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HIV-1 Tat transactivates viral genes through strong interaction with TAR RNA. The stem-loop bulged region of TAR consisting of three nucleotides at the position 23–25 and the loop region consisting of six nucleotides at the position 30–35 are essential for viral transactivation. The arginine motif of Tat (five arginine residues on subtype TatC) is critically important for TAR interaction. Any mutations in this motif could lead to reduce transactivation ability and pathogenesis. Here, we identified structurally important residues (arginine and lysine residues) of Tat in this motif could bind to TAR via hydrogen bond interactions which is critical for transactivation. Natural mutant Ser46Phe in the core motif could likely led to conformational change resulting in more hydrogen bond interactions than the wild type Tat making it highly potent transactivator. Importantly, we report the possible probabilities of number of hydrogen bond interactions in the wild type Tat and the mutants with TAR complexes. This study revealed the differential transactivation of subtype B and C Tat could likely be due to the varying number of hydrogen bonds with TAR. Our data support that the N-terminal and the C-terminal domains of Tat is involved in the TAR interactions through hydrogen bonds which is important for transactivation. This study highlights the evolving pattern of structurally important determinants of Tat in the arginine motif for viral transactivation.

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HIV-1 evades host defense through mutations and recombination events, generating numerous variants in an infected patient. These variants with an undiminished virulence can multiply rapidly in order to progress to AIDS. One of the targets to intervene in HIV-1 replication is the trans-activator of transcription (Tat), a major regulatory protein that transactivates the long terminal repeat promoter through its interaction with trans-activation response (TAR) RNA. In this study, HIV-1 infected patients (n = 120) from North India revealed Ser46Phe (20%) and Ser61Arg (2%) mutations in the Tat variants with a strong interaction toward TAR leading to enhanced transactivation activities. Molecular dynamics simulation data verified that the variants with this mutation had a higher binding affinity for TAR than both the wild-type Tat and other variants that lacked Ser46Phe and Ser61Arg. Other mutations in Tat conferred varying affinities for TAR interaction leading to differential transactivation abilities. This is the first report from North India with a clinical validation of CD4 counts to demonstrate the influence of Tat genetic variations affecting the stability of Tat and its interaction with TAR. This study highlights the co-evolution pattern of Tat and predominant nucleotides for Tat activity, facilitating the identification of genetic determinants for the attenuation of viral gene expression.

Background Women continue to be underrepresented in cardiology and even more so in leadership positions. We evaluated the trends and gender differences in the guideline writing groups of the American College of Cardiology/American Heart Association (ACC/AHA), Canadian Cardiovascular Society (CCS), and European Society of Cardiology (ESC) guidelines from 2006 to 2020. Methods and Results We extracted all guidelines authors from 2006 to 2020, assessed their gender from publicly available profiles, and compared differences based on subspecialties and specific societies. Stratified and trend analyses were performed using χ 2 and average annual percentage change/average 5 year percentage change. A total of 80 ACC/AHA (1288 authors [28% women]), 64 CCS (988 authors [26% women]), and 59 ESC (1157 authors [16% women]) guidelines were analyzed. A significant increase in inclusion of women was seen in ACC/AHA (12.6% [2006] to 42.6% [2020]; average annual percentage change, 6.6% [2.3% to 11.1%]; P =0.005) and ESC (7.1% [2006] to 25.8% [2020]; average annual percentage change, 6.6% [0.2% to 13.5%]; P =0.04), but the trend remained similar in CCS (20.6% [2006] to 36.3% [2020]; average annual percentage change, −0.1% (−3.7% to 3.5%); P =0.94), guideline authors. More women were coauthors in the ACC/AHA and ESC guidelines when women were chairs of guidelines. There was a persistent disparity of women among guideline authors for general cardiology and all subspecialties, except for pediatric cardiology and heart failure guidelines. The appointment of women authors as a chair was significantly low in all societies (22.4% [ACC/AHA], 16.9% [CCS], and 7.2% [ESC]; P =0.008). Conclusions There is a significant disparity in the inclusion of women on all national guideline committees, in addition to serving as a chair of cardiology guidelines. Further advocacy is required to promote equity, diversity, and inclusion in our cardiology guidelines globally.