Special Issue "Structural and Molecular Biology of HIV"

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A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (15 May 2012)

Special Issue Editor

Guest Editor
Prof. Dr. Andrew P. Rice

Nancy Chang Professor, Rice Lab - Molecular Virology & Microbiology, One Baylor Plaza, Mail Stop BCM-385, Houston, Texas 77030, USA
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Phone: 713-798-5774

Special Issue Information

Dear Colleagues,

Since the discovery of HIV almost 30 years ago, an enormous research effort has been conducted worldwide with the goal of conquering this infectious agent.  Although an effective HIV vaccine is not on the horizon, HIV research has partially achieved this goal, as effective anti-HIV drugs have been developed.  When used in combination, these drugs can suppress viral replication to almost undetectable levels in many patients.  Unfortunately, suppression of HIV replication requires lifelong adherence to the antiviral drugs, as a long-lived reservoir of latent viruses spontaneously reactivate when the drugs are discontinued.  A major effort in HIV research is now directed to discovering how this reservoir is established and maintained, with the long term goal of purging the reservoir and thereby curing HIV infection.
Basic research has provided the knowledge that lead to development of the existing anti-HIV drugs.   Continued research is required to produce more effective antiviral drugs, devise strategies to purge the viral reservoir, and develop an effective vaccine.  This special issue seeks to cover a broad range of HIV research in the areas of HIV molecular biology, host-virus interactions, and structural biology.  We welcome scientific perspectives, reviews, and original research papers.

Prof. Dr. Andrew P. Rice
Guest Editor

Published Papers (14 papers)

