Relevance of Viral Phenotype in the Early AIDS Outcome of Pediatric HIV-1 Primary Infection

Kopka, Julieta

doi:10.1203/01.pdr.0000028056.74614.e0

Cited by 5 publications

(7 citation statements)

References 18 publications

(22 reference statements)

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“…[7][8][9][10] This type of bystander killing often involves cell-to-cell fusion events that lead to the formation of syncytia. Such syncytia are relatively rare in lymphoid tissues from HIV-1-infected patients, 11,12 perhaps due to their short half-live. However, syncytia dubbed as "giant multinuclear cells" are pathognonomic for the diagnosis of HIV-1-associated encephalitis (also called "neuro-AIDS"), a neurodegenerative condition that leads to dementia.…”

Section: Introductionmentioning

confidence: 99%

Pro-apoptotic function of checkpoint kinase-2 in syncytia elicited by the HIV-1 envelope

Séror¹,

Raza²,

Brottes³

et al. 2009

Cell Cycle

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Fusogenic HIV-1 isolates induce the fusion of infected and bystander cells. Such syncytia can be found as "multinucleated giant cells" in the brain from HIV-1-infected individuals, as well as in lymphoid tissues. Syncytia elicited by the HIV-1 envelope glycoprotein (Env) manifest the aggregation of PML in discrete nuclear bodies and the recruitment of TopBP1, NBS1 and ATM to DNA damage foci containing phosphorylated ATM and histone H2AX (g-H2AX). This DNA damage response then culminates in p53-dependent activation of the mitochondrial pathway of apoptosis. Here, we show that Env-elicited syncytia also manifest activating phosphorylations of the checkpoint kinases 1 and 2 (Chk1 and Chk2), and both Chk1 and Chk2 colocalize with g-H2AX foci. However, only the siRNA-mediated knockdown of Chk2, not the depletion of Chk1, inhibits mitochondrial outer membrane permeabilization and subsequent syncytial apoptosis. Depletion of PML, TopBP1, NBS1 or ATM inhibit the activating phosphorylation of Chk2. Altogether, these results indicate that Chk2 (but not Chk1) participates in the DNA damage-elicited proapoptotic cascade that leads to the demise of Env-elicited syncytia.

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Section: Introductionmentioning

confidence: 99%

Pro-apoptotic function of checkpoint kinase-2 in syncytia elicited by the HIV-1 envelope

Séror¹,

Raza²,

Brottes³

et al. 2009

Cell Cycle

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“…According to the time of p24 Ag detection HIV-1 isolates were classified as: rapid (R) when p24 Ag was detected within the first 5 days of culture or slow (S) when the lag phase was of 6 or more days. To determine SI or NSI viral phenotype, culture supernatants with p24 Ag ≥ 200 pg/ml were used to infect MT-2 cells as previously described (Kopka et al, 2002). Briefly, supernatants from HIV-1 positive co-cultures were added to MT-2 cells in RPMI 1640 medium supplemented with 10% fetal bovine serum in 96 well plates.…”

Section: Viral Isolation and Phenotype Determinationmentioning

confidence: 99%

“…Since the emergence of SI strains in HIV-1 infection is associated to CD4+ T lymphopenia (Koot et al, 1993;Kopka et al, 2002), we investigated whether the presence of SI phenotype in the setting of high levels of IL-7 in plasma could be independent of the percentage of circulating CD4+ T lymphocytes. IL-7 levels were compared among patients stratified into 4 groups according to CD4+ T lymphocyte counts >20% or ≤20% and to their SI or NSI viral phenotype (Table 1).…”

Section: Il-7 Levels and Hiv-1 Phenotypementioning

confidence: 99%

“…In absence of antiretroviral (ARV) therapy, approximately one fourth of perinatally HIV-1 infected children develop early AIDS, within the first two years of life (Blanche et al, 1989;European Collaborative Study, 1991;Duliege et al, 1992), while the remaining infants follow a slower clinical course similar to that of adults. We have recently observed that in pediatric primary infection SI or rapid replicating HIV-1 strains are associated with an early outcome of immunosuppression and clinical AIDS, accounting for the first peak of the AIDS bimodal profile observed in infants (Kopka et al, 2002). Among the host factors activated in response to immunosuppression, it has been observed that IL-7 levels increase in the setting of lymphopenia due to a variety of causes, such as cancer chemotherapy (Fry et al, 2001), bone marrow transplantation (Bolotin et al, 1996), and HIV-1 infection (Napolitano et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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High IL-7 plasma levels may induce and predict the emergence of HIV-1 virulent strains in pediatric infection

Kopka

Mecikovsky

Aulicino

et al. 2005

Journal of Clinical Virology

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“…[9][10][11][12] We have previously observed that the presence of HIV-1 SI variants at acute infection, with rapid replication capability, is indicative of a poor prognosis favoring a rapid onset of AIDS in vertically infected children. 13 The presence of SI/CXCR4using viruses at an early stage of vertical transmission may be particularly relevant in pediatric immunopathogenesis, specially at birth due to an extremely active thymus with an unusual high number of potential target cells. [14][15][16] Other factors such as antiretroviral (ARV) therapy and host genotype related to coreceptor usage may affect viral tropism.…”

Section: Introductionmentioning

confidence: 99%

Relevance of Early Detection of HIV Type 1 SI/CXCR4-Using Viruses in Vertically Infected Children

Crudeli

Aulicino²,

Rocco³

et al. 2012

AIDS Research and Human Retroviruses

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The aim of the study was to investigate the prevalence and persistence of syncytium-inducing (SI) strains in HIV-1-infected children along time of infection and to evaluate the influence of antiretroviral therapy and host factors on viral tropism. This is a retrospective analysis carried out in 267 HIV-1 vertically infected children from an Argentinean cohort. The viral phenotype was screened in MT-2 cells and coreceptor usage confirmed by the GHOST cell assay. Also, CD4(+) T cell count, viral load, antiretroviral therapy, and human CCR5-Δ32 and CCR2-64I genotypes were analyzed. A high frequency of HIV-1 SI/CXCR4-using variants (22%) was found among children within the first trimester of life, reaching 46% after 10 years of infection. At acute infection, zidovudine prophylaxis did not significantly affect the proportions of SI HIV-1 strains, while their presence was favored by the CCR5(+)/Δ32 genotype. Interestingly, the majority of the early SI strains did not persist over time, probably due to a higher susceptibility to antiretroviral (ARV) treatment or immunologic pressure. At the chronic stage, SI variants emerged even in the presence of HAART reaching 36% at 120 months of infection. Also the HIV-1 SI phenotype was associated with lower CD4(+) T cell counts all along the course of infection. These findings highlight the need to evaluate the presence of SI/CXCR4 variants early at primary infection. This will make it possible to optimize the use of CCR5 inhibitors in children who are apparently carriers of the R5 virus preventing early therapeutic failure due to the reemergence of SI strains from reservoirs.

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Relevance of Viral Phenotype in the Early AIDS Outcome of Pediatric HIV-1 Primary Infection

Cited by 5 publications

References 18 publications

Pro-apoptotic function of checkpoint kinase-2 in syncytia elicited by the HIV-1 envelope

Pro-apoptotic function of checkpoint kinase-2 in syncytia elicited by the HIV-1 envelope

High IL-7 plasma levels may induce and predict the emergence of HIV-1 virulent strains in pediatric infection

Relevance of Early Detection of HIV Type 1 SI/CXCR4-Using Viruses in Vertically Infected Children

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