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Flexible use of CCR5 in the absence of CXCR4 use explains the immune deficiency in HIV-1 infected children.

Cavarelli, Mariangela; Karlsson, Ingrid LU ; Ripamonti, Chiara; Plebani, Anna; Fenyö, Eva Maria LU and Scarlatti, Gabriella (2010) In AIDS 24. p.2521-2527
Abstract
DESIGN:: CCR5-using HIV-1 (R5 viruses) are usually isolated during acute infection from both adults and children. We have recently demonstrated that R5 viruses with a flexible use of CCR5 (called R5broad) can be detected in children close to birth and are predictive of a fast immunological failure. The aim of the present work was to investigate viral phenotype variation during disease progression in HIV-1 infected children, six slow and eight fast progressors. METHODS:: A total of 74 viral isolates obtained sequentially from 14 HIV-1 infected children were tested for their ability to infect U87.CD4 cells expressing a set of six different CCR5/CXCR4 chimeric receptors or wild-type coreceptors. The sensitivity of 35 R5 viruses to inhibition... (More)
DESIGN:: CCR5-using HIV-1 (R5 viruses) are usually isolated during acute infection from both adults and children. We have recently demonstrated that R5 viruses with a flexible use of CCR5 (called R5broad) can be detected in children close to birth and are predictive of a fast immunological failure. The aim of the present work was to investigate viral phenotype variation during disease progression in HIV-1 infected children, six slow and eight fast progressors. METHODS:: A total of 74 viral isolates obtained sequentially from 14 HIV-1 infected children were tested for their ability to infect U87.CD4 cells expressing a set of six different CCR5/CXCR4 chimeric receptors or wild-type coreceptors. The sensitivity of 35 R5 viruses to inhibition with the CC-chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted) was evaluated in a peripheral blood mononuclear cells based assay. RESULTS:: Viral evolution to R5broad or to R5X4 phenotype occurred with one exception, in all children, although at a different time point according to rate of disease progression. Immune deficiency in the children was significantly associated with the appearance of R5broad phenotype or R5X4 viruses. Analysis of the sensitivity to inhibition by RANTES revealed a significant correlation between the R5broad phenotype and an augmented resistance to this CC-chemokine. CONCLUSION:: We demonstrate that the viral evolution to a more flexible CCR5-use is sufficient to explain the immunological failure in the absence of CXCR4 usage. These results warrant detailed analysis of the R5 phenotype in forthcoming clinical studies introducing CCR5 inhibitors for the treatment of pediatric HIV-1 infection. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
AIDS
volume
24
pages
2521 - 2527
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000282952600012
  • pmid:20683317
  • scopus:78549232578
ISSN
1473-5571
DOI
10.1097/QAD.0b013e32833d7d8c
language
English
LU publication?
yes
id
034627e8-95c8-4d9e-a1f5-5852b8243e93 (old id 1665619)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20683317?dopt=Abstract
date added to LUP
2010-09-02 10:11:25
date last changed
2018-05-29 10:37:56
@article{034627e8-95c8-4d9e-a1f5-5852b8243e93,
  abstract     = {DESIGN:: CCR5-using HIV-1 (R5 viruses) are usually isolated during acute infection from both adults and children. We have recently demonstrated that R5 viruses with a flexible use of CCR5 (called R5broad) can be detected in children close to birth and are predictive of a fast immunological failure. The aim of the present work was to investigate viral phenotype variation during disease progression in HIV-1 infected children, six slow and eight fast progressors. METHODS:: A total of 74 viral isolates obtained sequentially from 14 HIV-1 infected children were tested for their ability to infect U87.CD4 cells expressing a set of six different CCR5/CXCR4 chimeric receptors or wild-type coreceptors. The sensitivity of 35 R5 viruses to inhibition with the CC-chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted) was evaluated in a peripheral blood mononuclear cells based assay. RESULTS:: Viral evolution to R5broad or to R5X4 phenotype occurred with one exception, in all children, although at a different time point according to rate of disease progression. Immune deficiency in the children was significantly associated with the appearance of R5broad phenotype or R5X4 viruses. Analysis of the sensitivity to inhibition by RANTES revealed a significant correlation between the R5broad phenotype and an augmented resistance to this CC-chemokine. CONCLUSION:: We demonstrate that the viral evolution to a more flexible CCR5-use is sufficient to explain the immunological failure in the absence of CXCR4 usage. These results warrant detailed analysis of the R5 phenotype in forthcoming clinical studies introducing CCR5 inhibitors for the treatment of pediatric HIV-1 infection.},
  author       = {Cavarelli, Mariangela and Karlsson, Ingrid and Ripamonti, Chiara and Plebani, Anna and Fenyö, Eva Maria and Scarlatti, Gabriella},
  issn         = {1473-5571},
  language     = {eng},
  pages        = {2521--2527},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {AIDS},
  title        = {Flexible use of CCR5 in the absence of CXCR4 use explains the immune deficiency in HIV-1 infected children.},
  url          = {http://dx.doi.org/10.1097/QAD.0b013e32833d7d8c},
  volume       = {24},
  year         = {2010},
}