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Research

Jump to: Review

Open AccessArticle HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods
Biology 2012, 1(2), 277-296; doi:10.3390/biology1020277
Received: 8 June 2012 / Revised: 9 July 2012 / Accepted: 26 July 2012 / Published: 13 August 2012
Cited by 2 | PDF Full-text (873 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The binding between the HIV-1 trans-activator of transcription (Tat) and p300/(CREB-binding protein)-associated factor (PCAF) bromodomain is a crucial step in the HIV-1 life cycle. However, the structure of the full length acetylated Tat bound to PCAF has not been yet determined experimentally.
[...] Read more.
The binding between the HIV-1 trans-activator of transcription (Tat) and p300/(CREB-binding protein)-associated factor (PCAF) bromodomain is a crucial step in the HIV-1 life cycle. However, the structure of the full length acetylated Tat bound to PCAF has not been yet determined experimentally. Acetylation of Tat residues can play a critical role in enhancing HIV-1 transcriptional activation. Here, we have combined a fully flexible protein-protein docking approach with molecular dynamics simulations to predict the structural determinants of the complex for the common HIV-1BRU variant. This model reproduces all the crucial contacts between the Tat peptide 46SYGR(AcK)KRRQRC56 and the PCAF bromodomain previously reported by NMR spectroscopy. Additionally, inclusion of the entire Tat protein results in additional contact points at the protein-protein interface. The model is consistent with the available experimental data reported and adds novel information to our previous structural predictions of the PCAF bromodomain in complex with the rare HIVZ2 variant, which was obtained with a less accurate computational method. This improved characterization of Tat.PCAF bromodomain binding may help in defining the structural determinants of other protein interactions involving lysine acetylation. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessArticle A Comparison of Two Single-Stranded DNA Binding Models by Mutational Analysis of APOBEC3G
Biology 2012, 1(2), 260-276; doi:10.3390/biology1020260
Received: 23 May 2012 / Revised: 1 July 2012 / Accepted: 14 July 2012 / Published: 2 August 2012
Cited by 8 | PDF Full-text (1889 KB) | HTML Full-text | XML Full-text
Abstract
APOBEC3G is the best known of several DNA cytosine deaminases that function to inhibit the replication of parasitic genetic elements including the lentivirus HIV. Several high-resolution structures of the APOBEC3G catalytic domain have been generated, but none reveal how this enzyme binds to
[...] Read more.
APOBEC3G is the best known of several DNA cytosine deaminases that function to inhibit the replication of parasitic genetic elements including the lentivirus HIV. Several high-resolution structures of the APOBEC3G catalytic domain have been generated, but none reveal how this enzyme binds to substrate single-stranded DNA. Here, we constructed a panel of APOBEC3G amino acid substitution mutants and performed a series of biochemical, genetic, and structural assays to distinguish between “Brim” and “Kink” models for single-strand DNA binding. Each model predicts distinct sets of interactions between surface arginines and negatively charged phosphates in the DNA backbone. Concordant with both models, changing the conserved arginine at position 313 to glutamate abolished both catalytic and restriction activities. In support of the Brim model, arginine to glutamate substitutions at positions 213, 215, and 320 also compromised these APOBEC3G activities. Arginine to glutamate substitutions at Kink model residues 374 and 376 had smaller effects. These observations were supported by A3G catalytic domain-ssDNA chemical shift perturbation experiments. The overall data set is most consistent with the Brim model for single-stranded DNA binding by APOBEC3G. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessArticle HIV-1 Resistant CDK2-Knockdown Macrophage-Like Cells Generated from 293T Cell-Derived Human Induced Pluripotent Stem Cells
Biology 2012, 1(2), 175-195; doi:10.3390/biology1020175
