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Results for “RNA-RNA interactions”

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PubMed1998

Base pairing with U6atac snRNA is required for 5' splice site activation of U12-dependent introns in vivo.

The minor U12-dependent class of eukaryotic nuclear pre-mRNA introns is spliced by a distinct spliceosomal mechanism that requires the function of U11, U12, U5, U4atac, and U6atac snRNAs. Previous work has shown that U11 snRNA plays a role similar to U1 snRNA in the major class spliceosome by base pairing to the conserved 5' splice site sequence. Here we show that U6atac snRNA also base pairs to the 5' splice site in a manner analogous to that of U6 snRNA in the major class spliceosome. We show that splicing defective mutants of the 5' splice site can be activated for splicing in vivo by the coexpression of compensatory U6atac snRNA mutants. In some cases, maximal restoration of splicing required the coexpression of compensatory U11 snRNA mutants. The allelic specificity of mutant phenotype suppression is consistent with Watson-Crick base pairing between the pre-mRNA and the snRNAs. These results provide support for a model of the RNA-RNA interactions at the core of the U12-dependent spliceosome that is strikingly similar to that of the major class U2-dependent spliceosome.

Base Sequence↗

PubMed1998

The rhinovirus type 14 genome contains an internally located RNA structure that is required for viral replication.

Cis-acting RNA signals are required for replication of positive-strand viruses such as the picornaviruses. Although these generally have been mapped to the 5' and/or 3' termini of the viral genome, RNAs derived from human rhinovirus type 14 are unable to replicate unless they contain an internal cis-acting replication element (cre) located within the genome segment encoding the capsid proteins. Here, we show that the essential cre sequence is 83-96 nt in length and located between nt 2318-2413 of the genome. Using dicistronic RNAs in which translation of the P1 and P2-P3 segments of the polyprotein were functionally dissociated, we further demonstrate that translation of the cre sequence is not required for RNA replication. Thus, although it is located within a protein-coding segment of the genome, the cre functions as an RNA entity. Computer folds suggested that cre sequences could form a stable structure in either positive- or minus-strand RNA. However, an analysis of mutant RNAs containing multiple covariant and non-covariant nucleotide substitutions within these putative structures demonstrated that only the predicted positive-strand structure is essential for efficient RNA replication. The absence of detectable minus-strand synthesis from RNAs that lack the cre suggests that the cre is required for initiation of minus-strand RNA synthesis. Since a lethal 3' noncoding region mutation could be partially rescued by a compensating mutation within the cre, the cre appears to participate in a long-range RNA-RNA interaction required for this process. These data provide novel insight into the mechanisms of replication of a positive-strand RNA virus, as they define the involvement of an internally located RNA structure in the recognition of viral RNA by the viral replicase complex. Since internally located RNA replication signals have been shown to exist in several other positive-strand RNA virus families, these observations are potentially relevant to a wide array of related viruses.

Amino Acid Sequence↗

PubMed1999

Long-distance RNA-RNA interactions and conserved sequence elements affect potato virus X plus-strand RNA accumulation.

Conserved octanucleotide sequences located upstream of two major potato virus X (PVX) subgenomic RNAs (sgRNAs), as well as elements in the 5' end of the genome, affect accumulation of sgRNA. To determine if complementarity between these sequences is important for PVX RNA accumulation, we analyzed the effects of mutations within these elements and compensatory mutations in a tobacco protoplast system and in plants. Mutations in the 5' nontranslated region (NTR mutants) that reduced complementarity resulted in lower genomic RNA (gRNA) and sgRNA levels, whereas mutations to the octanucleotide elements affected only the corresponding sgRNA levels. However, for both the NTR and octanucleotide mutants, the extent of reductions in RNA levels did not directly correlate with the degree of complementarity, suggesting that the sequences of these elements are also important. Mutants containing changes in the NTR and compensatory changes in one of the octanucleotide elements restored levels of gRNA and the other sgRNA species with an unaltered octanucleotide element to those of wild-type. Although compensatory changes significantly increased levels of the sgRNA species with the modified octanucleotide element, levels were not restored to those of wild-type. Our data indicate that long distance RNA-RNA interactions and the sequences of the interacting elements are required for PVX plus-strand RNA accumulation.

5' Untranslated Regions↗

PubMed1999

Subgenomic mRNA regulation by a distal RNA element in a (+)-strand RNA virus.

