scholarly journals Structure and Function of CC-Chemokine Receptor 5 Homologues Derived from Representative Primate Species and Subspecies of the Taxonomic Suborders Prosimii and Anthropoidea

2003 ◽  
Vol 77 (22) ◽  
pp. 12310-12318 ◽  
Author(s):  
Kevin J. Kunstman ◽  
Bridget Puffer ◽  
Bette T. Korber ◽  
Carla Kuiken ◽  
Una R. Smith ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chemokine Receptor ◽  
Transmembrane Domain ◽  
Structure And Function ◽  
Primate Species ◽  
Amino Acid Substitutions ◽  
Immunodeficiency Virus ◽  
And Function ◽  
Cc Chemokine Receptor 5 ◽  
Hiv 1

ABSTRACT A chemokine receptor from the seven-transmembrane-domain G-protein-coupled receptor superfamily is an essential coreceptor for the cellular entry of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) strains. To investigate nonhuman primate CC-chemokine receptor 5 (CCR5) homologue structure and function, we amplified CCR5 DNA sequences from peripheral blood cells obtained from 24 representative species and subspecies of the primate suborders Prosimii (family Lemuridae) and Anthropoidea (families Cebidae, Callitrichidae, Cercopithecidae, Hylobatidae, and Pongidae) by PCR with primers flanking the coding region of the gene. Full-length CCR5 was inserted into pCDNA3.1, and multiple clones were sequenced to permit discrimination of both alleles. Compared to the human CCR5 sequence, the CCR5 sequences of the Lemuridae, Cebidae, and Cercopithecidae shared 87, 91 to 92, and 96 to 99% amino acid sequence homology, respectively. Amino acid substitutions tended to cluster in the amino and carboxy termini, the first transmembrane domain, and the second extracellular loop, with a pattern of species-specific changes that characterized CCR5 homologues from primates within a given family. At variance with humans, all primate species examined from the suborder Anthropoidea had amino acid substitutions at positions 13 (N to D) and 129 (V to I); the former change is critical for CD4-independent binding of SIV to CCR5. Within the Cebidae, Cercopithecidae, and Pongidae (including humans), CCR5 nucleotide similarities were 95.2 to 97.4, 98.0 to 99.5, and 98.3 to 99.3%, respectively. Despite this low genetic diversity, the phylogeny of the selected primate CCR5 homologue sequences agrees with present primate systematics, apart from some intermingling of species of the Cebidae and Cercopithecidae. Constructed HOS.CD4 cell lines expressing the entire CCR5 homologue protein from each of the Anthropoidea species and subspecies were tested for their ability to support HIV-1 and SIV entry and membrane fusion. Other than that of Cercopithecus pygerythrus, all CCR5 homologues tested were able to support both SIV and HIV-1 entry. Our results suggest that the shared structure and function of primate CCR5 homologue proteins would not impede the movement of primate immunodeficiency viruses between species.

scholarly journals Effects of single-point amino acid substitutions on the structure and function neuraminidase proteins in influenza A virus

2008 ◽  
Vol 52 (4) ◽  
pp. 216-223 ◽  
Author(s):  
Takuya Yano ◽  
Eri Nobusawa ◽  
Alexander Nagy ◽  
Setsuko Nakajima ◽  
Katsuhisa Nakajima
Keyword(s):  
Amino Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Single Point ◽  
Structure And Function ◽  
Amino Acid Substitutions ◽  
And Function

scholarly journals Determinants of Tetherin Antagonism in the Transmembrane Domain of the Human Immunodeficiency Virus Type 1 Vpu Protein

2010 ◽  
Vol 84 (24) ◽  
pp. 12958-12970 ◽  
Author(s):  
Raphaël Vigan ◽  
Stuart J. D. Neil
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Cell Surface ◽  
Human Immunodeficiency Virus Type ◽  
Transmembrane Domain ◽  
Human Tetherin ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Tetherin Antagonism

