The reverse transcriptase of HIV‐1: from enzymology to therapeutic intervention

  title={The reverse transcriptase of HIV‐1: from enzymology to therapeutic intervention},
  author={Laura Tarrago-Litvak and Marie Line Andreola and Georgy A. Nevinsky and L Sarih-Cottin and Simon Litvak},
  journal={The FASEB Journal},
  pages={497 - 503}
The human immunodeficiency virus type 1 (HIV‐1) is the etiologic agent of AIDS. Replication of this virus requires the activity of a retrovirus encoded RNA‐dependent DNA polymerase, or reverse transcriptase (RT). HIV‐1 RT is required for the synthesis of the double‐stranded proviral DNA from the single‐stranded retroviral RNA genome. HIV‐1 RT has two subunits of 66 kDa and 51 kDa. The 66‐kDa subunit contains the DNA polymerase and RNase H domains whereas the 51‐kDa subunit, obtained by… 
Phosphorothioate oligonucleotides derived from human immunodeficiency virus type 1 (HIV-1) primer tRNALys3 are strong inhibitors of HIV-1 reverse transcriptase and arrest viral replication in infected cells
It is shown that primer tRNA-derived oligodeoxynucleotides (ODNs) carrying a phosphorothioate (PS) modification are strong inhibitors of HIV-1 RT, and that the inhibitory effect of the PS-AS may be mediated via both a sense and an antisense mechanism.
Interaction of human immunodeficiency virus type 1 reverse transcriptase with primer tRNALys3 and affinity modification of the enzyme by tRNALys3 derivatives.
The results obtained with new chemically reactive derivatives of tRNA bearing three or seven hydrophobic residues are described, which indicate that the recognition of primer tRNA by retroviral reverse transcriptase is a crucial step in the replication of retroviruses.
Effect of nucleoside analogs and non-nucleoside inhibitors of HIV-1 reverse transcriptase on cell-free virions
The data indicate that the effect of Curie pyridinone on intact virions may be related to its capacity to tightly bind the target RT, which may lead to the design and synthesis of new drugs able to interact with the retroviral enzyme inside the viral core.
Identification and Characterization of a Novel HIV-1 Nucleotide-Competing Reverse Transcriptase Inhibitor Series
A novel NcRTI series with optimized antiviral activity, minimal cross-resistance to existing RT inhibitor classes, and a distinct resistance profile has been discovered and is established as an emerging class of antiretroviral agents.
High-affinity interaction of human immunodeficiency virus type-1 reverse transcriptase with partially complementary primers.
Comparisons of Km and Vmax values for various primers in the reaction of polymerization catalyzed by the human immunodeficiency virus type-1 (HIV-1) reverse transcriptase suggest that HIV-1 reverse Transcriptase forms additional contacts with the 5'-end region of the non-complementary primer.
Immunogenic properties of reverse transcriptase of HIV type 1 assessed by DNA and protein immunization of rabbits.
Rabbits immunized with a plasmid carrying the gene for reverse transcriptase HIV-1 (RT DNA) developed potent antibody and cellular responses to the gene product, and subdomains of reverse transcripts involved in the enzymatic activity of RT were highly immunogenic.
Interaction of HIV-1 Reverse Transcriptase with New Minor Groove Binders and Their Conjugates with Oligonucleotides
The effect on polymerization catalyzed by reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) was studied for new nonnatural regular minor groove binders (MGBs) containing
Cellular reservoirs of HIV-1 and their role in viral persistence.
Cell populations of the monocyte-macrophage lineage, which originate in the bone marrow, are of particular importance in HIV-1 persistence due to their ability to cross the blood-brain barrier and spread HIV- 1 infection in the immunoprivileged central nervous system (CNS).
A neutravidin-based assay for reverse transcriptase suitable for high throughput screening of retroviral activity.
A non-isotopic neutravidin-based reverse transcriptase (RT) assay adapted for high throughput screening of HIV activity was shown to be as sensitive as a radioactive assay and the RT activity correlated well with levels of cell-associated HIVp24.


HIV‐1 reverse transcriptase specifically interacts with the anticodon domain of its cognate primer tRNA.
It is demonstrated that the HIV‐1 RT p66/p51 specifically binds to its cognate primer tRNALys,3 even in the presence of a 100‐fold molar excess of other tRNAs.
Structure of HIV-1 reverse transcriptase/DNA complex at 7 Å resolution showing active site locations
The structure at 7 Å resolution of a ternary complex of the HIV-1 reverse transcriptase heterodimer, a monoclonal antibody Fab fragment8, and a duplex DNA template-primer is reported, allowing tentative identification of the polymerase nucleoside triphosphate binding site.
HIV reverse transcriptase structure-function relationships.
The unexpected realization is the unexpected realization that the substrate for proteolytic maturation of the HIV-1 RT p66/p66 homodimer to the p 66/p51 heterodimer is most likely an unfolded RNase H domain.
Localization of a polynucleotide binding region in the HIV-1 reverse transcriptase: implications for primer binding.
Evaluation of primer recognition by purified human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) p66 homodimer indicates that a polynucleotide binding site is in close proximity to residues in the peptide comprising amino acids 195 approximately 300, which may be part of a primer-binding groove within the HIV-1reverse transcriptase.
Review of HIV-1 reverse transcriptase three-dimensional structure : implications for drug design
The structure of the reverse transcriptase heterodimer is reviewed and a detailed description of the folding and topology of the individual subdomains is provided and the first indication of an HIV-1 RT drug-resistant mutation manifested in the p51 subunit is presented.
Domain structure of the Moloney murine leukemia virus reverse transcriptase: mutational analysis and separate expression of the DNA polymerase and RNase H activities.
  • N. Tanese, S. Goff
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1988
A library of linker insertion mutants of the Moloney murine leukemia virus enzyme expressed in bacteria are generated and assays of the proteins encoded by these plasmids showed that each domain exhibited only the expected activity.
Crystal structure of the ribonuclease H domain of HIV-1 reverse transcriptase.
Interestingly, the peptide bond cleaved by HIV-1 protease near the polymerase-RNase H junction of p66 is completely inaccessible to solvent in the structure reported here, which suggests that the homodimeric p66-p66 precursor of mature RT is asymmetric with one of the two RNase H domains at least partially unfolded.
Mechanisms of the inhibition of reverse transcription by antisense oligonucleotides.
We have demonstrated that the synthesis of cDNA by avian myeloblastosis virus and Moloney murine leukemia virus reverse transcriptases can be prevented by oligonucleotides bound to the RNA template
6 Roles of Ribonuclease H in Reverse Transcription
The DNA polymerase and RNase H activities of reverse transcriptase appear to be the only enzymes required to produce the linear double-stranded DNA copy of the RNA genome that is subsequently integrated into the retroviral genome RNA.