Received: 15 May 2012 / Revised: 11 July 2012 / Accepted: 16 July 2012 / Published: 26 July 2012
Cited by 6 | PDF Full-text (1004 KB) | HTML Full-text | XML Full-text
Abstract
A major challenge in studies of human diseases involving macrophages is low yield and heterogeneity of the primary cells and limited ability of these cells for transfections and genetic manipulations. To address this issue, we developed a simple and efficient three steps method
[...] Read more.
A major challenge in studies of human diseases involving macrophages is low yield and heterogeneity of the primary cells and limited ability of these cells for transfections and genetic manipulations. To address this issue, we developed a simple and efficient three steps method for somatic 293T cells reprogramming into monocytes and macrophage-like cells. First, 293T cells were reprogrammed into induced pluripotent stem cells (iPSCs) through a transfection-mediated expression of two factors, Oct-4 and Sox2, resulting in a high yield of iPSC. Second, the obtained iPSC were differentiated into monocytes using IL-3 and M-CSF treatment. And third, monocytes were differentiated into macrophage-like cells in the presence of M-CSF. As an example, we developed HIV-1-resistant macrophage-like cells from 293T cells with knockdown of CDK2, a factor critical for HIV-1 transcription. Our study provides a proof-of-principle approach that can be used to study the role of host cell factors in HIV-1 infection of human macrophages. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessArticle Free Energy Profile of APOBEC3G Protein Calculated by a Molecular Dynamics Simulation
Biology 2012, 1(2), 245-259; doi:10.3390/biology1020245
Received: 17 May 2012 / Revised: 4 July 2012 / Accepted: 5 July 2012 / Published: 26 July 2012
PDF Full-text (535 KB) | HTML Full-text | XML Full-text
Abstract
The human APOBEC3G protein (A3G) is a single-stranded DNA deaminase that inhibits the replication of retrotransposons and retroviruses, including HIV-1. Atomic details of A3G’s catalytic mechanism have started to emerge, as the structure of its catalytic domain (A3Gctd) has been revealed by NMR
[...] Read more.
The human APOBEC3G protein (A3G) is a single-stranded DNA deaminase that inhibits the replication of retrotransposons and retroviruses, including HIV-1. Atomic details of A3G’s catalytic mechanism have started to emerge, as the structure of its catalytic domain (A3Gctd) has been revealed by NMR and X-ray crystallography. The NMR and crystal structures are similar overall; however, differences are apparent for β2 strand (β2) and loops close to the catalytic site. To add some insight into these differences and to better characterize A3Gctd dynamics, we calculated its free energy profile by using the Generalized-Born surface area (GBSA) method accompanied with a molecular dynamics simulation. The GBSA method yielded an enthalpy term for A3Gctd’s free energy, and we developed a new method that takes into account the distribution of the protein’s dihedral angles to calculate its entropy term. The structure solved by NMR was found to have a lower energy than that of the crystal structure, suggesting that this conformation is dominant in solution. In addition, β2-loop-β2’ configuration was stable throughout a 20-ns molecular dynamics (MD) simulation. This finding suggests that in solution A3Gctd is not likely to adopt the continuous β2 strand configuration present in the APOBEC2 crystal structure. In the NMR structure, the solvent water accessibility of the catalytic Zn2+ was limited throughout the 20-ns MD simulation. This result explains previous observations in which A3G did not bind or catalyze single cytosine nucleotide, even when at excessive concentrations. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessArticle Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease
Biology 2012, 1(1), 81-93; doi:10.3390/biology1010081
Received: 30 April 2012 / Revised: 23 May 2012 / Accepted: 25 May 2012 / Published: 31 May 2012
Cited by 3 | PDF Full-text (775 KB) | HTML Full-text | XML Full-text
Abstract
Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined.
[...] Read more.
Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)