Subgenomic (sg) mRNAs are synthesized by (+)-strand RNA viruses to allow for efficient translation of products encoded 3' in their genomes. This strategy also provides a means for regulating the expression of such products via modulation of sg mRNA accumulation. We have studied the mechanism by which sg mRNAs levels are controlled in tomato bushy stunt virus, a small (+)-strand RNA virus which synthesizes two sg mRNAs during infections. Neither the viral capsid nor movement proteins were found to play any significant role in modulating the accumulation levels of either sg mRNA. Deletion analysis did, however, identify a 12-nt-long RNA sequence located approximately 1,000 nt upstream from the site of initiation of sg mRNA2 synthesis that was required specifically for accumulation of sg mRNA2. Further analysis revealed a potential base-pairing interaction between this sequence and a sequence located just 5' to the site of initiation for sg mRNA2 synthesis. Mutant genomes in which this interaction was either disrupted or maintained were analyzed and the results indicated a positive correlation between the predicted stability of the base-pairing interaction and the efficiency of sg mRNA2 accumulation. The functional significance of the long-distance interaction was further supported by phylogenetic sequence analysis which revealed conservation of base-pairing interactions of similar stability and relative position in the genomes of different tombusviruses. It is proposed that the upstream sequence represents a cis-acting RNA element which facilitates sg mRNA accumulation by promoting efficient synthesis of sg mRNA2 via a long-distance RNA-RNA interaction.

Amino Acid Sequence↗

PubMed1999

A selection system for functional internal ribosome entry site (IRES) elements: analysis of the requirement for a conserved GNRA tetraloop in the encephalomyocarditis virus IRES.

Picornavirus internal ribosome entry site (IRES) elements direct cap-independent internal initiation of protein synthesis within mammalian cells. These RNA elements (about 450 nt) contain extensive secondary structure including a hairpin loop with a conserved GNRA motif. Such loops are important in RNA-RNA and RNA-protein interactions. Plasmids that express dicistronic mRNAs of the structure GUS/IRES/HOOK have been constructed. The HOOK sequence encodes a cell-surface-targeted protein (sFv); the translation of this open reading frame within mammalian cells from these dicistronic mRNAs requires a functional IRES element. Cells that express the sFv can be selected from nonexpressing cells. A pool of up to 256 mutant encephalomyocarditis virus IRES elements was generated by converting the wild-type hairpin loop sequence (GCGA) to NNNN. Following transfection of this pool of mutants into COS-7 cells, plasmids were recovered from selected sFv-expressing cells. These DNAs were amplified in Escherichia coli and transfected again into COS-7 cells for further cycles to enrich for plasmids encoding functional IRES elements. The sequence of individual selected IRES elements was determined. All functional IRES elements had a tetraloop with a 3' terminal A residue. Optimal IRES activity, assayed in vitro and within cells, was obtained from plasmids encoding an IRES with the hairpin loop sequence fitting a RNRA consensus. In contrast, IRES elements containing YCYA tetraloops were severely defective.

Animals↗

PubMed1999

Long-range RNA interactions between structural domains of the aphthovirus internal ribosome entry site (IRES).

Internal initiation of translation is promoted by internal ribosome entry site (IRES) cis-acting elements. Using transcripts that correspond to the structural domains of the foot-and-mouth disease virus (FMDV) IRES, we have identified RNA-RNA interactions between separated domains (1-2, 3, 4-5, or HH) of the IRES structure. All the assayed domains were able to interact with the full-length IRES as well as with domain 3, although to a different extent, with the most efficient interactions being those occurring between domains 3 and 4-5, and domains 3 and 1-2. RNA-RNA complexes were stable over 1 h of incubation at 37 degrees C, and depended on Mg2+ and RNA concentration. Neither the antisense domain 1-2 nor tRNA interacted with domain 3, providing experimental evidence of the specificity for the sense strand of the IRES sequence. Additionally, domain 1-2 did not interact with 4-5, leading to the suggestion that domain 3 acts as a scaffold structure where the other domains bind. The thermal disassociation profile of these complexes indicated different strength in these interactions. Whereas 50% of the complexes between domains 3 and 4-5 were destabilized at 45 degrees C, those formed by domain 1-2 and 3 required temperatures higher than 51 degrees C. Efficient self-dimerization of domains 3 and 4-5 was found in the absence of other transcripts. Formation of domain 3 homodimer competed with formation of heterocomplexes with other domains, and conversely, domain 3 homodimers were competed out by the presence of the other domains. RNA interactions were also observed at physiological concentrations of Mg2+ and K1+. The identification of the RNA-RNA complexes reported here provide direct experimental evidence of tertiary interactions within IRES elements.

