Cell-Associated HIV-1 DNA and RNA Decay Dynamics During Early Combination Antiretroviral Therapy in HIV-1-Infected Infants.
BACKGROUND
The decay of human immunodeficiency virus type 1 (HIV-1)-infected cells during early combination antiretroviral therapy (cART) in infected infants is not defined.


METHODS
HIV-1 DNA, including 2-long terminal repeat (2-LTR) circles, and multiply spliced (ms-) and unspliced (us-) HIV-1 RNA concentrations were measured at 0, 24, 48, and 96 weeks of cART in infants from the IMPAACT P1030 trial receiving lopinavir-ritonavir-based cART. The ratio of HIV-1 DNA concentrations to replication-competent genomes was also estimated. Linear mixed effects models with random intercept and linear splines were used to estimate patient-specific decay kinetics of HIV-1 DNA.


RESULTS
The median HIV-1 DNA concentration before cART at a median age of 2 months was 3.2 log10 copies per million PBMC. With cART, the average estimated patient-specific change in HIV-1 DNA concentrations was -0.040 log10/week (95% confidence interval [CI], -.05, -.03) between 0 and 24 weeks and -0.017 log10/week between 24 and 48 weeks (95% CI, -.024, -.01). 2-LTR circles decreased with cART but remained detectable through 96 weeks. Pre-cART HIV-1 DNA concentration was correlated with time to undetectable plasma viral load and post-cART HIV-1 DNA at 96 weeks; although HIV-1 DNA concentrations exceeded replication-competent HIV-1 genomes by 148-fold. Almost all infants had ms- and usRNA detected pre-cART, with 75% having usRNA through 96 weeks of cART.


CONCLUSIONS
By 2 months of age, a large pool of HIV-1-infected cells is established in perinatal infection, which influences time to undetectable viral load and reservoir size. This has implications for informing novel approaches aimed at early restriction of HIV-1 reservoirs to enable virologic remission and cure.
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Priyanka
P
Uprety
Department of Pediatrics, Northwestern University School of Medicine, Chicago, Illinois.
Ellen G
EG
Chadwick
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Kaitlin
K
Rainwater-Lovett
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Carrie
C
Ziemniak
Department of Pediatrics, University of Massachusetts Medical School, Worcester.
Katherine
K
Luzuriaga
Department of Pediatrics, University of California, San Diego.
Edmund V
EV
Capparelli
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Gayane
G
Yenokyan
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Deborah
D
Persaud
D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D004279:DNA, Viral / Q000032:analysis*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000821:virology*; D008297:Male; D020871:RNA Stability; D012367:RNA, Viral / Q000032:analysis*; D055502:Secondary Prevention; D019562:Viral Load
D044966:Anti-Retroviral Agents; D004279:DNA, Viral; D012367:RNA, Viral
HIV-1 DNA decay; HIV-1 RNA decay; early combination antiretroviral therapy; perinatal HIV-1 infection; reservoir