In silico Analyses of Subtype Specific HIV-1 Tat-TAR RNA Interaction Reveals the Structural Determinants for Viral Activity

Abstract

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.

The HIV-1 Subtype B Epidemic in French Guiana and Suriname Is Driven by Ongoing Transmissions of Pandemic and Non-pandemic Lineages

“…The analysis of clinical characteristics of individuals from French Guiana revealed a significant trend for higher RNA viral loads among B PANDEMIC -infected relative to B CAR -infected subjects, despite no significant differences in clinical condition or CD4 + T cell counts between groups. Previous studies suggested that viral genetic factors contribute to the heritability and variation of viral load set point ( Bonhoeffer et al, 2015 ; Bertels et al, 2018 ) and may also modulate viral replication ( Ronsard et al, 2017a , b ). Whether differences in viral load here observed between subjects reflect selective advantages for BPANDEMIC strains over B CAR ones cannot be answered by the present study.…”

Mathematical Analysis of Viral Replication Dynamics and Antiviral Treatment Strategies: From Basic Models to Age-Based Multi-Scale Modeling

“…For example, the trans-activating regulatory protein Tat controls gene expression and activates viral transcription by binding at the trans-activating response element TAR (Karn and Stoltzfus, 2012 ). It has been shown that point mutations in Tat may lead to more virulent HIV strains with higher stability and transcription efficiency which aggravate the development of novel antiretroviral drugs (Ronsard et al, 2014 , 2017a ; Ronsard, 2017b ). On the other hand, Tat might be a promising vaccine candidate and has shown potential in the reduction of HIV plasma viremia associated with a reduced immune activation (Gray et al, 2016 ).…”

Autophagy Intertwines with Different Diseases—Recent Strategies for Therapeutic Approaches

“…The high genetic diversity of this virus has increased the concern for developing countries like India, where it has generated various recombinants such as A/C, A/E, and B/C [138]. Critically, genetic variations in the viral genes like Tat and Vif result in differential viral activities, such as 1. varying levels of Tat interaction with the transactivation response RNA (TAR) element [139] and 2. Vif gene-induced differential APOBEC3 degradation [140], which results in a drastic increase of viral gene expression [141].…”