Differential HIV-1 replication in neonatal and adult blood mononuclear cells is influenced at the level of HIV-1 gene expression

Sundaravaradan, Vasudha; Saxena, Shailendra K.; Ramakrishnan, Rajesh; Yedavalli, Venkat R. K.; Harris, David T.; Ahmad, Nafees

doi:10.1073/pnas.0602185103

Cited by 36 publications

(31 citation statements)

References 34 publications

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“…However, one clone also derived from patient 19, now designated the clone 19-18 LTR, exhibited a marginally lower basal level of transcription in Jurkat T cells but much lower basal transcription in U-937 cells, suggesting that LTR-mediated gene expression may be modulated by different transcription factors in a cell typedependent manner. This result is consistent with reports showing that different cells can affect the level of HIV-1 replication and gene expression owing to their distinct expression of cell typespecific transcription factors [31][32][33]. We have also reported herein that the 19-18 HIV-1 LTR clone did not respond to Tatmediated transactivation with strain IIIB Tat in Jurkat T cells and U-937 cells (Figure 2).…”

Section: Discussionsupporting

confidence: 82%

Impact of Naturally Occurring Genetic Variation in the HIV-1 LTR TAR Region and Sp Binding Sites on Tat-Mediated Transcription

Wigdahl¹

2015

JHVRV

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HIV-1 Tat-mediated transactivation of the long terminal repeat (LTR) requires an interaction with the transactivation response element (TAR) and is facilitated by NF-κB and Sp factors binding to sequences upstream of the transcriptional start site. Studies conducted pre-and post antiretroviral therapy identified HIV-1-infected patients harboring a C-to-T change at position 5 of the consensus B sequence of Sp binding site III (a knockout configuration with respect to binding of Sp1). HIV-1 LTRs and Tat were amplified and cloned from patients in the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. As one simple approach to examine the impact of sequence variation on LTR fitness, LTR clones from a single patient (patient 19) were used in transient expression studies in both T-cell and monocyte-macrophage cell lines. These results demonstrated that one of 4 clones could not be transactivated by Tat derived from laboratory strain IIIB or from the patient. After inspection of the sequence of the patient-derived LTR clone defective with respect to Tat-mediated transactivation, additional alterations within the LTR were identified in a number of transcription factor binding sites in the LTR core region as well as in the TAR element that suggested that these sites may also contribute to the Tat non responsiveness. In this regard, site-directed mutagenesis indicated that optimal Tat-mediated transactivation depended on both position 32 of the TAR element and binding of Sp to all three Sp binding sites within the LTR. These studies indicate that a vast majority of LTRs derived from the integrated provirus in the peripheral blood compartment of a number of infected patients maintained the ability to drive basal and Tatmediated transcription but that just a small number of nucleotides were shown to have a detrimental impact on LTR activation in both T cells and cells of the monocyte-macrophage lineage.

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Section: Discussionsupporting

confidence: 82%

Impact of Naturally Occurring Genetic Variation in the HIV-1 LTR TAR Region and Sp Binding Sites on Tat-Mediated Transcription

Wigdahl¹

2015

JHVRV

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“…In 2011, there were 3.3 million children living with HIV and an estimated 330,000 children who became newly infected with HIV worldwide, primarily through mother-to-child transmission of HIV [2, 4]. In the United States, HIV/AIDS is ranked the third leading cause of death among women aged 25 to 44 years old and accounts for the most common cause of death among African-American women in this age group [5, 6]. Since the institution of antiretroviral therapy, the incidence of vertical transmission of HIV in the U.S. and other resource-rich countries has decreased significantly but continues to be a critical issue in resource-poor nations and among poor populations in resource-rich nations.…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that immune cells from neonates are more susceptible to HIV infection than those from adults [6, 21, 22]. It is likely that acute or chronic alcohol exposure can exacerbate neonatal cellular immune system defects.…”

