Predominance of Three NF-κB Binding Sites in the Long Terminal Repeat Region of HIV Type 1 Subtype C Isolates from Zambia

Munkanta, Mwansa; Handema, Ray; Kasai, Hirotake; Gondwe, Clement; Deng, Xuewen; Yamashita, Atsuya; Asagi, Tsukasa; Yamamoto, Naoki; Ito, Masahiko; Kasolo, Francis

doi:10.1089/aid.2005.21.901

Cited by 12 publications

(9 citation statements)

References 14 publications

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“…The HIV-1 LTR promoter controls transcription of viral genes and is reported to have NF-κB binding sites [57], [58]. The transcription factor NF-κB can translocate to nucleus in response to various internal or external stimuli [59].…”

Section: Resultsmentioning

confidence: 99%

Chemokine CXCL8 Promotes HIV-1 Replication in Human Monocyte-Derived Macrophages and Primary Microglia via Nuclear Factor-κB Pathway

Mamik

Ghorpade

2014

PLoS ONE

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BackgroundChemokine CXCL8 is an important neutrophil chemoattractant implicated in various neurodegenerative disorders. Cytokine/chemokine imbalance, with an increase in proinflammatory cytokines like interleukin-1β and tumor necrosis factor-α within the central nervous system, is a hallmark of human immunodeficiency virus (HIV)-1 infection. We previously reported that HIV-1 infection is linked to upregulation of CXCL8 in brain tissues and human astrocytes. Chemokines play crucial roles in trafficking of leukocytes and trafficking of HIV-1-infected across the blood-brain barrier play an important role in HIV-1 central nervous system disease. In the post-antiretroviral therapy era, low level of productive replication of HIV-1 in brain is a critical component of neuropathogenesis regulation. The present study investigated the effect of CXCL8 on productive infection of HIV-1 in human monocytes-derived macrophages (MDM) and primary human microglia.ResultsHuman MDM and microglia were infected with the blood or brain derived HIV-1 isolates, HIV-1ADA or HIV-1JRFL. Treatment with CXCL8 significantly upregulated HIV-1p24 levels in supernatants of both HIV-1-infected MDM as well as microglia. In addition, the formation of 2-long terminal repeat (LTR) circles, a measure of viral genome integration, was significantly higher in CXCL8-treated, HIV-1-infected MDM and microglia. Transient transfection of U937 cells with HIV-1 LTR luciferase reporter construct resulted in increased promoter activity when treated with CXCL8. Moreover, increased nuclear translocation of nuclear factor-κB was seen in HIV-1-infected MDM following CXCL8 treatment. Blocking CXCL8 receptors CXCR1 and CXCR2 abrogated the CXCL8-mediated enhanced HIV-1 replication.ConclusionOur results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2. These results demonstrate that CXCL8 exerts its downstream effects by increasing translocation of nuclear factor-κB into the nucleus, thereby promoting HIV-1 LTR activity.

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Section: Resultsmentioning

confidence: 99%

Chemokine CXCL8 Promotes HIV-1 Replication in Human Monocyte-Derived Macrophages and Primary Microglia via Nuclear Factor-κB Pathway

Mamik

Ghorpade

2014

PLoS ONE

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“…Most HIV-1 clade B isolates are characterized by two NF-B binding sites, whereas the majority of HIV-1 clade C isolates have an extra NF-B binding site (23,39). The number of NF-B binding elements is associated with the efficacy of transcriptional initiation from the proviral genome, and TNF-␣ leads to the up-regulation of NF-B (19,44).…”

Section: Discussionmentioning

confidence: 99%

Molecularly Cloned SHIV-1157ipd3N4: a Highly Replication- Competent, Mucosally Transmissible R5 Simian-Human Immunodeficiency Virus Encoding HIV Clade Cenv

Song

Chenine

Rasmussen

et al. 2006

J Virol

150

221

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Human immunodeficiency virus type 1 (HIV-1) clade C causes >50% of all HIV infections worldwide, and an estimated 90% of all transmissions occur mucosally with R5 strains. A pathogenic R5 simian-human immunodeficiency virus (SHIV) encoding HIV clade C env is highly desirable to evaluate candidate AIDS vaccines in nonhuman primates. To this end, we generated SHIV-1157i, a molecular clone from a Zambian infant isolate that carries HIV clade C env. SHIV-1157i was adapted by serial passage in five monkeys, three of which developed peripheral CD4 ؉ T-cell depletion. After the first inoculated monkey developed AIDS at week 137 postinoculation, transfer of its infected blood to a naïve animal induced memory T-cell depletion and thrombocytopenia within 3 months in the recipient. In parallel, genomic DNA from the blood donor was amplified to generate the late proviral clone SHIV-1157ipd3. To increase the replicative capacity of SHIV1157ipd3, an extra NF-B binding site was engineered into its 3 long terminal repeat, giving rise to SHIV1157ipd3N4. This virus was exclusively R5 tropic and replicated more potently in rhesus peripheral blood mononuclear cells than SHIV-1157ipd3 in the presence of tumor necrosis factor alpha. Rhesus macaques of Indian and Chinese origin were next inoculated intrarectally with SHIV-1157ipd3N4; this virus replicated vigorously in both sets of monkeys. We conclude that SHIV-1157ipd3N4 is a highly replication-competent, mucosally transmissible R5 SHIV that represents a valuable tool to test candidate AIDS vaccines targeting HIV-1 clade C Env.

