Table 1
Interfering strategy | Target RNA/protein | Interference site(s) | Mechanism | References |
|---|---|---|---|---|
Anti-sense RNA | Cellular CCR5 and CXCR4 co-receptors | Viral entry | Inhibition of CCR5 and CXCR4 gene expression | 6, 18, 19 |
Psi-gag and U3-5'UTR-gag-env regions | Pre-integration | Co-packaged with genomic RNA, inhibits RT in incoming virions | 6 | |
Cellular CyPA gene | Pre-integration | The skipping of internal CyPA encoding exons reduces CyPA biosynthesis and thereby inhibits the reverse transcription | 37 | |
Tat/TAR interaction | HIV-1 transcription | Inhibits transcriptional regulation of HIV-1 gene expression | 6, 7, 45, 76 | |
Rev/RRE interaction | Nuclear export | Inhibits transport of unspliced and single spiced viral RNAs | 6 | |
5'UTR | HIV-1 translation | Inhibits the translation process | 6 | |
Psi-gag region | Viral assembly | Inhibits packaging of genomic RNA | 6, 7, 45 | |
5'-leader-gag region | Viral assembly | Inhibits the formation of Gag and Env multimeric complexes during viral assembly. | 7, 18 | |
Env and Vif encoding regions | Viral assembly | Inhibits env and vif gene expression | 70 | |
Nef encoding region | Viral release | Inhibits nef gene expression and thereby CD4 and MHC I downregulation | 7 | |
Pol encoding region | Viral maturation | Inhibits pol gene expression | 70 | |
RNA decoys | RT enzyme | Pre-integration | Competes with HIV-1 RNA for the binding of RT | 6 |
HIV-1 TAR region | Pre-integration | Competes with cellular tRNA3Lys for the binding to RT and primes the reverse transcription from the TAR region instead of the PBS region | 6 | |
Tat and Tat-containing RNA polymerase II transcription complexes | HIV-1 transcription | Inhibits Tat regulated transcription | 6, 7, 18, 51 | |
Rev protein | Nuclear export | Recruits Rev molecules and thereby prevents their interaction with the viral transcript | 6 | |
NC domain of the Gag protein | Viral assembly | Inhibits packaging by interfering with the NC domains ability to recognize the genomic RNA | 6, 45 | |
Ribozymes | Cellular CCR5 and CXCR4 co-receptors | Viral entry | Cleaves CCR5 and CXCR4 mRNAs | 6, 18 |
HIV-1 Gag and Pol encoding region and the U5 region | Pre-integration | Cleaves the viral RNA before reverse transcription is completed | 6, 36 | |
RRE and the Rev encoding region | Nuclear export | Cleaves the viral RNA | 6, 7 | |
U5 | HIV-1 translation | Cleaves off the 5'-cap structure localized on HIV-1 mRNAs | 6, 7 | |
Psi | Viral assembly | Cleaves HIV-1 RNAs before packaging | 6, 7 | |
Gag encoding transcripts | Viral assembly | Inhibits the formation of multimeric Gag and Env complexes | 7, 18 | |
SU encoding region | Viral assembly | Cleaves different conserved regions in the SU sequence | 7 | |
Nef encoding region | Viral release | Inhibits downregulation of CD4 and MHC I | 7 | |
RNA aptamers | RT enzyme | Pre-integration | Displays high affinity and specificity for the RT enzyme and acts as templates analogues | 31 |
Rev protein | Nuclear export | Possesses higher affinity for Rev than the RRE sequence and can therefore interfere with Rev function | 57 | |
siRNA | Cellular CCR5 and CXCR4 co-receptors | Viral entry | Impairs the SU-chemokine co-receptor interaction | 21, 22 |
CD4 protein | Viral entry | CD4 protein expression inhibited | 23, 24 | |
CD4-binding domain of the SU protein | Viral entry | Inhibits the CD4-SU interaction | 26 | |
The viral LTR region or the vif and nef encoding regions | Pre-integration | Guides the viral genomic RNA towards a siRNA-mediated destruction | 34, 52 | |
RT encoding region | Pre-integration | Inhibits RT gene expression | 35 | |
Cellular CyPA gene | Pre-integration | Reduces CyPA biosynthesis and thereby the reverse transcription | 37 | |
CA encoding region | Pre-integration | Mediates cleavage of pre-spliced viral RNA in the cytoplasm and prevents integration | 23, 24, 42 | |
Tat encoding region | HIV-1 transcription | Inhibits Tat transactivation | 35, 49, 50 | |
NF-κB p65 subunit | HIV-1 transcription | Inhibits NF-κB transcriptional activation | 35, 49 | |
