title: The HLA-C*04: 01/KIR2DS4 gene combination and human leukocyte antigen alleles with high population frequency drive rate of HIV disease progression.
abstract: OBJECTIVE
  The objective of this study is to identify human leukocyte antigen (HLA) class I and killer-cell immunoglobulin-like receptor (KIR) genotypes associated with different risks for HIV acquisition and HIV disease progression.
  
  
  METHODS
  A cross-sectional study of a cohort of 468 high-risk individuals (246 HIV-positive and 222 HIV-negative) from outpatient clinics in Lima (Perú).
  
  
  METHODS
  The cohort was high-resolution HLA and KIR-typed and analysed for potential differences in single-allele frequencies and allele combinations between HIV-positive and HIV-negative individuals and for associations with HIV viral load and CD4 cell counts in infected individuals.
  
  
  RESULTS
  HLA class I alleles associated with a lack of viral control had a significantly higher population frequency than relatively protective alleles (P = 0.0093), in line with a rare allele advantage. HLA-A02 : 01 and HLA-C04 : 01 were both associated with high viral loads (P = 0.0313 and 0.0001, respectively) and low CD4 cell counts (P = 0.0008 and 0.0087, respectively). Importantly, the association between HLA-C04 : 01 and poor viral control was not due to its linkage disequilibrium with other HLA alleles. Rather, the coexpression of its putative KIR ligand KIR2DS4f was critically linked to elevated viral loads.
  
  
  CONCLUSIONS
  These results highlight the impact of population allele frequency on viral control and identify a novel association between HLA-C04 : 01 in combination with KIR2DS4f and uncontrolled HIV infection. Our data further support the importance of the interplay of markers of the adaptive and innate immune system in viral control.
authors.affiliation: aIrsiCaixa AIDS Research Institute - HIVACAT, Hospital Germans Trias i bUniversitat Autònoma de Barcelona, Barcelona, Spain cDepartment of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA dAsociación Civil IMPACTA Salud y Educación, Lima, Peru eDepartment of Global Health, University of Washington, Seattle, Washington fUniversity of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA gResearch Institute of the McGill University Health Centre, Montreal, Quebec, Canada hDepartament d'Estadística i Investigació Operativa, Universitat Politècnica de Catalunya iInstitució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona jUniversitat de Vic (UVIC-UCC), Vic, Spain. *Alex Olvera and Susana Pérez-Álvarez contributed equally to this work.
authors.forename: Alex
authors.initials: A
authors.lastname: Olvera
authors.forename: Susana
authors.initials: S
authors.lastname: Pérez-Álvarez
authors.forename: Javier
authors.initials: J
authors.lastname: Ibarrondo
authors.forename: Carmela
authors.initials: C
authors.lastname: Ganoza
authors.forename: Javier R
authors.initials: JR
authors.lastname: Lama
authors.forename: Aldo
authors.initials: A
authors.lastname: Lucchetti
authors.forename: Steven
authors.initials: S
authors.lastname: Cate
authors.forename: William
authors.initials: W
authors.lastname: Hildebrand
authors.forename: Nicole
authors.initials: N
authors.lastname: Bernard
authors.forename: Lupe
authors.initials: L
authors.lastname: Gomez
authors.forename: Jorge
authors.initials: J
authors.lastname: Sanchez
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
mesh_terms: D018791:CD4 Lymphocyte Count; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000473:pathology* / Q000821:virology; D015236:HLA-C Antigens / Q000235:genetics*; D006801:Humans; D010568:Peru; D054340:Receptors, KIR / Q000235:genetics*; D019562:Viral Load
chemical_list: D015236:HLA-C Antigens; C039966:HLA-C*04 antigen; C473953:KIR2DS4 protein, human; D054340:Receptors, KIR