Alterations in HIV-1 LTR promoter activity during AIDS progression

Hiebenthal-Millow, Kirsten; Greenough, Thomas C.; Bretttler, Doreen B.; Schindler, Michael; Wildum, Steffen; Sullivan, John L.; Kirchhoff, Frank

doi:10.1016/j.virol.2003.08.034

Cited by 17 publications

(13 citation statements)

References 25 publications

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“… a Comparison of the number of HIV-1 genetic polymorphisms in the near full-length HIV-1 genome that have been associated with impaired HIV-1 replicative fitness and/or disease progression [11, 31, 32, 40, 42, 44–62, 77, 78] among the three groups of patients, i.e., VNP, RP, and TP. Unpaired t test was used to assess the statistical significance between VNP and TP patients.…”

Section: Resultsmentioning

confidence: 99%

“…Here we used deep sequencing to analyze near full-length HIV-1 genomes from all VNP-derived viruses, and compared them with the sequences from the TP- and RP-derived viral genomes. Despite identifying a series of SNPs in different genomic regions, some of them previously associated with a reduction in replicative fitness and/or disease progression [11, 31, 32, 40, 42, 44–62, 77, 78], no clear pattern of signature mutations was detected in the viruses from the VNPs that could explain the impairment in replication capacity. Interestingly, it was the number of these HIV-1 genetic polymorphisms that correlated significantly with the replicative fitness of each HIV-1 isolate.…”

Section: Discussionmentioning

confidence: 99%

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Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

et al. 2017

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BackgroundProgression rates from initial HIV-1 infection to advanced AIDS vary significantly among infected individuals. A distinct subgroup of HIV-1-infected individuals—termed viremic non-progressors (VNP) or controllers—do not seem to progress to AIDS, maintaining high CD4+ T cell counts despite high levels of viremia for many years. Several studies have evaluated multiple host factors, including immune activation, trying to elucidate the atypical HIV-1 disease progression in these patients; however, limited work has been done to characterize viral factors in viremic controllers.MethodsWe analyzed HIV-1 isolates from three VNP individuals and compared the replicative fitness, near full-length HIV-1 genomes and intra-patient HIV-1 genetic diversity with viruses from three typical (TP) and one rapid (RP) progressor individuals.ResultsViremic non-progressors and typical patients were infected for >10 years (range 10–17 years), with a mean CD4+ T-cell count of 472 cells/mm3 (442–529) and 400 cells/mm3 (126–789), respectively. VNP individuals had a less marked decline in CD4+ cells (mean −0.56, range −0.4 to −0.7 CD4+/month) than TP patients (mean −10.3, −8.2 to −13.1 CD4+/month). Interestingly, VNP individuals carried viruses with impaired replicative fitness, compared to HIV-1 isolates from the TP and RP patients (p < 0.05, 95% CI). Although analyses of the near full-length HIV-1 genomes showed no clear patterns of single-nucleotide polymorphisms (SNP) that could explain the decrease in replicative fitness, both the number of SNPs and HIV-1 population diversity correlated inversely with the replication capacity of the viruses (r = −0.956 and r = −0.878, p < 0.01, respectively).ConclusionIt is likely that complex multifactorial parameters govern HIV-1 disease progression in each individual, starting with the infecting virus (phenotype, load, and quasispecies diversity) and the intrinsic ability of the host to respond to the infection. Here we analyzed a subset of viremic controller patients and demonstrated that similar to the phenomenon observed in patients with a discordant response to antiretroviral therapy (i.e., high CD4+ cell counts with detectable plasma HIV-1 RNA load), reduced viral replicative fitness seems to be linked to slow disease progression in these antiretroviral-naïve individuals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12981-017-0144-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

et al. 2017

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“…Sequence variation has been documented within the HIV-1 LTR, including the AP-1 binding site, in virus-infected patients (Ait-Khaled and Emery, 1994). In 3 of 12 HIV-1 infected individuals, mutations within the U3 and TAR region of the HIV LTR seem to be responsible for enhanced promoter transcription, possibly leading to accelerated disease progression (Hiebenthal-Millow et al, 2003). …”

