title: Continued production of drug-sensitive human immunodeficiency virus type 1 in children on combination antiretroviral therapy who have undetectable viral loads.
abstract: Highly active antiretroviral therapy (HAART) can suppress plasma human immunodeficiency virus type 1 (HIV-1) levels to below the detection limit of ultrasensitive clinical assays. However, HIV-1 persists in cellular reservoirs, and in adults, persistent low-level viremia is detected with more sensitive assays. The nature of this viremia is poorly understood, and it is unclear whether viremia persists in children on HAART, particularly those who start therapy shortly after birth. We therefore developed a reverse transcriptase PCR (RT-PCR) assay that allows genotyping of HIV-1 protease even when viremia is present at levels as low as 5 copies of HIV-1 RNA/ml. We demonstrated that viremia persists in children with plasma virus levels below the limit of detection of clinical assays. Viremia was detected even in children who began HAART in early infancy and maintained such strong suppression of viremia that HIV-1-specific antibody responses were absent or minimal. The low-level plasma virus lacked protease inhibitor resistance mutations despite the frequent use of nelfinavir, which has a low mutational barrier to resistance. Protease sequences resembled those of viruses in the latent reservoir in resting CD4(+) T cells. Thus, in most children on HAART with clinically undetectable viremia, there is continued virus production without evolution of resistance in the protease gene.
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21205, USA. dpers@jhmi.edu
authors.forename: Deborah
authors.initials: D
authors.lastname: Persaud
authors.forename: George K
authors.initials: GK
authors.lastname: Siberry
authors.forename: Aima
authors.initials: A
authors.lastname: Ahonkhai
authors.forename: Joleen
authors.initials: J
authors.lastname: Kajdas
authors.forename: Daphne
authors.initials: D
authors.lastname: Monie
authors.forename: Nancy
authors.initials: N
authors.lastname: Hutton
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Watson
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Quinn
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Ray
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000595:Amino Acid Sequence; D023241:Antiretroviral Therapy, Highly Active; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy / Q000821:virology
chemical_list: D012367:RNA, Viral; D016333:HIV Protease