Animals↗

PubMedDate not supplied

Proximity of a Tat peptide to the HIV-1 TAR RNA loop region determined by site-specific photo-cross-linking.

Transcriptional regulation in human immunodeficiency virus type 1 (HIV-1) requires specific interactions of Tat protein with the trans-activation responsive region (TAR) RNA, a 59-base stem-loop structure located at the 5'-ends of all HIV-1 mRNAs. We have used a site-specific cross-linking method based on 4-thio-uracil (4-thioU) photochemistry to determine the interactions of a Tat peptide, Tat(38-72), with the loop region of TAR RNA under physiological conditions. A TAR RNA construct with a single 4-thioU residue at positions U31 in the loop sequence was synthesized by chemical methods. Upon UV irradiation, 4-thioU at U31 formed a covalent cross-link with the Tat peptide. We did not observe any RNA-RNA cross-link formation. Competition experiments revealed that a specific RNA-protein complex formation was necessary for the RNA-protein cross-linking reaction. Our results demonstrate that, during RNA-protein recognition, the Tat peptide is located in close proximity to O4 of U31 in the TAR RNA loop sequence.

Amino Acid Sequence↗

PubMed1993

The Leptomonas collosoma spliced leader RNA can switch between two alternate structural forms.

We have used a combination of physical and molecular biological techniques to examine the structure of Leptomonas collosoma spliced leader RNA. We confirm the general features of the previously proposed structure for the 3' half of the RNA, in which a single-stranded region is flanked by two stem loops. However, we find that the 5' half of the RNA, which contains the splice site, has two competing secondary structures which differ only slightly in stability and which can interconvert on a fast (<1 s) time scale. In the favored conformation, a stable hairpin helix is augmented by conserved complementarity between the splice site and the 5' end of the SL RNA. This putative helix has anomalous nuclease sensitivity and thermal stability features, suggesting that it is probably coupled by unknown tertiary interactions to other nucleotides in the 5' half-molecule. The structure offers intriguing parallels with RNA-RNA interactions in the mammalian splicing system.

Animals↗

PubMed1994

Rational design of self-cleaving pre-tRNA-ribonuclease P RNA conjugates.

Ribonuclease P (RNaseP) generates the mature 5' end of tRNAs by removing 5'leader sequences from pre-tRNAs. In vitro, the RNA subunit is sufficient to catalyze this reaction and is therefore a ribozyme. The kinetic analysis of RNase P-mediated catalysis is complicated because product release is normally rate-limiting. Furthermore, the intermolecular nature of the cleavage reaction precludes many applications of in vitro selection schemes to the analysis of RNaseP. To examine and manipulate the RNase P function more effectively, we designed a pair of ribozymes in which the RNase P RNA is covalently linked to a pre-tRNA substrate. To facilitate intramolecular cleavage, pre-tRNA molecules were tethered to circulatory permuted RNaseP RNA molecules at nucleotides implicated in substrate binding. These "active-site-tethered" pre-tRNA-RNaseP RNA conjugates undergo accurate and efficient self-cleavage in vitro, with first-order reaction rates equivalent to the rate of the chemical step of the native RNase P reaction. Unlike most ribozymes, RNase P recognizes its substrate through tertiary RNA-RNA interactions, rather than through extensive Watson-Crick base-pairing. However, the development of the active-site-tethered conjugates has led us to create a sequence-specific endonuclease, termed Endo.P. In the Endo.P configuration, the 3'half of the pre-tRNA acceptor stem binds exogenous RNA substrates via Watson-Crick base-pairing; the bound substrate is subsequently cleaved at the predicted site. The demonstration of sequence-specific cleavage by Endo.P expands the potential of RNase P and its derivatives as reagents in gene therapy.

Base Sequence↗

PubMed1983

Characterization of translational-control ribonucleic acid isolated from embryonic chick muscle.