ABSTRACT Tetherin (BST2/CD317) potently restricts the particle release of human immunodeficiency virus type 1 (HIV-1) mutants defective in the accessory gene vpu. Vpu antagonizes tetherin activity and induces its cell surface downregulation and degradation in a manner dependent on the transmembrane (TM) domains of both proteins. We have carried out extensive mutagenesis of the HIV-1 NL4.3 Vpu TM domain to identify three amino acid positions, A14, W22, and, to a lesser extent, A18, that are required for tetherin antagonism. Despite the mutants localizing indistinguishably from the wild-type (wt) protein and maintaining the ability to multimerize, mutation of these positions rendered Vpu incapable of coimmunoprecipitating tetherin or mediating its cell surface downregulation. Interestingly, these amino acid positions are predicted to form one face of the Vpu transmembrane alpha helix and therefore potentially contribute to an interacting surface with the transmembrane domain of tetherin either directly or by modulating the conformation of Vpu oligomers. While the equivalent of W22 is invariant in HIV-1/SIVcpz Vpu proteins, the positions of A14 and A18 are highly conserved among Vpu alleles from HIV-1 groups M and N, but not those from group O or SIVcpz that lack human tetherin (huTetherin)-antagonizing activity, suggesting that they may have contributed to the adaption of HIV-1 to human tetherin.

scholarly journals Human Immunodeficiency Virus Type 1 Resistance to the Small Molecule Maturation Inhibitor 3-O-(3′,3′-Dimethylsuccinyl)-Betulinic Acid Is Conferred by a Variety of Single Amino Acid Substitutions at the CA-SP1 Cleavage Site in Gag

2006 ◽  
Vol 80 (24) ◽  
pp. 12095-12101 ◽  
Author(s):  
Jing Zhou ◽  
Chin Ho Chen ◽  
Christopher Aiken
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Betulinic Acid ◽  
Cleavage Site ◽  
Amino Acid Substitutions ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The compound 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid (DSB) potently and specifically inhibits human immunodeficiency virus type 1 (HIV-1) replication by delaying the cleavage of the CA-SP1 junction in Gag, leading to impaired maturation of the viral core. In this study, we investigated HIV-1 resistance to DSB by analyzing HIV-1 mutants encoding a variety of individual amino acid substitutions in the CA-SP1 cleavage site. Three of the substitutions were lethal to HIV-1 replication owing to a deleterious effect on particle assembly. The remaining mutants exhibited a range of replication efficiencies; however, each mutant was capable of replicating in the presence of concentrations of DSB that effectively inhibited wild-type HIV-1. Mutations conferring resistance to DSB also led to impaired binding of the compound to immature HIV-1 virions and loss of DSB-mediated inhibition of cleavage of Gag. Surprisingly, two of the DSB-resistant mutants retained an intermediate ability to bind the compound, suggesting that binding of DSB to immature HIV-1 particles may not be sufficient for antiviral activity. Overall, our results indicate that Gag amino acids L363 and A364 are critical for inhibition of HIV-1 replication by DSB and suggest that these residues form key contacts with the drug in the context of the assembling HIV-1 particle. These results have implications for the design of and screening for novel inhibitors of HIV-1 maturation.

scholarly journals Effects of the Δ67 Complex of Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Nucleoside Analog Excision