3'-terminus of the nef gene | HIV-1 transcription | Mediates cleavage of all spliced and unspliced RNA produced from the provirus | 42 | |
Rev transcript | Nuclear export | Inhibits Rev mediated export of unspliced and single spliced RNAs | 49, 61 | |
Gag and Nef encoding regions | HIV-1 translation | Mediates cleavage of both spliced and unspliced RNA produced from the provirus | 23, 24, 34, 42 | |
shRNA/ miRNA | Nef encoding region | HIV-1 translation | nef shRNAs act by blocking RNA stability or RNA translation | 62 |
Transdominant negative proteins (TNPs) | Interactions between Tat/TAR complex and cellular co-factors | HIV-1 transcription | Tat-mutants inhibit the function of the Tat protein by recruiting important cellular co-factors | 7, 18, 45 |
Rev protein | Nuclear export | Rev-mutants e.g. act by preventing the interaction with cellular co-factors or by sequestering the Rev protein in the cytoplasm | 7, 18, 25, 57, 58, 59 | |
Cellular Sam68 | Nuclear export | Sam68 mutants inhibit Sam68 transactivation of RRE and Rev function | 60 | |
Cellular Tsg101 | Viral assembly | Tsg101 mutants inhibit the transport of the Gag polyprotein into multivesicular bodies | 71 | |
Vif protein | Viral assembly | Vif mutants block an early processing of the Gag protein | 66 | |
Cellular INI1 | Viral assembly | INI1 mutants e.g. interact with the integrase domain of the Gag-Pol polyprotein and interfere with prober multimerization of Gag and Gag-Pol | 39 | |
The formation of Gag and Env multimeric complexes | Viral assembly | E.g. interferes with complex formation | 4, 6, 18 | |
Nef protein | Viral release | Nef mutants e.g. inhibit CD4 downregulation | 66 | |
SU protein | Viral release | Overexpressed CD4 variants bind and sequester virion progeny within the cell | 19 | |
HIV-1 protease | Viral maturation | Pro-mutants prevent protease activation | 7 | |
Chimeric / fusion proteins | SU protein | Viral entry | A tetrameric version of sCD4, PRO542, which is fused to the conserved region of IgG2, prevents the CD4-SU interaction | 8, 13 |
Proviral DNA | Pre-integration | An IN targeted sFv-nuclease fusion protein associates with the pre-integration complex and cleaves proviral DNA after integration has occurred | 7, 18 | |
TAR element | HIV-1 transcription | Designed Tat-nuclease fusion proteins recognize and cleave all HIV-1 RNA transcripts | 5 | |
RRE sequence | Nuclear export | Designed Rev-nuclease fusion proteins recognize and cleave all HIV-1 RNAs carrying the RRE sequence | 5 | |
Rev protein | Nuclear export | A NS1RM-Rev mutant, with a dominant retention activity, forms mixed oligomers together with Rev and inhibits nuclear export | 7, 57 | |
The TAR and RRE elements | HIV-1 transcription / nuclear export | A designed fusion protein, Tev, containing the RNA binding domains of both Tat and Rev fused to a nuclease, inhibits both early and late viral gene products | 5 | |
Viral genomic RNAs | Viral assembly | Gag-, Vpr- and Nef-nuclease fusion proteins cleaves viral RNA, either during or after the viral assembly | 5, 7 | |
Psi-element | Viral assembly | A NC-nuclease fusion protein recognizes and cleaves all unspliced RNAs in the cytoplasm | 5 | |
HIV-1 protease | Viral maturation | An overexpressed Vpr fused to several protease cleavage sites overwhelms the protease activity by a competitive mechanism | 7, 74 | |
Nucleases | Tat encoding region | HIV-1 transcription | Inhibits Tat transactivation | 6, 7, 45 |
TAR element | HIV-1 transcription | Inhibits Tat transactivation | 6, 7, 45 | |
Chemokine ligands | Cellular CCR5 and CXCR4 co-receptors | Viral entry | E.g. interacts directly with the co-receptors, mediates receptor blockade or mediates receptor down-regulation | 8, 9, 11, 12, 13, 14, 16 |
Anti-infectious cellular proteins | SU protein | Viral entry | A truncated form of CD4, sCD4, inhibits the fusion event by binding to the SU protein and thereby extending the distance to the TM protein | 8, 13, 19 |