Section: Introductionmentioning

confidence: 99%

Alcohol Enhances HIV Infection of Cord Blood Monocyte-Derived Macrophages

Mastrogiannis¹,

Wang²,

Dai³

et al. 2014

CHR

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Alcohol consumption or alcohol abuse is common among pregnant HIV+ women and has been identified as a potential behavioral risk factor for the transmission of HIV. In this study, we examined the impact of alcohol on HIV infection of cord blood monocyte-derived macrophages (CBMDM). We demonstrated that alcohol treatment of CBMDM significantly enhanced HIV infection of CBMDM. Investigation of the mechanisms of alcohol action on HIV demonstrated that alcohol inhibited the expression of several HIV restriction factors, including anti-HIV microRNAs, APOBEC3G and APOBEC3H. Additionally, alcohol also suppressed the expression of IFN regulatory factor 7 (IRF-7) and retinoic acid-inducible gene I (RIG-I), an intracellular sensor of viral infection. The suppression of these IFN regulatory factors was associated with reduced expression of type I IFN. These experimental findings suggest that maternal alcohol consumption may facilitate HIV infection, promoting vertical transmission of HIV.

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“…However, genetic diversity in children from 0 to 2 year-old was significantly lower than in adults, which suggests that certain selection is acting on the virus variants that are vertically transmitted. After perinatal transmission, very high rates of HIV-1 replication have been detected in younger infected children that can persist for long periods of time, especially in untreated patients [25,62]. High rates of virus replication increase HIV-1B population sizes and, due to the error-prone nature of the HIV-1B polymerase, may result in random accumulation of mutations in the virus population.…”

Section: Discussionmentioning

confidence: 99%

Clinical Determinants of HIV-1B Between-Host Evolution and their Association with Drug Resistance in Pediatric Patients

et al. 2016

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Understanding the factors that modulate the evolution of virus populations is essential to design efficient control strategies. Mathematical models predict that factors affecting viral within-host evolution may also determine that at the between-host level. Although HIV-1 within-host evolution has been associated with clinical factors used to monitor AIDS progression, such as patient age, CD4 cells count, viral load, and antiretroviral experience, little is known about the role of these clinical factors in determining between-host HIV-1 evolution. Moreover, whether the relative importance of such factors in HIV-1 evolution vary in adult and children patients, in which the course of infection is different, has seldom been analysed. To address these questions, HIV-1 subtype B (HIV-1B) pol sequences of 163 infected children and 450 adults of Madrid, Spain, were used to estimate genetic diversity, rates of synonymous and non-synonymous mutations, selection pressures and frequency of drug-resistance mutations (DRMs). The role and relative importance of patient age, %CD4, CD4/mm3, viral load, and antiretroviral experience in HIV-1B evolution was analysed. In the pediatric HIV-1B population, three clinical factors were primary predictors of virus evolution: Higher HIV-1B genetic diversity was observed with increasing children age, decreasing CD4/mm3 and upon antiretroviral experience. This was mostly due to higher rates of non-synonymous mutations, which were associated with higher frequency of DRMs. Using this data, we have also constructed a simple multivariate model explaining between 55% and 66% of the variance in HIV-1B evolutionary parameters in pediatric populations. On the other hand, the analysed clinical factors had little effect in adult-infecting HIV-1B evolution. These findings highlight the different evolutionary dynamics of HIV-1B in children and adults, and contribute to understand the factors shaping HIV-1B evolution and the appearance of drug-resistance mutation in pediatric patients.

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Differential HIV-1 replication in neonatal and adult blood mononuclear cells is influenced at the level of HIV-1 gene expression

Cited by 36 publications

References 34 publications

Impact of Naturally Occurring Genetic Variation in the HIV-1 LTR TAR Region and Sp Binding Sites on Tat-Mediated Transcription

Impact of Naturally Occurring Genetic Variation in the HIV-1 LTR TAR Region and Sp Binding Sites on Tat-Mediated Transcription

Alcohol Enhances HIV Infection of Cord Blood Monocyte-Derived Macrophages

Clinical Determinants of HIV-1B Between-Host Evolution and their Association with Drug Resistance in Pediatric Patients

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