Structural and computational studies of HIV-1 RNA

Abstract

Viruses remain a global threat to animals, plants, and humans. The type 1 human immunodeficiency virus (HIV-1) is a member of the retrovirus family and carries an RNA genome, which is reverse transcribed into viral DNA and further integrated into the host-cell DNA for viral replication and proliferation. The RNA structures from the HIV-1 genome provide valuable insights into the mechanisms underlying the viral replication cycle. Moreover, these structures serve as models for designing novel therapeutic approaches. Here, we review structural data on RNA from the HIV-1 genome as well as computational studies based on these structural data. The review is organized according to the type of structured RNA element which contributes to different steps in the viral replication cycle. This is followed by an overview of the HIV-1 transactivation response element (TAR) RNA as a model system for understanding dynamics and interactions in the viral RNA systems. The review concludes with a description of computational studies, highlighting the impact of biomolecular simulations in elucidating the mechanistic details of various steps in the HIV-1’s replication cycle.

Bioinformatics Insights on Viral Gene Expression Transactivation: From HIV-1 to SARS-CoV-2

“…To determine if SARS-CoV-2 might also use gene expression transactivation, we first searched for a Tat-binding-like site in the SARS-CoV-2 leader and found the sequence AGAUCUG, which is identical to the HIV-1 and JCV TAR sequences to which HIV-1 Tat binds (AGA UCU , binding sequence underlined, with an additional guanosine residue), and spans the entire right stem half of stem-loop (SL) 2 up to the first nucleotide of SL3 ( Figure 1 ). The secondary structure for the segment, including the AGAUCUG sequence of the SARS-CoV-2 leader sequence, is similar to that by which Tat recognizes TAR, i.e., with an indispensable first uridine in the bulge (AGA U CU) and G-C (A G AUCU) and A-U (AG A UCU) base pairs in the upper stem of the HIV-1 TAR stem–bulge–stem [ 21 , 22 , 23 , 25 , 92 , 93 , 94 , 95 , 96 , 97 ]. In JCV TAR, the Tat-binding sequence is at its loop, not its bulge.…”

“…and spans the entire right stem half of stem-loop (SL) 2 up to the first nucleotide of SL3 (Figure 1). The secondary structure for the segment, including the AGAUCUG sequence of the SARS-CoV-2 leader sequence, is similar to that by which Tat recognizes TAR, i.e., with an indispensable first uridine in the bulge (AGAUCU) and G-C (AGAUCU) and A-U (AGAUCU) base pairs in the upper stem of the HIV-1 TAR stem-bulge-stem [21][22][23]25,[92][93][94][95][96][97]. In JCV TAR, the Tat-binding sequence is at its loop, not its bulge.…”

“…The SEC includes the heterodimer positive transcription elongation factor-b (P-TEFb) complex comprising Cyclin T1 and CDK9 [ 9 , 10 , 11 , 12 , 13 , 14 ], and the polymerase-associated factor 1 (PAF-1) complex [ 15 , 16 ] to the transacting responsive region (TAR). Located downstream of the initiation site for HIV-1 transcription (nucleotides +1 to +59), TAR adopts an A-form stem-loop structure with a bulge [ 4 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

“…and the polymerase-associated factor 1 (PAF-1) complex [15,16] to the transacting responsive region (TAR). Located downstream of the initiation site for HIV-1 transcription (nucleotides +1 to +59), TAR adopts an A-form stem-loop structure with a bulge [4,[17][18][19][20][21][22][23][24][25].…”

Bioinformatics Insights on Viral Gene Expression Transactivation: From HIV-1 to SARS-CoV-2

“…To determine if SARS-CoV-2 might also use gene expression transactivation, we first searched for a Tat-binding-like site in the SARS-CoV-2 leader and found the sequence AGAUCUG, which is identical to the HIV-1 and JCV TAR sequences to which HIV-1 Tat binds (AGAUCU, binding sequence underlined, with an additional guanosine residue), and spans the entire right stem half of stem-loop (SL) 2 up to the first nucleotide of SL3 (Figure 1). The secondary structure for the segment, including the AGAUCUG sequence of the SARS-CoV-2 leader sequence, is similar to that by which Tat recognizes TAR, i.e., with an indispensable first uridine in the bulge (AGAUCU) and G-C (AGAUCU) and A-U (AGAUCU) base pairs in the upper stem of the HIV-1 TAR stem-bulge-stem [21][22][23]25,[92][93][94][95][96][97]. In JCV TAR, the Tat-binding sequence is at its loop, not its bulge.…”