Intracellular antibodies (sFvs) | SU protein | Viral entry | Inhibits the CD4-SU interaction | 18 |
The TM pre-hairpin intermediate | Viral entry | Inhibits the interaction between the fusion peptide and the cell membrane | 29 | |
RT enzyme | Pre-integration | Inhibits RT function | 7, 18 | |
IN enzyme | Pre-integration | Inhibits IN function | 7, 18 | |
Tat protein | HIV-1 transcription | Interacts with the Tat protein and restrains it in the cytoplasm | 7, 18 | |
Rev protein | Nuclear export | Recruits Rev in the cytoplasm | 7, 18, 25, 57 | |
The CD4 binding region of the SU protein | Viral assembly | Interacts with the Env protein and restrains it in the ER | 7, 18 | |
Monoclonal antibodies (Mabs) | Cellular CCR5 and CXCR4 co-receptors | Viral entry | E.g. inhibit the SU-chemokine co-receptor interaction, HIV-1 fusion or entry | 12 |
Extracellular loop on CCR5 | SU-chemokine co-receptor interaction | Inhibits HIV-1 fusion and entry | 12 | |
Nucleoside analogues (NRTIs) | RT enzyme | Pre-integration | Prevents the continued polymerization of the DNA chain | 8 |
Non-nucleoside analogues (NNRTIs) | RT enzyme | Pre-integration | Interact directly and non-competitively with the RT enzyme and inhibits its function | 8 |
Integrase inhibitors (Oligonucleotides, dinucleotides and chemical agents) | IN enzyme | Pre-integration | These inhibiting agents either block the catalytic function of the IN enzyme by binding to the integrase binding site located in the viral DNA, or by interacting with the catalytic core domain of the IN enzyme itself | 40, 41 |
Protease inhibitors | Protease enzyme | Viral maturation | Act as transition state analogous and bind to the protease more tightly than the natural substrate | 11, 8, 73 |
Examples of other inhibiting agents | Cellular CCR5 and CXCR4 co-receptor | Viral entry | Chemokine ligands potently inhibit the SU-chemokine co-receptor interaction | 8, 9, 10, 11, 12, 13 |
Cellular CCR5 and CXCR4 co-receptors | Viral entry | Designed peptides e.g. act by disrupting helix-helix interactions, which may influence co-receptor structure, or by associating with the co-receptor surfaces and thereby inhibit the interaction with the SU protein | 8, 12 | |
Cellular CXCR4 co-receptor | Viral entry | AMD3100, a small organic molecule, acts by spanning the main ligand-binding cavity of CXCR4, which constrains the co-receptor in an inactive conformation | 12 | |
Cellular CCR5 co-receptor | Viral entry | Cyclophilin-18, a protein derived from T. Gondii acts as a CCR5 antagonist and thereby inhibits fusion and infectivity of R5 HIV-1 isolates | 17 | |
SU protein | Viral entry | CV-N, a 11 kDa protein with high affinity for the SU protein, inhibits the SU-CD4 interaction | 15 | |
The N- and C-peptide regions on the TM pre-hairpin intermediate | Viral entry | Designed N-, C-, and D-peptides interacts with the pre-hairpin intermediate and inhibit the fusion event | 13, 27, 28 | |
RT enzyme | Pre-integration | Small peptides, about 15–19 amino acid long, act by interfering the dimerization process of the RT enzyme | 30 | |
The Tat/TAR interaction | HIV-1 transcription | The TR87 compound acts by competing with Tat for binding to TAR-RNA | 46 | |
Protein /TAR RNA interaction | HIV-1 transcription | Pyrrolo [2,1-c][1,4]benzodiazepine-oligopyrrolo hybrids act by interrupting binding of cellular proteins and Tat to the TAR-RNA | 47 | |
Protein /TAR RNA interaction | HIV-1 transcription | Aromatic polyamidines carrying a Br atom inhibit cellular and viral protein-TAR RNA interactions | 48 | |
Cellular NF-κB | HIV-1 transcription | NF-κB activity is inhibited by minocycline, a second-generation tetracycline | 38, 54 | |
Rev | Nuclear export | Peptides targeted against the NES domain inhibit Rev function | 57 | |
The cellular protease furin | Viral assembly | Peptides mimicking a conserved target sequence inhibit furin activity and thereby cleavage of the Env protein within the ER | 72 | |
HIV-1 infected cells | All | A Tat-Casp3 fusion protein induces apoptosis after cleavage and activation by the HIV-1 protease | 79 |