Myosin heavy chain (MHC) mRNP particles have been purified from 13-day chick embryonic skeletal muscle by a combination of sucrose density gradient centrifugation and metrizamide buoyant density centrifugation. Associated with the mRNPs are at least three distinct low molecular weight RNA molecules including translational-control RNA (tcRNA). This particular RNA contains 102 nucleotides and is uridine and guanine rich, and its nucleotide sequence has been determined. tcRNA102 is capable of inhibiting the translation of the mRNAs with which it is associated upon preincubation in stoichiometric amounts. Under these conditions, endogenous reticulocyte mRNA is not inhibited. Under appropriate salt and temperature conditions, tcRNA102 is capable of reassociating with myosin heavy chain (MHC) mRNA, thus altering the sedimentation characteristics of the mRNA. This suggests that the mRNA-tcRNA102 interactions alter the secondary structure of the mRNA. In addition, tcRNA102 does not associate with ribosomal RNA or globin mRNA, suggesting that some degree of specificity is involved with the RNA-RNA interactions.

Animals↗

PubMed1985

Detection of high-affinity intercalator sites in a ribosomal RNA fragment by the affinity cleavage intercalator methidiumpropyl-EDTA-iron(II).

The affinity cleavage reagent methidiumpropyl-EDTA (MPE) [Hertzberg, R. P., & Dervan, P. B. (1982) J. Am. Chem. Soc. 104, 313-315] intercalates between base pairs in helical DNA and, when complexed with Fe(II), cleaves the DNA by oxidative degradation of the deoxyribose. We find that this reagent is useful for mapping structure in some RNA molecules. The reagent binds to poly(A)-poly(U) with the same or slightly lower affinity as the related ethidium intercalator, selectively binds double-helical in preference to single-stranded RNA, and when complexed with Fe(II) readily cleaves the RNA backbone. The reagent binds to three or four helical locations in tRNAPhe with an affinity of 10(5)-10(6) M-1 (0.1 M Na+, pH 7.6, 37 degrees C). With a 345-base RNA fragment covering the S8/S15 protein binding region of Escherichia coli 16S ribosomal RNA, MPE-Fe(II) intercalates strongly at two helical sites: one is located at or near a single base bulge and the other at the end of a helix. Intense cutting is also seen in a region that is not part of a Watson-Crick helix. Ethidium bromide binds at these sites with high affinity (about 10(7) M-1 at 0.1 M Na+, pH 7.6, 37 degrees C). The sites are all clustered in a region of the RNA thought to bind S15. Tertiary folding of the RNA may distort helices in the molecule to create sites with particularly high affinities for intercalators; such sites may have functional significance in protein recognition or RNA-RNA interactions.

Base Sequence↗

PubMed2002

Apical loop-internal loop interactions: a new RNA-RNA recognition motif identified through in vitro selection against RNA hairpins of the hepatitis C virus mRNA.

We performed in vitro selection of oligoribonucleotides in order to identify high-affinity motifs recognizing RNA hairpins located at the 3' end (SL1) and at the 5' end (domain IV of the internal ribosome entry site) of the hepatitis C virus mRNA. We selected aptamers constituted by an internal loop complementary to the SL1 apical loop, flanked by G-C-rich double-stranded regions, able to form complexes with a K(d) of 70 nM, at 37 degrees C under ionic conditions close to intracellular ones. The complex involves selective apical loop (SL1)-internal loop (aptamer) interactions. Similar structurally organized aptamers were independently identified against domain IV and were shown to also give rise to such complexes. Apical loop-internal loop interaction could constitute a new recognition motif allowing specific intra- or intermolecular RNA-RNA association.

Base Sequence↗

PubMed2003

Extending the family of UNCG-like tetraloop motifs: NMR structure of a CACG tetraloop from coxsackievirus B3.