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“…Likewise, while a large number of HIV-1 subtypes (A, B, D, F, G, H, J, and K) and several subtypes of SIV contain two copies of NF-B binding sites in the enhancer, subtype A/E of HIV-1 (10,11), all HIV-2 subtypes, and the other strains of SIV contain a single NF-B binding site. Subtype C of HIV-1 is the only viral family that contains three binding sites for NF-B (12)(13)(14)(15). Second, a great sequence variation characterizes the Sp1 binding sites, especially in Sp1III and Sp1II sites, with only the Sp1I motif being highly conserved among most of the HIV-1 subtypes (16).…”

mentioning

confidence: 99%

Functional Incompatibility between the Generic NF-κB Motif and a Subtype-Specific Sp1III Element Drives the Formation of the HIV-1 Subtype C Viral Promoter

Verma

Rajagopalan

Lotke

et al. 2016

J Virol

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Of the various genetic subtypes of human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and simian immunodeficiency virus (SIV), only in subtype C of HIV-1 is a genetically variant NF-B binding site found at the core of the viral promoter in association with a subtype-specific Sp1III motif. How the subtype-associated variations in the core transcription factor binding sites (TFBS) influence gene expression from the viral promoter has not been examined previously. Using panels of infectious viral molecular clones, we demonstrate that subtype-specific NF-B and Sp1III motifs have evolved for optimal gene expression, and neither of the motifs can be replaced by a corresponding TFBS variant. The variant NF-B motif binds NF-B with an affinity 2-fold higher than that of the generic NF-B site. Importantly, in the context of an infectious virus, the subtype-specific Based on genetic variation, human immunodeficiency virus type 1 (HIV-1) is classified into four distinct groups (M, N, O, and P), and group M is subclassified into nine molecular subtypes (A, B, C, D, F, G, H, J, and K) and numerous circulating recombinant forms, including A/E (1). The global distribution of HIV-1 subtypes is uneven, with C, A, and B being the most widespread subtypes. Subtype C is predominant in southern and eastern African countries, India, and Nepal and in recombinant forms in China, and it is currently emerging in southern Brazil. Subtype C is responsible for approximately half of the global HIV-1 infections and more than 95% of the infections in India (2). The factors that contribute to the widespread expansion of subtype C are not well understood. Diverse viral subtypes differ from one another up to 30 to 35% in certain gene segments, such as the envelope (3). A genetic variation to this large an extent is expected to have a significant impact on the biological properties of the subtypes influencing their relative fitness properties. Subtype-specific genetic variations in elements such as the viral promoter (enhancer and other regulatory elements), regulatory proteins, and structural proteins may underlie the biological differences, although drawing such a correlation between these factors may not always be possible.The individual components of the viral promoter, including the modulator region, the enhancer, and the core promoter, are characterized by several subtype-specific molecular variations. Such differences have been mapped to many transcription factor binding sites (TFBS), including USF, c-Myb, NF-AT, Ap-1, NF-B, and Sp1, and regulatory elements such as the TATA box and

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Predominance of Three NF-κB Binding Sites in the Long Terminal Repeat Region of HIV Type 1 Subtype C Isolates from Zambia

Cited by 12 publications

References 14 publications

Chemokine CXCL8 Promotes HIV-1 Replication in Human Monocyte-Derived Macrophages and Primary Microglia via Nuclear Factor-κB Pathway

Chemokine CXCL8 Promotes HIV-1 Replication in Human Monocyte-Derived Macrophages and Primary Microglia via Nuclear Factor-κB Pathway

Molecularly Cloned SHIV-1157ipd3N4: a Highly Replication- Competent, Mucosally Transmissible R5 Simian-Human Immunodeficiency Virus Encoding HIV Clade Cenv

Functional Incompatibility between the Generic NF-κB Motif and a Subtype-Specific Sp1III Element Drives the Formation of the HIV-1 Subtype C Viral Promoter

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