2004 ◽  
Vol 78 (18) ◽  
pp. 9987-9997 ◽  
Author(s):  
Paul L. Boyer ◽  
Tomozumi Imamichi ◽  
Stefan G. Sarafianos ◽  
Edward Arnold ◽  
Stephen H. Hughes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Coding Region ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Long-term use of combination therapy against human immunodeficiency virus type (HIV-1) provides strong selective pressure on the virus, and HIV-1 variants that are resistant to multiple inhibitors have been isolated. HIV-1 variants containing amino acid substitutions within the coding region of HIV-1 reverse transcriptase (RT), such as the 3′-azido-3′-deoxythymidine (AZT)-resistant variant AZT-R (M41L/D67N/K70R/T215Y/K219Q) and a variant containing an insertion in the fingers domain (S69SGR70/T215Y), are resistant to the nucleoside RT inhibitor (NRTI) AZT because of an increase in the level of excision of AZT monophosphate (AZTMP) from the primer. While rare, variants have also been isolated which contain deletions in the RT coding region. One such virus, described by Imamichi et al. (J. Virol 74:10958-10964, 2000; J. Virol. 74:1023-1028, 2000; J. Virol. 75:3988-3992, 2001), contains numerous amino acid substitutions and a deletion of codon 67, which we have designated the Δ67 complex of mutations. We have expressed and purified HIV-1 RT containing these mutations. We compared the polymerase and pyrophosphorolysis (excision) activity of an RT with the Δ67 complex of mutations to wild-type RT and the two other AZT-resistant variants described above. All of the AZT-resistant variants we tested excise AZTMP and 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA [tenofovir]) from the end of a primer more efficiently than wild-type RT. Although the variant RTs excised d4TMP less efficiently than AZTMP and PMPA, they were able to excise d4TMP more efficiently than wild-type RT. HIV-1 RT containing the Δ67 complex of mutations was not able to excise as broad a range of NRTIs as the fingers insertion variant SSGR/T215Y, but it was able to polymerize efficiently with low concentrations of deoxynucleoside triphosphates and seems to be able to excise AZTMP and PMPA at lower ATP concentrations than AZT-R or SSGR/T215Y, suggesting that a virus containing the Δ67 complex of mutations would replicate reasonably well in quiescent cells, even in the presence of AZT.

scholarly journals The HIV-1 Vpu transmembrane domain topology and formation of a hydrophobic interface with BST-2 are critical for Vpu-mediated BST-2 downregulation

2020 ◽  
Author(s):  
Nabab Khan ◽  
Siladitya Padhi ◽  
Paresh Patel ◽  
U. Deva Priyakumar ◽  
Shahid Jameel
Keyword(s):  
Amino Acid ◽  
Transmembrane Domain ◽  
Virus Production ◽  
Cell Protein ◽  
Amino Acid Residues ◽  
Host Cell Protein ◽  
Immunodeficiency Virus ◽  
Molecular Modeling Studies ◽  
Hiv 1 ◽  
Hydrophobic Interface

AbstractViruses belonging to the M group of human immunodeficiency virus (HIV-1) are the most virulent among the four HIV-1 groups. One factor that distinguishes the M group HIV-1 from others is Vpu, a membrane localized accessory protein, which promotes the release of virions by neutralizing the antiviral host cell protein BST-2. To investigate if this activity is determined by the topology of Vpu or by conserved amino acid residues, we prepared chimeric forms of Vpu by replacing its transmembrane domain with those from its topological homologs. Although the chimeric Vpu proteins downregulated BST-2, these substantially reduced virus production as well. Molecular modeling studies on Vpu from different HIV-1 groups and the chimeric Vpu proteins showed that shape and the availability of a hydrophobic interface are more important for BST-2 antagonism than conservation of the amino acid sequence. Our data suggest that the HIV-1 Vpu-M protein has evolved topologically to interact with BST-2, and that the Vpu/BST-2 interface can be exploited as a target to limit HIV-1 replication.

S-1153 Inhibits Replication of Known Drug-Resistant Strains of Human Immunodeficiency Virus Type 1

