A stable latent reservoir for HIV-1 in resting CD4(+) T lymphocytes in infected children.
HIV-1 persists in a latent state in resting CD4(+) T lymphocytes of infected adults despite prolonged highly active antiretroviral therapy (HAART). To determine whether a latent reservoir for HIV-1 exists in infected children, we performed a quantitative viral culture assay on highly purified resting CD4(+) T cells from 21 children with perinatally acquired infection. Replication-competent HIV-1 was recovered from all 18 children from whom sufficient cells were obtained. The frequency of latently infected resting CD4(+) T cells directly correlated with plasma virus levels, suggesting that in children with ongoing viral replication, most latently infected cells are in the labile preintegration state of latency. However, in each of 7 children who had suppression of viral replication to undetectable levels for 1-3 years on HAART, latent replication-competent HIV-1 persisted with little decay, owing to a stable reservoir of infected cells in the postintegration stage of latency. Drug-resistance mutations generated by previous nonsuppressive regimens persisted in this compartment despite more than 1 year of fully suppressive HAART, rendering untenable the idea of recycling drugs that were part of failed regimens. Thus the latent reservoir for HIV-1 in resting CD4(+) T cells will be a major obstacle to HIV-1 eradication in children.
Persaud
D
D
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. dpers@welch.jhu.edu
Pierson
T
T
Ruff
C
C
Finzi
D
D
Chadwick
K R
KR
Margolick
J B
JB
Ruff
A
A
Hutton
N
N
Ray
S
S
Siliciano
R F
RF
D000293:Adolescent; D019380:Anti-HIV Agents / Q000627:therapeutic use; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D015751:Genes, pol; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D016296:Mutagenesis; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D017735:Virus Latency; D014779:Virus Replication / Q000276:immunology; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; D004279:DNA, Viral; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine