PMID- 34061023
OWN - NLM
STAT- MEDLINE
DCOM- 20211019
LR  - 20211019
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 10
DP  - 2021 Jun 1
TI  - Systematic screening of viral and human genetic variation identifies 
      antiretroviral resistance and immune escape link.
LID - 10.7554/eLife.67388 [doi]
LID - e67388
AB  - BACKGROUND: Considering the remaining threat of drug-resistantmutations (DRMs) to 
      antiretroviral treatment (ART) efficacy, we investigated how the selective 
      pressure of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes 
      drives certain DRMs' emergence and retention. METHODS: We systematically screened 
      DRM:HLA class I allele combinations in 3997 ART-naive Swiss HIV Cohort Study 
      (SHCS) patients. For each pair, a logistic regression model preliminarily tested 
      for an association with the DRM as the outcome. The three HLA:DRM pairs remaining 
      after multiple testing adjustment were analyzed in three ways: cross-sectional 
      logistic regression models to determine any HLA/infection time interaction, 
      survival analyses to examine if HLA type correlated with developing specific 
      DRMs, and via NetMHCpan to find epitope binding evidence of immune escape. 
      RESULTS: Only one pair, RT-E138:HLA-B18, exhibited a significant interaction 
      between infection duration and HLA. The survival analyses predicted two pairs 
      with an increased hazard of developing DRMs: RT-E138:HLA-B18 and RT-V179:HLA-B35. 
      RT-E138:HLA-B18 exhibited the greatest significance in both analyses (interaction 
      term odds ratio [OR] 1.169 [95% confidence interval (CI) 1.075-1.273]; 
      p-value<0.001; survival hazard ratio 12.211 [95% CI 3.523-42.318]; 
      p-value<0.001). The same two pairs were also predicted by netMHCpan to have 
      epitopic binding. CONCLUSIONS: We identified DRM:HLA pairs where HLA presence is 
      associated with the presence or emergence of the DRM, indicating that the 
      selective pressure for these mutations alternates direction depending on the 
      presence of these HLA alleles. FUNDING: Funded by the Swiss National Science 
      Foundation within the framework of the SHCS, and the University of Zurich, 
      University Research Priority Program: Evolution in Action: From Genomes 
      Ecosystems, in Switzerland.
CI  - (c) 2021, Nguyen et al.
FAU - Nguyen, Huyen
AU  - Nguyen H
AUID- ORCID: 0000-0003-1486-8970
AD  - Division of Infectious Diseases and Hospital Epidemiology, University Hospital 
      Zurich, University of Zurich, Zurich, Switzerland.
AD  - Institute of Medical Virology, Swiss National Center for Retroviruses, University 
      of Zurich, Zurich, Switzerland.
FAU - Thorball, Christian Wandell
AU  - Thorball CW
AD  - School of Life Sciences, Ecole Polytechnique, Federale de Lausanne, Switzerland.
AD  - Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, 
      Lausanne, Switzerland.
FAU - Fellay, Jacques
AU  - Fellay J
AUID- ORCID: 0000-0002-8240-939X
AD  - School of Life Sciences, Ecole Polytechnique, Federale de Lausanne, Switzerland.
AD  - Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, 
      Lausanne, Switzerland.
FAU - Boni, Jurg
AU  - Boni J
AD  - Institute of Medical Virology, Swiss National Center for Retroviruses, University 
      of Zurich, Zurich, Switzerland.
FAU - Yerly, Sabine
AU  - Yerly S
AD  - Laboratory of Virology, Geneva University Hospital, University of Geneva, Geneva, 
      Switzerland.
FAU - Perreau, Matthieu
AU  - Perreau M
AD  - Division of Immunology and Allergy, University Hospital Lausanne, University of 
      Lausanne, Lausanne, Switzerland.
FAU - Hirsch, Hans H
AU  - Hirsch HH
AD  - Transplantation & Clinical Virology, Department of Biomedicine, University of 
      Basel, Basel, Switzerland.
AD  - Infectious Diseases and Hospital Epidemiology, Department of Medicine, University 
      Hospital Basel, Basel, Switzerland.
AD  - Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, 
      Switzerland.
FAU - Kusejko, Katharina
AU  - Kusejko K
AUID- ORCID: 0000-0002-4638-1940
AD  - Division of Infectious Diseases and Hospital Epidemiology, University Hospital 
      Zurich, University of Zurich, Zurich, Switzerland.