1998 ◽  
Vol 42 (6) ◽  
pp. 1340-1345 ◽  
Author(s):  
Tamio Fujiwara ◽  
Akihiko Sato ◽  
Mohamed El-Farrash ◽  
Shigeru Miki ◽  
Kenji Abe ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Reverse Transcriptase ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Reverse Transcriptase Inhibitors ◽  
Human T Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT S-1153 is a new imidazole compound that inhibits human immunodeficiency virus (HIV) type 1 (HIV-1) replication by acting as a nonnucleoside reverse transcriptase inhibitor (NNRTI). This compound inhibits replication of HIV-1 strains that are resistant to nucleoside and nonnucleoside reverse transcriptase inhibitors. S-1153 has a 50% effective concentration in the range of 0.3 to 7 ng/ml for strains with single amino acid substitutions that cause NNRTI resistance, including the Y181C mutant, and also has potent activity against clinical isolates. The emergence of S-1153-resistant variants is slower than that for nevirapine, and S-1153-resistant variants contained at least two amino acid substitutions, including F227L or L234I. S-1153-resistant variants are still sensitive to the nucleoside reverse transcriptase inhibitors zidovudine (AZT) and lamivudine. In a mouse and MT-4 (human T-cell line) in vivo HIV replication model, S-1153 and AZT administered orally showed a marked synergy for the inhibition of HIV-1 replication. S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur. S-1153 may be an appropriate candidate for two- to three-drug combination therapy for HIV infection.

scholarly journals In vitro induction of human immunodeficiency virus type 1 variants resistant to 2'-beta-Fluoro-2',3'-dideoxyadenosine.

1997 ◽  
Vol 41 (6) ◽  
pp. 1313-1318 ◽  
Author(s):  
M Tanaka ◽  
R V Srinivas ◽  
T Ueno ◽  
M F Kavlick ◽  
F K Hui ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Amino Acid Substitutions ◽  
Infectious Clones ◽  
Immunodeficiency Virus ◽  
Hiv 1

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA) is an acid-stable purine dideoxynucleoside analog active against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) and HIV-2 strains in vitro. F-ddA is presently undergoing a phase I clinical trial at the National Cancer Institute. We induced HIV-1 variants resistant to F-ddA by exposing wild-type HIV-1 (HIV-1LAI) to increasing concentrations of F-ddA in vitro. After 18 passages, the virus was fourfold less sensitive to F-ddA than HIV-1LAI. Sequence analyses of the passage 18 virus revealed changes in three amino acids in the reverse transcriptase (RT)-encoding region of the pol gene: P to S at codon 119 (P119S; present in 3 of 13 and 28 of 28 molecular clones before and after F-ddA exposure, respectively), V179D (0 of 13 and 9 of 28, respectively), and L214F (9 of 13 and 28 of 28, respectively). Drug sensitivity assays using recombinant infectious clones confirmed that P119S was directly responsible for the reduced sensitivity of HIV-1 to F-ddA. Various infectious clones with single or multiple amino acid substitutions conferring viral resistance against nucleoside RT inhibitors, including HIV-1 variants with multi-dideoxynucleoside resistance, were generally sensitive to F-ddA. The moderate level of resistance of HIV-1 to F-ddA, together with the lack of conferment of significant cross-resistance by the F-ddA-associated amino acid substitutions, warrants further investigation of F-ddA as a potential antiviral agent for use in treatment of HIV-1 infection.

scholarly journals Anti-CXCR4 Monoclonal Antibodies Recognizing Overlapping Epitopes Differ Significantly in Their Ability To Inhibit Entry of Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 79 (3) ◽  
pp. 1930-1933 ◽  
Author(s):  
Xavier Carnec ◽  
Lan Quan ◽  
William C. Olson ◽  
Uriel Hazan ◽  
Tatjana Dragic
Keyword(s):  
Monoclonal Antibodies ◽  
Structure And Function ◽  
Cxcr4 Expression ◽  
Target Cells ◽  
Cell Type ◽  
Immunodeficiency Virus ◽  
Cell Type Specific ◽  
And Function ◽  
Hiv 1

ABSTRACT CXCR4 is one of two physiologically relevant human immunodeficiency type 1 (HIV-1) entry coreceptors. Studies of CXCR4 mutants have not clearly identified the determinants of coreceptor function and specificity. We therefore used a panel of monoclonal antibodies to further elucidate CXCR4 expression, structure, and function. Our findings show the existence of conformational subpopulations of CXCR4 that are in equilibrium on the cell surface but are not cell type specific as previously reported. HIV-1 X4 isolates can interact with multiple CXCR4 conformations in order to gain entry into target cells.

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