymphocyte Count; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D019562:Viral Load; D055815:Young Adult
keywords: HIV clinical outcomes research; HIV transmission; HIV/AIDS pathogenesis; natural hosts; restriction factors