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Functional relevance of nonsynonymous mutations in the HIV-1 tat gene within an epidemiologically-linked transmission cohort.

ABSTRACT: Here we investigated the nature and functional consequences of mutations in the HIV-1 tat gene within an epidemiologically-linked AIDS transmission cohort consisting of a non-progressing donor (A) and two normal progressing recipients (B and C). Multiple nonsynonymous mutations in the tat first exon were observed across time in all individuals. Some mutations demonstrated striking host specificity despite the cohort being infected with a common virus. Phylogenetic segregation of the tat clones at the time of progression to AIDS was also observed especially in recipient C. Tat clones supporting high levels of transactivation were present at all time points in all individuals, although a number of clones defective for transactivation were observed for recipient C in later time points. Here we show that the tat quasispecies in a linked transmission cohort diversify and evolve independently between hosts following transmission. It supports the belief that quasispecies variation in HIV-1 is a mechanism for selection towards defining a fitter gene variant that is capable of resisting the human immune system.

SUBMITTER: Sivakumaran H

PROVIDER: S-EPMC2174444 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Functional relevance of nonsynonymous mutations in the HIV-1 tat gene within an epidemiologically-linked transmission cohort.

Sivakumaran Haran H Wang Bin B Gill M John MJ Beckholdt Brenda B Saksena Nitin K NK Harrich David D

Virology journal 20071025

Here we investigated the nature and functional consequences of mutations in the HIV-1 tat gene within an epidemiologically-linked AIDS transmission cohort consisting of a non-progressing donor (A) and two normal progressing recipients (B and C). Multiple nonsynonymous mutations in the tat first exon were observed across time in all individuals. Some mutations demonstrated striking host specificity despite the cohort being infected with a common virus. Phylogenetic segregation of the tat clones a ...[more]

PMID: 17958917

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Project description:BACKGROUND:Transmission of human immunodeficiency virus type 1 (HIV-1) drug resistance mutations, particularly that of minority drug-resistant variants, remains poorly understood. Population-based studies suggest that drug-resistant HIV-1 is less transmissible than drug-susceptible viruses. We compared HIV-1 drug-resistant genotypes among partner-pairs in order to assess the likelihood of transmission of drug resistance mutations and investigate the role of minority variants in HIV transmission. METHODS AND FINDINGS:From 1992-2010, 340 persons with primary HIV-1 infection and their partners were enrolled into observational research studies at the University of Washington Primary Infection Clinic (UWPIC). Out of 50 partner-pairs enrolled, 36 (72%) transmission relationships were confirmed by phylogenetic distance analysis of HIV-1 envelope (env) sequences, and 31 partner-pairs enrolled after 1995 met criteria for this study. Drug resistance mutations in the region of the HIV-1 polymerase gene (pol) that encodes protease and reverse transcriptase were assessed by 454-pyrosequencing. In 25 partner-pairs where the transmission direction could be determined, 12 (48%) transmitters had 1-4 drug resistance mutations (23 total) detected in their HIV-1 populations at a median frequency of 6.0% (IQR 1.5%-98.7%, range 1.0%-99.6%). Of 10 major mutations detected in five transmitters at a frequency >95%, 100% (95% CI 69.2%-100%) were detected in recipients. All of these transmitters were antiretroviral (ARV)-naïve at the time of specimen collection. Fourteen mutations (eight major mutations and six accessory mutations) were detected in nine transmitters at low frequencies (1.0%-11.8%); four of these transmitters had previously received ARV therapy. Two (14% [95% CI 1.8%-42.8%]) G73S accessory mutations were detected in both transmitter and recipient. This number is not significantly different from the number expected based on the observed frequencies of drug-resistant viruses in transmitting partners. Limitations of this study include the small sample size and uncertainties in determining the timing of virus transmission and mutation history. CONCLUSIONS:Drug-resistant majority variants appeared to be commonly transmitted by ARV-naïve participants in our analysis and may contribute significantly to transmitted drug resistance on a population level. When present at low frequency, no major mutation was observed to be shared between partner-pairs; identification of accessory mutations shared within a pair could be due to transmission, laboratory artifact, or apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs), and warrants further study.

Project description:BACKGROUND: HIV latency is an obstacle for the eradication of HIV from infected individuals. Stable post-integration latency is controlled principally at the level of transcription. The HIV trans-activating protein, Tat, plays a key function in enhancing HIV transcriptional elongation. The HIV core promoter is specifically required for Tat-mediated trans-activation of HIV transcription. In addition, the HIV core promoter has been shown to be a potential anti-HIV drug target. Despite the pivotal role of the HIV core promoter in the control of HIV gene expression, the molecular mechanisms that couple Tat function specifically to the HIV core promoter remain unknown. RESULTS: Using electrophoretic mobility shift assays (EMSAs), the TATA box and adjacent sequences of HIV essential for Tat trans-activation were shown to form specific complexes with nuclear extracts from peripheral blood mononuclear cells, as well as from HeLa cells. These complexes, termed pre-initiation complexes of HIV (PICH), were distinct in composition and DNA binding specificity from those of prototypical eukaryotic TATA box regions such as Adenovirus major late promoter (AdMLP) or the hsp70 promoter. PICH contained basal transcription factors including TATA-binding protein and TFIIA. A mutational analysis revealed that CTGC motifs flanking the HIV TATA box are required for Tat trans-activation in living cells and correct PICH formation in vitro. The binding of known core promoter binding proteins AP-4 and USF-1 was found to be dispensable for Tat function. TAR RNA prevented stable binding of PICH-2, a complex that contains the general transcription factor TFIIA, to the HIV core promoter. The impact of TAR on PICH-2 specifically required its bulge sequence that is also known to interact with Tat. CONCLUSION: Our data reveal that CTGC DNA motifs flanking the HIV TATA box are required for correct formation of specific pre-initiation complexes in vitro and that these motifs are also required for Tat trans-activation in living cells. The impact of TAR RNA on PICH-2 stability provides a mechanistic link by which pre-initiation complex dynamics could be coupled to the formation of the nascent transcript by the elongating transcription complex. Together, these findings shed new light on the mechanisms by which the HIV core promoter specifically responds to Tat to activate HIV gene expression.

Dataset Information

Functional relevance of nonsynonymous mutations in the HIV-1 tat gene within an epidemiologically-linked transmission cohort.

Publications

Functional relevance of nonsynonymous mutations in the HIV-1 tat gene within an epidemiologically-linked transmission cohort.

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