Increased replication of non-syncytium-inducing HIV type 1 isolates in monocyte-derived macrophages is linked to advanced disease in infected children.
Non-syncytium-inducing (NSI) strains of HIV-1 prevail among most infected children, including pediatric patients who develop advanced disease, severe immune suppression, and die. A study was designed to address the hypothesis that genotypic and/or phenotypic markers can distinguish NSI viruses isolated during early infection from NSI viruses found in advanced disease. Primary HIV-1 isolates, which were obtained from 43 children, adolescents, and adults who displayed a cross-section of clinical disease and immune suppression but were untreated by protease inhibitor antiretroviral therapy, were characterized for replication phenotype in different cell types. Most individuals (81%) harbored NSI viruses and almost half had progressed to advanced disease or severe immune deficiency. About 51% of NSI isolates produced low levels of p24 antigen (median, 142 pg/ml) in monocyte-derived macrophages (MDMs), 31% produced medium levels (median, 1584 pg/ml), and 17% produced high levels (median, 81,548 pg/ml) (p < 0.001). Seven of eight syncytium-inducing isolates also replicated in MDMs and displayed a dual-tropic phenotype that was associated with advanced disease. Replication of NSI viruses in MDMs varied as much as 100- to 1000-fold and was independent of replication in peripheral blood mononuclear cells. Replication in MDMs provided a clear biological feature to distinguish among viruses that were otherwise identical by NSI phenotype, V3 genotype, and CCR5 coreceptor usage. Low-level MDM replication was characteristic of viruses isolated from asymptomatic individuals, including long-term survivors. Enhanced MDM replication was related to morbidity and mortality among patients. Replication levels in MDMs provide a novel prognostic indicator of pathogenic potential by NSI viruses.
Tuttle
Daniel L
DL
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Anders
Cynthia B
CB
Aquino-De Jesus
M Janette
MJ
Poole
Paul P
PP
Lamers
Susanna L
SL
Briggs
Daniel R
DR
Pomeroy
Steven M
SM
Alexander
Louis
L
Peden
Keith W C
KW
Andiman
Warren A
WA
Sleasman
John W
JW
Goodenow
Maureen M
MM
D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000473:pathology / Q000821:virology; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004279:DNA, Viral / Q000032:analysis; D018450:Disease Progression; D005838:Genotype; D015726:Giant Cells / Q000821:virology; D016655:HIV Core Protein p24 / Q000032:analysis; D015658:HIV Infections / Q000097:blood / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification*; D006801:Humans; D007223:Infant; D008264:Macrophages / Q000821:virology*; D009000:Monocytes / Q000821:virology; D010641:Phenotype; D010802:Phylogeny; D011379:Prognosis; D014759:Viral Envelope Proteins / Q000737:chemistry; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication
D004279:DNA, Viral; D016655:HIV Core Protein p24; D014759:Viral Envelope Proteins; D014764:Viral Proteins