Section: Discussionmentioning

confidence: 99%

Peripheral immunophenotype and viral promoter variants during the asymptomatic phase of feline immunodeficiency virus infection

2014

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Feline immunodeficiency virus (FIV)-infected cats enter a clinically asymptomatic phase during chronic infection. Despite the lack of overt clinical disease, the asymptomatic phase is characterized by persistent immunologic impairment. In the peripheral blood obtained from cats experimentally infected with FIV-C for approximately 5 years, we identified a persistent inversion of the CD4/CD8 ratio. We cloned and sequenced the FIV-C long terminal repeat containing the viral promoter from cells infected with the inoculating virus and from in vivo-derived peripheral blood mononuclear cells and CD4 T cells isolated at multiple time points throughout the asymptomatic phase. Relative to the inoculating virus, viral sequences amplified from cells isolated from all of the infected animals demonstrated multiple single nucleotide mutations and a short deletion within the viral U3, R and U5 regions. A transcriptionally inactivating proviral mutation in the U3 promoter AP-1 site was identified at multiple time points from all of the infected animals but not within cell-associated viral RNA. In contrast, no mutations were identified within the sequence of the viral dUTPase gene amplified from PBMC isolated at approximately 5 years post-infection relative to the inoculating sequence. The possible implications of these mutations to viral pathogenesis are discussed.

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“…Truncation mutants of tat (wherein the second coding exon is deleted) have highlighted the importance of the second coding exon for MRC in MDM [119] despite preserved single-cycle replication of these tat mutants in reporter cell lines, which implies the second coding exon may have additional activity in MDM separate from transcriptional activation [119]. In a study of LTR sequences, amplified by nested PCR and cloned into luciferase-expressing pseudoviruses from patients during progression to AIDS, there was an increase in the in vitro single-cycle transcription activity of late stage HIV-1 LTR in various target cells (including MDM) in a subset of patients, suggesting the enhanced replication capacity of isolates observed later in disease (see Section 3) may be partially mediated by LTR transactivation activity [120]. However, compartmentalization of PCR-amplified tat sequences in neural versus lymphoid tissues was not convincingly demonstrated in a recent study, and no enhancement of LTR transactivation activity by brain-derived tat sequences in patients with HIV-associated dementia (HAD) was observed [121], again suggesting that if tat is important in determining MRC this function may be distinct from LTR transactivation.…”

Section: Molecular Determinants — Post Entrymentioning

confidence: 99%

Viral Determinants of HIV-1 Macrophage Tropism

Duncan

Sattentau

2011

Viruses

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Macrophages are important target cells for HIV-1 infection that play significant roles in the maintenance of viral reservoirs and other aspects of pathogenesis. Understanding the determinants of HIV-1 tropism for macrophages will inform HIV-1 control and eradication strategies. Tropism for macrophages is both qualitative (infection or not) and quantitative (replication capacity). For example many R5 HIV-1 isolates cannot infect macrophages, but for those that can the macrophage replication capacity can vary by up to 1000-fold. Some X4 viruses are also capable of replication in macrophages, indicating that cellular tropism is partially independent of co-receptor preference. Preliminary data obtained with a small number of transmitted/founder viruses indicate inefficient macrophage infection, whereas isolates from later in disease are more frequently tropic for macrophages. Thus tropism may evolve over time, and more macrophage tropic viruses may be implicated in the pathogenesis of advanced HIV-1 infection. Compartmentalization of macrophage-tropic brain-derived envelope glycoproteins (Envs), and non-macrophage tropic non-neural tissue-derived Envs points to adaptation of HIV-1 quasi-species in distinct tissue microenvironments. Mutations within and adjacent to the Env-CD4 binding site have been identified that determine macrophage tropism at the entry level, but post-entry molecular determinants of macrophage replication capacity involving HIV-1 accessory proteins need further definition.

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Alterations in HIV-1 LTR promoter activity during AIDS progression

Cited by 17 publications

References 25 publications

Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

Peripheral immunophenotype and viral promoter variants during the asymptomatic phase of feline immunodeficiency virus infection

Viral Determinants of HIV-1 Macrophage Tropism

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