Structural defects and variations in the HIV-1 nef gene from rapid, slow and non-progressor children

Casartelli, Nicoletta; Matteo, Gigliola Di; Argentini, C.; Cancrini, Caterina; Bernardi, Stefania; Castelli, Guido; Scarlatti, Gabriella; Plebani, A; Rossi, Paolo; Doria, Margherita

doi:10.1097/00002030-200306130-00003

Cited by 42 publications

(57 citation statements)

References 42 publications

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“…On the other hand, due to the large variability of the nef gene, functional studies on a single allelic variant, although containing representative amino acid variations, may greatly constrain the analysis of possible Nef phenotypes in a given patient. This is why in a previous study we isolated and sequenced a large number of nef alleles sequentially derived from perinatally infected children with different progression rates: six nonprogressors (NPs), three slow progressors (SPs), and four rapid progressors (RPs) (8). We found that a higher proportion of disrupted sequences were derived from NPs compared to the other patients.…”

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confidence: 81%

“…Patients' characteristics as well as isolation and subcloning of patients' nef genes are described elsewhere (8). Briefly, we studied 13 perinatally HIV-1-infected children of Italian origin showing different modality of disease progression: six NPs, three SPs, and four RPs.…”

Section: Methodsmentioning

confidence: 99%

“…Nef proteins contained several mutations at various amino acid residues, although none of these changes was consistently associated with a specific progression rate. However, some residues localized in the folded core domain at CTL epitopes were frequently changed in NP-derived Nef proteins, while other residues located at the N-and C-terminal loops varied frequently in proteins derived from RP and SP patients (8). The role of these residues in the structure and function of the Nef protein is unknown, although it is conceivable that epitope variations in NP-derived proteins can induce a broad range CTL response thus limiting viral replication in NP patients.…”

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confidence: 95%

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CD4 and Major Histocompatibility Complex Class I Downregulation by the Human Immunodeficiency Virus Type 1 Nef Protein in Pediatric AIDS Progression

Casartelli

Matteo

Potestà

et al. 2003

J Virol

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The human immunodeficiency virus type 1 (HIV-1) nef gene is a crucial determinant in AIDS disease progression. Although several in vitro activities have been attributed to the Nef protein, identifying the one critical for in vivo pathogenicity remains elusive. In this study, we examined a large number of nef alleles derived at various time points from 13 perinatally infected children showing different progression rates: six nonprogressors (NPs), three slow progressors (SPs), and four rapid progressors (RPs). The patient-derived nef alleles were analyzed for their steady-state expression of a Nef protein, for their relative ability to downregulate cell surface expression of CD4 and major histocompatibility complex class I (MHC-I) and for their capacity to bind the clathrin adaptor AP-1 complex. We found that NP-derived nef alleles, compared to nef alleles isolated from SPs and RPs, had reduced CD4 and MHC-I downregulation activities. In contrast, SP-and RP-derived nef alleles did not differ and efficiently downregulated both CD4 and MHC-I. AP-1 binding was a conserved function of primary nef alleles not correlated with clinical progression. Defective Nef proteins from NPs, rather than sharing common specific changes in their sequences, accumulated various amino acid substitutions, mainly located outside the conserved domains previously associated with Nef biological properties. Our data indicate that Nef-mediated downregulation of cell surface CD4 and MHC-I significantly contributes to the expression of the pathogenic potential of HIV-1.

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confidence: 81%

Section: Methodsmentioning

confidence: 99%

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confidence: 95%

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CD4 and Major Histocompatibility Complex Class I Downregulation by the Human Immunodeficiency Virus Type 1 Nef Protein in Pediatric AIDS Progression

Casartelli

Matteo

Potestà

et al. 2003

J Virol

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“…Finally, data from in vitro studies also show an association of CD4 down-modulation with disease progression: Nef alleles from HIV strains isolated from patients with progression to AIDS efficiently down-regulate CD4, whereas Nef alleles from HIV strains isolated from longterm nonprogressors are compromised in their ability to down-modulate CD4. [15][16][17][18] Importantly, the progressive CD4 down-modulation on CD4 þ T cells in HIV þ patients may contribute to the functional impairment of CD4 þ T cells observed in HIV infection. 39 CD4 plays an essential role in the generation of adaptive immune responses by acting as a coreceptor with the T cell receptor/CD3 complex, which binds peptide-MHC complexes.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14] Furthermore, Nef alleles from HIV strains isolated from patients with progression to AIDS efficiently down-regulate CD4, whereas Nef alleles from HIV strains isolated from long-term nonprogressors are ineffective in down-modulating CD4. [15][16][17][18] The well-known CD4 down-regulation by HIV in vitro is mediated by the viral proteins Nef, Env, and Vpu. 19 explanations have been proposed for why CD4 downmodulation favors HIV, including attenuation of CD4 signaling that might decrease viral transcription, prevention of superinfection, and enhancement of virion release.…”

