Human Immunodeficiency Virus Type 1 Subtype C Exhibits Higher Transactivation Activity of Tat than Subtypes B and E

Kurosu, Takeshi; Mukai, T.; Komoto, Satoshi; Ibrahim, Madiha S.; Li, Yonggang; Kobayashi, Takeshi; Tsuji, Shoutaro; Ikuta, Kazuyoshi

doi:10.1111/j.1348-0421.2002.tb02766.x

Cited by 32 publications

(25 citation statements)

References 65 publications

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“…Several publications previously demonstrated that an HIV-1 LTR containing three NF-B binding sites is a stronger viral promoter than the one that contains only two such sites (7,16,22,23). It was further proposed that the stronger viral promoter contributed significantly to the widespread global expansion of subtype C (5,24).…”

Section: Fig 2 Genetic Variation Within the C-b And Sp1iii Motifs Of 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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Section: Fig 2 Genetic Variation Within the C-b And Sp1iii Motifs Of 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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“…These processes may be especially important in rapidly evolving genomes, such as those of RNA viruses, which feature high rates of mutation and recombination during replication (1,2). For example, the retrovirus human immunodeficiency virus-1 (HIV-1), 4 exhibits enormous sequence diversity, both within individual patients and among numerous subtypes and recombinants circulating throughout the world, which in many cases reduces viral fitness but can also promote its ability to adapt to different selective pressures applied by the host immune system and anti-retroviral drugs (2)(3)(4)(5)(6). In many cases, purifying selection purges mutations that reduce overall fitness; however, deleterious mutations at one residue may also be compensated for by mutations at other sites to maintain protein structure and function (7).…”

mentioning

confidence: 99%

Mutual Information Analysis Reveals Coevolving Residues in Tat That Compensate for Two Distinct Functions in HIV-1 Gene Expression

Dey

Xue

Joachimiak

et al. 2012

Journal of Biological Chemistry

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Background: It is not well understood how HIV-1 Tat performs complex functions despite its considerable sequence diversity. Results: Individually nonconserved but functionally coevolving sites in Tat were identified. Conclusion: In contrast to most coevolving sites, these sites are critical for two distinct functions regulating viral gene expression. Significance: Balancing the two mechanisms is a strategy to maintain Tat function and may impact viral latency.

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“…Although Tat based vaccines would not be able to prevent an individual acquiring infection it could block viral replication and disease onset (post exposure vaccine) [11]. Invitro studies have shown subtype C Tat protein to have a higher transactivational potential than subtype B [5,6,13]. Development of such inhibitor/vaccines would have to take into consideration the variation of the Tat proteins not only in terms of their activity but also the variation in amino acid sequence analyzed in this study which could determine epitope presentation on MHC class I antigen for afferent immune response.…”

Section: Discussionmentioning

confidence: 99%

“…One such functional gene tat mediates an important role in transcription of the HIV-1 LTR [4]. Studies have also shown that there is a variation in levels of Tat transactivation among the different subtypes [5,6]. The tat mRNA is a multiply spliced mRNA and consists of two coding (1 and 2) and one noncoding exon.…”

Section: Introductionmentioning

confidence: 99%

Amino acid sequence divergence of Tat protein (exon1) of subtype B and C HIV-1 strains: Does it have implications for vaccine development?

Kandathil¹,

Kannangai²,

Abraham³

et al. 2009

Bioinformation

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Functional genes of HIV-1 like the tat express proteins essential for viral survival and propagation. There are variations reported in levels of Tat transactivation among the different subtypes of HIV-1. This study looked at the amino acid differences in the different regions of Tat protein (exon 1) of subtype B and C strains of HIV-1 and tried to observe a molecular basis for protein function. HIV-1 sequences of subtype B (n=30) and C (n=60) strains were downloaded from HIV-1 Los Alamos data base. Among the 60 subtype C strain sequences, 30 each were from India and Africa. A HIV-1 Tat protein (exon 1) sequence, the consensus B and C sequence was obtained from the ’sequence search interface‘ in the Los Alamos HIV-1 sequence data. The sequences were visualized using Weblogo and the RNA binding regions of the three consensus sequences were also determined using BindN software program. Compared to subtype B, there was a high level of divergence in the auxiliary domain of tat exon 1 (amino acid positions 58- 69). The net charge of the subtype C (Indian) Tat protein (exon 1) auxiliary domain was -1.9 at pH 7 and it had an isoelectric point of 4.1. The net charge of the subtype C (African) auxiliary domain was -2.9 at pH 7 and it had an isoelectric point of 3.7 while the net charge of same region in subtype B was -0.9 at pH 7 with an isoelectric point of 4.9. The ratio of the hydrophilic residues to the total number of residues was 60% in the in both the Indian and African subtype C in the auxiliary domain while this was 50% in subtype B. The consensus subtype B sequence was found to have 36 RNA binding sites while subtype C (India) had 33 and subtype C (Africa) had 32 RNA binding sites. The HIV-1 Tat-TAR interaction is a potential target for inhibitors and being considered for its potential use in HIV-1 vaccines. Development of such inhibitor/vaccines would have to take into consideration the variation in amino acid sequence analyzed in this study as this could determine epitope presentation on MHC class I antigen for afferent immune response.

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Human Immunodeficiency Virus Type 1 Subtype C Exhibits Higher Transactivation Activity of Tat than Subtypes B and E

Cited by 32 publications

References 65 publications

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

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

Mutual Information Analysis Reveals Coevolving Residues in Tat That Compensate for Two Distinct Functions in HIV-1 Gene Expression

Amino acid sequence divergence of Tat protein (exon1) of subtype B and C HIV-1 strains: Does it have implications for vaccine development?

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