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Differential HIV-1 Proviral Defects in Children vs. Adults on Antiretroviral Therapy.

Jenna M Hasson1, Mary Grace Katusiime1, Adam A Capoferri1

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Investigating human immunodeficiency virus type 1 (HIV-1) proviral DNA in children on long-term antiretroviral therapy (ART) revealed significant gene deletions, particularly in the env gene. This suggests distinct selection pressures in pediatric HIV-1 infection compared to adults.

Keywords:
HIV in childrenHIV latencyHIV persistenceHIV provirusesHIV reservoirintact provirus

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Area of Science:

  • Virology
  • Immunology
  • Genetics

Background:

  • Understanding the human immunodeficiency virus type 1 (HIV-1) proviral landscape is crucial for developing effective remission strategies.
  • Pediatric HIV-1 infection presents unique challenges due to ongoing development and different exposure timelines compared to adult infections.

Purpose of the Study:

  • To characterize the near full-length HIV-1 proviral DNA structures in children with long-term vertically acquired infection on antiretroviral therapy (ART).
  • To compare these proviral landscapes with existing datasets from children pre-ART, on short-term ART, and from adults on ART.
  • To identify potential genetic targets for measuring the intact HIV reservoir and achieving HIV remission in children.

Main Methods:

  • Near full-length HIV-1 single-genome sequencing was performed on blood samples from 5 children on ART for approximately 7-9 years.
  • Proviral structures were analyzed and compared to published data from different pediatric and adult HIV-1 cohorts.

Main Results:

  • A strong selection for large internal proviral deletions, especially within the env gene, was observed in children on long-term ART.
  • Sequence-intact proviruses were found at a lower frequency (2.5%) in children compared to adults.
  • Defects in the major splice donor site (MSD) and packaging signal were less frequent in children on ART compared to adults, while tat gene defects were more common in children.

Conclusions:

  • Different selection pressures shape the HIV-1 proviral landscape in children compared to adults, with a notable preference for large deletions.
  • The findings suggest distinct genetic regions may be relevant for measuring the intact HIV reservoir and for developing pediatric HIV remission strategies.