Stable RNA tetraloop motifs are found frequently in biologically active RNAs. These motifs carry out a wide variety of functions in RNA folding, in RNA-RNA and RNA-protein interactions. A great deal of knowledge about the structures and functions of tetraloop motifs has accumulated largely due to intensive theoretical, biochemical, and biophysical studies on three most frequently occurring families of tetraloop sequences, namely, the cUNCGg, the cGNRAg, and the gCUUGc sequences. Our knowledge surely is not exhaustive, and efforts are still being made to gain a better understanding. Here we report the NMR structure of a uCACGg tetraloop that occurs naturally within the cloverleaf RNA structure of the 5'-UTR of coxsackievirus B3. This tetraloop is the major determinant for interaction between the cloverleaf RNA and viral 3C protease, which is an essential part of a ribonucleoprotein complex that plays a critical role in the regulation of viral translation and replication. Our structure shows that the CACG tetraloop is closed by a wobble U.G base pair. The structure of the CACG tetraloop is stabilized by extensive base stacking and hydrogen bonding interactions strikingly similar to those previously reported for the cUUCGg tetraloop. Identification of these hallmark structural features strongly supports the existence of an extended YNCG tetraloop family. The U.G base pair closing the stem and the A residue in the loop introduce some small structural and themodynamic distinctions from the canonical cUUCGg tetraloop that may be important for recognition by the viral 3C protease.

Enterovirus B, Human↗

PubMed2003

Probing the molecular mechanisms of AZT drug resistance mediated by HIV-1 reverse transcriptase using a transient kinetic analysis.

Several hypotheses have been proposed to explain the development of resistance to the anti-HIV drug AZT. Clinical findings show that AZT resistance mutations in HIV-1 reverse transcriptase (RT) not only reduce susceptibility to thymidine analogues but may also confer multi-dideoxynucleoside resistance. In this report, we describe transient kinetic studies establishing the biochemical effects of AZT resistance mutations in HIV-1 RT on the incorporation and removal of natural and unnatural deoxynucleotides. While the physiological role remains to be elucidated, the largest biochemical difference between wild-type and AZT resistant HIV-1 RT manifested itself during ATP-mediated deoxynucleotide removal. Enhanced removal resulted from an increase in the maximum rate of chain terminator excision, suggesting that mutated residues play a role in the optimal alignment of substrates for ATP-mediated removal. The efficiency of pyrophosphorolysis was not increased by the presence of AZT resistance mutations. However, a 2-fold decrease in the extent of inhibition caused by the next correct nucleotide during pyrophosphorolytic cleavage of a D4TMP chain-terminated primer may illustrate how this mutant can utilize pyrophosphate to enhance resistance. The inability of RT to catalyze removal of a chain terminator from an RNA-RNA primer-template may show how slight changes in selectivity against AZTMP incorporation during the initiation of DNA synthesis can contribute to high-level resistance. Taken together, these results suggest that multiple modes of resistance may be conferred by these mutations. Structure-activity studies of chain terminator removal suggest that analogues that form tight interactions with residues in the RT active site may be more prone to resistance mechanisms mediated by removal.

Adenosine Triphosphate↗

PubMed2004

Structural basis for the self-chaperoning function of an RNA collapsed state.

Prior to folding to a native functional structure, many large RNAs form conformationally collapsed states. Formation of the near-native collapsed state for the bI5 group I intron RNA plays an obligatory role in self-chaperoning assembly with its CBP2 protein cofactor by preventing formation of stable, misassembled complexes. We show that the collapsed state is essential because CBP2 assembles indiscriminately with the bI5 RNA in any folding state to form long-lived complexes. The most stable protein interaction site in the expanded state-CBP2 complex overlaps, but is not identical to, the native site. Folding to the collapsed state circumvents two distinct misassembly events: inhibitory binding by multiple equivalents of CBP2 and formation of bridged complexes in which CBP2 straddles cognate and noncognate RNAs. Strikingly, protein-bound sites in the expanded state RNA complex are almost the inverse of native RNA-RNA and RNA-protein interactions, indicating that folding to the collapsed state significantly reduces the fraction of RNA surfaces accessible for misassembly. The self-chaperoning function for the bI5 collapsed state is likely to be conserved in other ribonucleoproteins where a protein cofactor binds tightly at a simple RNA substructure or has an RNA binding surface composed of multiple functional sites.

Base Sequence↗

PubMed1996

Unambiguous structure characterization of a DNA-RNA triple helix by 15N- and 13C-filtered NOESY spectroscopy.

