title: Highly pathogenic adapted HIV-1 strains limit host immunity and dictate rapid disease progression.
abstract: OBJECTIVE
  The study of HIV-1 rapid progressors has been limited to specific case reports. Nevertheless, identification and characterization of the viral and host factors involved in rapid progression are crucial when attempting to uncover the correlates of rapid disease outcome.
  
  
  METHODS
  We carried out comparative functional analyses in rapid progressors (n = 46) and standard progressors (n = 46) early after HIV-1 seroconversion (≤1 year). The viral traits tested were viral replicative capacity, co-receptor usage, and genomic variation. Host CD8(+) T-cell responses, humoral activity, and HLA immunogenetic markers were also determined.
  
  
  RESULTS
  Our data demonstrate an unusual convergence of highly pathogenic HIV-1 strains in rapid progressors. Compared with standard progressors, rapid progressor viral strains show higher in-vitro replicative capacity (81.5 vs. 67.9%; P = 0.025) and greater X4/DM co-receptor usage (26.3 vs. 2.8%; P = 0.006) in early infection. Limited or absent functional HIV-1 CD8(+) T-cell responses and neutralizing activity were measured in rapid progressors. Moreover, the increase in common HLA allele-restricted CD8(+) T-cell escape mutations in rapid progressors acts as a signature of uncontrolled HIV-1 replication and early impairment of adaptive cellular responses.
  
  
  CONCLUSIONS
  Our data support a dominant role for viral factors in rapid progressors. Robust HIV-1 replication and intrinsic viral properties limit host adaptive immune responses, thus driving rapid disease progression.
authors.affiliation: aAIDS Research Institute -IrsiCaixa-iInstitut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain bInstitute of Microbiology, University Hospital Center and University of Lausanne, Lausanne cUniversity Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland dUniversidad Complutense de Madrid, Madrid, Spain eMonogram Biosciences, South San Francisco, California, USA fCentre d'Estudis Epidemiològics sobre les Infeccions de Transmissió Sexual i Sida de Catalunya (CEEISCAT), Badalona gBanc de Sang i Teixits, Barcelona hUniversitat de Vic (UVic-UCC), Vic iInstitució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. *Judith Dalmau and Margalida Rotger contributed equally to this article. †Amalio Talenti, Javier Martinez-Picado and Julia G. Prado contributed equally to the work.
authors.forename: Judith
authors.initials: J
authors.lastname: Dalmau
authors.forename: Margalida
authors.initials: M
authors.lastname: Rotger
authors.forename: Itziar
authors.initials: I
authors.lastname: Erkizia
authors.forename: Andri
authors.initials: A
authors.lastname: Rauch
authors.forename: Pedro
authors.initials: P
authors.lastname: Reche
authors.forename: Maria
authors.initials: M
authors.lastname: Pino
authors.forename: Anna
authors.initials: A
authors.lastname: Esteve
authors.forename: Eduard
authors.initials: E
authors.lastname: Palou
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
authors.forename: Pham
authors.initials: P
authors.lastname: Phung
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
authors.forename: Julia G
authors.initials: JG
authors.lastname: Prado
mesh_terms: D000220:Adaptation, Biological; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006801:Humans; D008297:Male; D015728:Receptors, HIV / Q000032:analysis; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D015483:HIV Antibodies; D015728:Receptors, HIV