AD  - Institute of Medical Virology, Swiss National Center for Retroviruses, University 
      of Zurich, Zurich, Switzerland.
FAU - Thurnheer, Maria Christine
AU  - Thurnheer MC
AD  - University Clinic of Infectious Diseases, University Hospital of Bern, University 
      of Bern, Bern, Switzerland.
FAU - Battegay, Manuel
AU  - Battegay M
AD  - Infectious Diseases and Hospital Epidemiology, Department of Medicine, University 
      Hospital Basel, Basel, Switzerland.
FAU - Cavassini, Matthias
AU  - Cavassini M
AD  - Department of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, 
      University of Lausanne, Lausanne, Switzerland.
FAU - Kahlert, Christian R
AU  - Kahlert CR
AUID- ORCID: 0000-0002-0784-3276
AD  - Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St. 
      Gallen, St. Gallen, Switzerland.
FAU - Bernasconi, Enos
AU  - Bernasconi E
AD  - Division of Infectious Diseases, Regional Hospital, Lugano, Switzerland.
FAU - Gunthard, Huldrych F
AU  - Gunthard HF
AD  - Division of Infectious Diseases and Hospital Epidemiology, University Hospital 
      Zurich, University of Zurich, Zurich, Switzerland.
AD  - Institute of Medical Virology, Swiss National Center for Retroviruses, University 
      of Zurich, Zurich, Switzerland.
FAU - Kouyos, Roger D
AU  - Kouyos RD
AUID- ORCID: 0000-0002-9220-8348
AD  - Division of Infectious Diseases and Hospital Epidemiology, University Hospital 
      Zurich, University of Zurich, Zurich, Switzerland.
AD  - Institute of Medical Virology, Swiss National Center for Retroviruses, University 
      of Zurich, Zurich, Switzerland.
CN  - Swiss HIV Cohort Study
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20210601
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Anti-Retroviral Agents)
RN  - 0 (HLA Antigens)
SB  - IM
MH  - Anti-Retroviral Agents/*therapeutic use
MH  - Cross-Sectional Studies
MH  - Drug Resistance, Viral/*genetics/immunology
MH  - Female
MH  - *Genome, Human
MH  - *Genome, Viral
MH  - HIV Infections/*drug therapy/genetics/immunology/mortality
MH  - HLA Antigens/*genetics/immunology
MH  - Humans
MH  - Longitudinal Studies
MH  - Male
MH  - Middle Aged
MH  - *Mutation
MH  - Mutation Rate
MH  - Prospective Studies
MH  - Risk Assessment
MH  - Risk Factors
MH  - Switzerland
MH  - T-Lymphocytes, Cytotoxic/*immunology
MH  - Treatment Outcome
PMC - PMC8169104
OTO - NOTNLM
OT  - HIV
OT  - HLA
OT  - epidemiology
OT  - global health
OT  - human
OT  - infectious disease
OT  - microbiology
OT  - mutations
COIS- HN, CT, JF, JB, SY, MP, HH, KK, MT, MB, CK, RK No competing interests declared, 
      MC has received research and travel grants for his institution from ViiV and 
      Gilead. EB has received fees for his institution for participation to advisory 
      board from MSD, Gilead Sciences, ViiV Healthcare, Abbvie and Janssen. HG HFG has 
      received unrestricted research grants from Gilead Sciences and Roche; fees for 
      data and safety monitoring board membership from Merck; consulting/advisory board 
      membership fees from Gilead Sciences, Sandoz and Mepha; and travel reimbursement 
      from Gilead.
EDAT- 2021/06/02 06:00
MHDA- 2021/10/21 06:00
PMCR- 2021/06/01
CRDT- 2021/06/01 12:18
PHST- 2021/02/09 00:00 [received]
PHST- 2021/05/18 00:00 [accepted]
PHST- 2021/06/01 12:18 [entrez]
PHST- 2021/06/02 06:00 [pubmed]
PHST- 2021/10/21 06:00 [medline]
PHST- 2021/06/01 00:00 [pmc-release]
AID - 67388 [pii]
AID - 10.7554/eLife.67388 [doi]
PST - epublish
SO  - Elife. 2021 Jun 1;10:e67388. doi: 10.7554/eLife.67388.