Section: -10mentioning

confidence: 99%

210 Low Post-Seroconversion CD4 Count and Rapid Decrease of CD4 Density Identify HIV+ Fast Progressors

Audigé

Taff

Rickenbach

et al. 2011

JAIDS Journal of Acquired Immune Deficiency Syndromes

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R (2010). Low postseroconversion CD4 count and rapid decrease of CD4 density identify HIV+ fast progressors. AIDS Research and Human Retroviruses, 26(9) CD4 expression in HIV replication is paradoxical: HIV entry requires high cell-surface CD4 densities, but replication requires CD4 down-modulation. However, is CD4 density in HIV þ patients affected over time? Do changes in CD4 density correlate with disease progression? Here, we examined the role of CD4 density for HIV disease progression by longitudinally quantifying CD4 densities on CD4þ T cells and monocytes of ARTnaive HIV þ patients with different disease progression rates. This was a retrospective study. We defined three groups of HIV þ patients by their rate of CD4 þ T cell loss, calculated by the time between infection and reaching a CD4 level of 200 cells/ml: fast (<7.5 years), intermediate (7.5-12 years), and slow progressors (>12 years). Mathematical modeling permitted us to determine the maximum CD4 þ T cell count after HIV seroconversion (defined as ''postseroconversion CD4 count'') and longitudinal profiles of CD4 count and density. CD4 densities were quantified on CD4 þ T cells and monocytes from these patients and from healthy individuals by flow cytometry. Fast progressors had significantly lower postseroconversion CD4 counts than other progressors. CD4 density on T cells was lower in HIV þ patients than in healthy individuals and decreased more rapidly in fast than in slow progressors. Antiretroviral therapy (ART) did not normalize CD4 density. Thus, postseroconversion CD4 counts define individual HIV disease progression rates that may help to identify patients who might benefit most from early ART. Early discrimination of slow and fast progressors suggests that critical events during primary infection define long-term outcome. A more rapid CD4 density decrease in fast progressors might contribute to progressive functional impairments of the immune response in advanced HIV infection. The lack of an effect of ART on CD4 density implies a persistent dysfunctional immune response by uncontrolled HIV infection.

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Unusual substitutions in HIV‐1 Vif from children infected perinatally without progression to AIDS for more than 8 years without therapy

Maio

Rocco

Aulicino

et al. 2012

Journal of Medical Virology

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The HIV-1 vif gene encodes for an accessory protein that is central for virus replication due mainly to its capacity to counteract the antiviral action of host APOBEC3 restriction factors. In order to evaluate whether HIV-1 vif alterations account for a delayed progression to AIDS in children infected perinatally, the vif genes from a group of 11 patients who exhibited an extremely slow disease progression (slow progressors) were studied by direct sequencing. In addition, the vif genes from a group of 93 children with typical disease progression (typical progressors) were analyzed for comparison. Phylogenetic analysis indicated that sequences from slow progressors did not have a common origin, discarding a shared ancestor of reduced virulence. There were no differences in the diversity between the vif genes from slow and typical progressors. No gross defects showing a clear distinction among sequences from both groups of children were found. However, in the deduced Vif proteins, changes V13I, V55T, and L81M were observed only in sequences from slow progressors. By analyzing sequences stored in databases, these mutations were determined as unusual substitutions occurring at highly conserved Vif sites across different HIV-1 clades, but were observed with an increased frequency in sequences from elite controllers. These mutations were in the Vif regions reported as relevant for protein activity. These findings suggest that the Vif sequences from slow progressors carry unusual substitutions, which may alter the protein function and may contribute to viral attenuation.

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Structural defects and variations in the HIV-1 nef gene from rapid, slow and non-progressor children

Cited by 42 publications

References 42 publications

CD4 and Major Histocompatibility Complex Class I Downregulation by the Human Immunodeficiency Virus Type 1 Nef Protein in Pediatric AIDS Progression

CD4 and Major Histocompatibility Complex Class I Downregulation by the Human Immunodeficiency Virus Type 1 Nef Protein in Pediatric AIDS Progression

210 Low Post-Seroconversion CD4 Count and Rapid Decrease of CD4 Density Identify HIV+ Fast Progressors

Unusual substitutions in HIV‐1 Vif from children infected perinatally without progression to AIDS for more than 8 years without therapy

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