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Genetic characterization of HIV type 1 Tat exon 1 from a southern Indian clinical cohort: identification of unique epidemiological signature residues.

ABSTRACT: The trans-activator of transcription (Tat) of HIV-1 plays an important role in viral infection and pathogenesis. We examined the genetic characteristics of exon 1 of the tat gene derived from 102 seropositive subjects from southern India. Database-derived Indian (n=105) and global (n=413) HIV-1C sequences were also used for viral epidemiological signature pattern analysis in the Tat open reading frame (ORF). We identified HIV-1C as the most predominant genetic subtype (99%) and the presence of a novel A1C recombinant strain in one study participant. After examining all the available HIV-1C Indian sequences from primary clinical isolates and database-derived sequences, we found a high level of sequence conservation (92.6 ± 12%) within Tat amino acid residues. Furthermore, signature pattern analysis identified five amino acid positions in Tat that contained signature residues unique for Indian HIV-1C consisting of 21A, 24N, 29K, 40K, and 60Q. Our data have direct relevance for subunit-based Tat HIV-1 vaccine development.

SUBMITTER: Neogi U

PROVIDER: S-EPMC3423656 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Genetic characterization of HIV type 1 Tat exon 1 from a southern Indian clinical cohort: identification of unique epidemiological signature residues.

Neogi Ujjwal U Gupta Soham S Sahoo Pravat Nalini PN Shet Anita A Rao Shwetha D SD Ranga Udaykumar U Prasad Vinayaka R VR

AIDS research and human retroviruses 20120502 9

The trans-activator of transcription (Tat) of HIV-1 plays an important role in viral infection and pathogenesis. We examined the genetic characteristics of exon 1 of the tat gene derived from 102 seropositive subjects from southern India. Database-derived Indian (n=105) and global (n=413) HIV-1C sequences were also used for viral epidemiological signature pattern analysis in the Tat open reading frame (ORF). We identified HIV-1C as the most predominant genetic subtype (99%) and the presence of a ...[more]

PMID: 22236201

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Project description:HIV-1 remains a global health concern and to date, nearly 38 million people are living with HIV. The complexity of HIV-1 pathogenesis and its subsequent prevalence is influenced by several factors including the HIV-1 subtype. HIV-1 subtype variation extends to sequence variation in the amino acids of the HIV-1 viral proteins. Of particular interest is the transactivation of transcription (Tat) protein due to its key function in viral transcription. The Tat protein predominantly functions by binding to the transactivation response (TAR) RNA element to activate HIV-1 transcriptional elongation. Subtype-specific Tat protein sequence variation influences Tat-TAR binding affinity. Despite several studies investigating Tat-TAR binding, it is not clear which regions of the Tat protein and/or individual Tat amino acid residues may contribute to TAR binding affinity. We, therefore, conducted a scoping review on studies investigating Tat-TAR binding. We aimed to synthesize the published data to determine (1) the regions of the Tat protein that may be involved in TAR binding, (2) key Tat amino acids involved in TAR binding and (3) if Tat subtype-specific variation influences TAR binding. A total of thirteen studies met our inclusion criteria and the key findings were that (1) both N-terminal and C-terminal amino acids outside the basic domain (47-59) may be important in increasing Tat-TAR binding affinity, (2) substitution of the amino acids Lysine and Arginine (47-59) resulted in a reduction in binding affinity to TAR, and (3) none of the included studies have investigated Tat subtype-specific substitutions and therefore no commentary could be made regarding which subtype may have a higher Tat-TAR binding affinity. Future studies investigating Tat-TAR binding should therefore use full-length Tat proteins and compare subtype-specific variations. Studies of such a nature may help explain why we see differential pathogenesis and prevalence when comparing HIV-1 subtypes.

Project description:BackgroundWe have shown that HIV-1 Tat interaction with MAP2K3, MAP2K6, and IRF7 promoters is key to IFN-stimulated genes (ISG) activation in immature dendritic cells and macrophages.ResultsWe evaluated how Tat alleles and mutants differ in cellular gene modulation of immature dendritic cells and monocyte-derived macrophages and what similarities this modulation has with that induced by interferons. The tested alleles and mutants modulated to different degrees ISG, without concomitant induction of interferons. The first exon TatSF21-72 and the minimal transactivator TatSF21-58, all modulated genes to a significantly greater extent than full-length wild type, two-exon Tat, indicating that Tat second exon is critical in reducing the innate response triggered by HIV-1 in these cells. Mutants with reduced LTR transactivation had a substantially reduced effect on host gene expression modulation than wild type TatSF2. However, the more potent LTR transactivator TatSF2A58T modulated ISG expression to a lower degree compared to TatSF2. A cellular gene modulation similar to that induced by Tat and Tat mutants in immature dendritic cells could be observed in monocyte-derived macrophages, with the most significant pathways affected by Tat being the same in both cell types. Tat expression in cells deleted of the type I IFN locus or receptor resulted in a gene modulation pattern similar to that induced in primary immature dendritic cells and monocyte-derived macrophages, excluding the involvement of type I IFNs in Tat-mediated gene modulation. ISG activation depends on Tat interaction with MAP2K3, MAP2K6, and IRF7 promoters and a single exon Tat protein more strongly modulated the luciferase activity mediated by MAP2K3, MAP2K6, and IRF7 promoter sequences located 5' of the RNA start site than the wild type two-exon Tat, while a cysteine and lysine Tat mutants, reduced in LTR transactivation, had negligible effects on these promoters. Chemical inhibition of CDK9 or Sp1 decreased Tat activation of MAP2K3-, MAP2K6-, and IRF7-mediated luciferase transcription.ConclusionsTaken together, these data indicate that the second exon of Tat is critical to the containment of the innate response stimulated by Tat in antigen presenting cells and support a role for Tat in stimulating cellular transcription via its interaction with transcription factors present at promoters.

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Genetic characterization of HIV type 1 Tat exon 1 from a southern Indian clinical cohort: identification of unique epidemiological signature residues.

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Genetic characterization of HIV type 1 Tat exon 1 from a southern Indian clinical cohort: identification of unique epidemiological signature residues.

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