DNA.DNA*RNA triple helices of the pyrimidine.purine*pyrimidine motif (where . indicates Watson-Crick pairing and * indicates Hoogsteen pairing) appear to be very stable, which has important implications for the development of novel antisense strategies. Here we present the first structural NMR studies on such a system, composed of a DNA hairpin with a homopurine-homopyrimidine stem sequence and a single-stranded RNA oligonucleotide containing exclusively pyrimidine residues. In these investigations an unlabeled DNA hairpin and a uniformly 13C/15N-enriched RNA oligonucleotide were utilized in combination with X-edited 1H NMR spectroscopy. Improved 15N (omega 2) filtered NOESY and 13C (omega 1) filtered NOESY are presented by which we were able to differentiate between intrastrand, i.e., DNA-DNA and RNA-RNA, and interstrand, i.e., DNA-RNA, NOE contacts. It is unambiguously established that the complex forms a right-handed triple helix, with the RNA strand situated in the major groove of the Watson-Crick stem of the hairpin. The interaction is stabilized by the formation of Hoogsteen-type base pairs between the RNA strand and the purine strand of the DNA. These strands run parallel to each other. The characterization of the DNA-RNA triple helix structure described here shows that this type of experiment forms a valuable instrument in the structure determination of bimolecular systems of nucleic acids.

Base Sequence↗

PubMed1996

RNA conformation in the Tat-TAR complex determined by site-specific photo-cross-linking.

Transcriptional regulation in human immunodeficiency virus type 1 (HIV-1) requires specific interactions of Tat protein with the transactivation responsive region (TAR) RNA, a 59-base stem-loop structure located at the 5'-end of all mRNAs. We have used a site-specific cross-linking method based on 4-thiouracil (4-thioU) photochemistry to determine the conformation of TAR RNA and its interaction with Tat protein under physiological conditions. Three different TAR RNA constructs with a single 4-thioU residue at position 23, 38, or 40 were synthesized. Upon UV irradiation, 4-thioU at all three positions formed interstrand covalent cross-links in TAR RNA. Determination of cross-link sites by RNA sequencing revealed that 4-thioU at position 23 makes a direct contact with U40, while a 4-thoU at position 40 cross-links to C24 and C25, and at position 38, 4-thioU contacts G26 in TAR RNA. The addition of arginine did not alter the yield or the site of RNA-RNA cross-link. However, in the presence of Tat(38-72), UV irradiation of RNA modified with 4-thioU at position 23 or 38 resulted in RNA- protein cross-links, but no RNA-RNA cross-links were observed. 4-thioU at position 40 formed both RNA-RNA and RNA-protein cross-links in the presence of Tat(38-72). An intriguing finding of our studies was that a cross-linked TAR RNA with 4-thioU at position 40 retained specific Tat-binding activity. Our results establish four important conclusions about Tat-TAR structure. (1) U23 of free TAR RNA is in close contact with U40. (2) U40 is in close proximity to C24 and C25 both in free TAR RNA and in a complex with Tat. (3) Tat protein directly contacts U23, U38, and U40 in the major groove of TAR RNA. (4) Tat protein can recognize a TAR RNA structure containing an interrupted bulge which is formed by a covalent link between U40 and two bulge residues, C24 and C25. These structural studies provide new insights into tertiary folding of TAR RNA and its interaction with Tat protein.

Base Sequence↗

PubMed1997

Implications of RNA structure on the annealing of a potent antisense RNA directed against the human immunodeficiency virus type 1.

Antisense RNA-mediated regulation in bacterial systems is related to the kinetics of RNA-RNA annealing in vitro. Here, we investigated the secondary structure of alphaY69, an effective HIV-directed antisense RNA in human cells. Purified RNA preparations contain a single conformer. The global structure was identified by a cleavage experiment under native conditions using a short complementary oligonucleotide and RNase H. Structural analyses indicate a three-domain structure of alphaY69 consisting of two stem-loop elements connected by a seven-nucleotide single-stranded hinge region. Kinetic data suggest that the formation of base pairs between a CGC triplet of alphaY69 and its target RNA is essential for fast annealing. The complementary sequence stretch of the target folds into a high-energy secondary structure. The relationship between modifications in structural elements of alphaY69 and the annealing kinetics suggested that rate-limiting steps of the annealing involve a single site of alphaY69 and do not involve its 5' or 3'-end. Further, the data indicate that both initial base-specific interactions and duplex formation are dependent on the CGC triplet of the central region of alphaY69. This mechanism represents a specific and efficient way of RNA-RNA annealing that is initiated by the interaction of unstructured RNA regions.

Anti-HIV Agents↗