Review

Jump to: Research

Open AccessReview Strategies to Block HIV Transcription: Focus on Small Molecule Tat Inhibitors
Biology 2012, 1(3), 668-697; doi:10.3390/biology1030668
Received: 11 October 2012 / Revised: 6 November 2012 / Accepted: 7 November 2012 / Published: 19 November 2012
Cited by 5 | PDF Full-text (408 KB) | HTML Full-text | XML Full-text
Abstract
After entry into the target cell, the human immunodeficiency virus type I (HIV) integrates into the host genome and becomes a proviral eukaryotic transcriptional unit. Transcriptional regulation of provirus gene expression is critical for HIV replication. Basal transcription from the integrated HIV promoter
[...] Read more.
After entry into the target cell, the human immunodeficiency virus type I (HIV) integrates into the host genome and becomes a proviral eukaryotic transcriptional unit. Transcriptional regulation of provirus gene expression is critical for HIV replication. Basal transcription from the integrated HIV promoter is very low in the absence of the HIV transactivator of transcription (Tat) protein and is solely dependent on cellular transcription factors. The 5' terminal region (+1 to +59) of all HIV mRNAs forms an identical stem-bulge-loop structure called the Transactivation Responsive (TAR) element. Once Tat is made, it binds to TAR and drastically activates transcription from the HIV LTR promoter. Mutations in either the Tat protein or TAR sequence usually affect HIV replication, indicating a strong requirement for their conservation. The necessity of the Tat-mediated transactivation cascade for robust HIV replication renders Tat one of the most desirable targets for transcriptional therapy against HIV replication. Screening based on inhibition of the Tat-TAR interaction has identified a number of potential compounds, but none of them are currently used as therapeutics, partly because these agents are not easily delivered for an efficient therapy, emphasizing the need for small molecule compounds. Here we will give an overview of the different strategies used to inhibit HIV transcription and review the current repertoire of small molecular weight compounds that target HIV transcription. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessReview Inhibitors of HIV-1 Reverse Transcriptase—Associated Ribonuclease H Activity
Biology 2012, 1(3), 521-541; doi:10.3390/biology1030521
Received: 18 August 2012 / Revised: 26 September 2012 / Accepted: 27 September 2012 / Published: 19 October 2012
Cited by 15 | PDF Full-text (656 KB) | HTML Full-text | XML Full-text
Abstract
HIV-1 enzyme reverse transcriptase (RT) is a major target for antiviral drug development, with over half of current FDA-approved therapeutics against HIV infection targeting the DNA polymerase activity of this enzyme. HIV-1 RT is a multifunctional enzyme that has RNA and DNA dependent
[...] Read more.
HIV-1 enzyme reverse transcriptase (RT) is a major target for antiviral drug development, with over half of current FDA-approved therapeutics against HIV infection targeting the DNA polymerase activity of this enzyme. HIV-1 RT is a multifunctional enzyme that has RNA and DNA dependent polymerase activity, along with ribonuclease H (RNase H) activity. The latter is responsible for degradation of the viral genomic RNA template during first strand DNA synthesis to allow completion of reverse transcription and the viral dsDNA. While the RNase H activity of RT has been shown to be essential for virus infectivity, all currently used drugs directed at RT inhibit the polymerase activity of the enzyme; none target RNase H. In the last decade, the increasing prevalence of HIV variants resistant to clinically used antiretrovirals has stimulated the search for inhibitors directed at stages of HIV replication different than those targeted by current drugs. HIV RNase H is one such novel target and, over the past few years, significant progress has been made in identifying and characterizing new RNase H inhibitor pharmacophores. In this review we focus mainly on the most potent low micromolar potency compounds, as these provide logical bases for further development. We also discuss why HIV RNase H has been a difficult target for antiretroviral drug development. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessReview Transcriptional Gene Silencing (TGS) via the RNAi Machinery in HIV-1 Infections
Biology 2012, 1(2), 339-369; doi:10.3390/biology1020339
Received: 29 June 2012 / Revised: 3 August 2012 / Accepted: 13 August 2012 / Published: 24 August 2012
Cited by 4 | PDF Full-text (451 KB) | HTML Full-text | XML Full-text
Abstract
Gene silencing via non-coding RNA, such as siRNA and miRNA, can occur at the transcriptional, post-transcriptional, and translational stages of expression. Transcriptional gene silencing (TGS) involving the RNAi machinery generally occurs through DNA methylation, as well as histone post-translational modifications, and corresponding remodeling
[...] Read more.
Gene silencing via non-coding RNA, such as siRNA and miRNA, can occur at the transcriptional, post-transcriptional, and translational stages of expression. Transcriptional gene silencing (TGS) involving the RNAi machinery generally occurs through DNA methylation, as well as histone post-translational modifications, and corresponding remodeling of chromatin around the target gene into a heterochromatic state. The mechanism by which mammalian TGS occurs includes the recruitment of RNA-induced initiation of transcriptional gene silencing (RITS) complexes, DNA methyltransferases (DNMTs), and other chromatin remodelers. Additionally, virally infected cells encoding miRNAs have also been shown to manipulate the host cell RNAi machinery to induce TGS at the viral genome, thereby establishing latency. Furthermore, the introduction of exogenous siRNA and shRNA into infected cells that target integrated viral promoters can greatly suppress viral transcription via TGS. Here we examine the latest findings regarding mammalian TGS, specifically focusing on HIV-1 infected cells, and discuss future avenues of exploration in this field. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessReview Computer-Aided Approaches for Targeting HIVgp41
Biology 2012, 1(2), 311-338; doi:10.3390/biology1020311
Received: 17 July 2012 / Revised: 9 August 2012 / Accepted: 12 August 2012 / Published: 20 August 2012
Cited by 6 | PDF Full-text (848 KB) | HTML Full-text | XML Full-text
Abstract
Virus-cell fusion is the primary means by which the human immunodeficiency virus-1 (HIV) delivers its genetic material into the human T-cell host. Fusion is mediated in large part by the viral glycoprotein 41 (gp41) which advances through four distinct conformational states: (i
[...] Read more.
Virus-cell fusion is the primary means by which the human immunodeficiency virus-1 (HIV) delivers its genetic material into the human T-cell host. Fusion is mediated in large part by the viral glycoprotein 41 (gp41) which advances through four distinct conformational states: (i) native, (ii) pre-hairpin intermediate, (iii) fusion active (fusogenic), and (iv) post-fusion. The pre-hairpin intermediate is a particularly attractive step for therapeutic intervention given that gp41 N-terminal heptad repeat (NHR) and C‑terminal heptad repeat (CHR) domains are transiently exposed prior to the formation of a six-helix bundle required for fusion. Most peptide-based inhibitors, including the FDA‑approved drug T20, target the intermediate and there are significant efforts to develop small molecule alternatives. Here, we review current approaches to studying interactions of inhibitors with gp41 with an emphasis on atomic-level computer modeling methods including molecular dynamics, free energy analysis, and docking. Atomistic modeling yields a unique level of structural and energetic detail, complementary to experimental approaches, which will be important for the design of improved next generation anti-HIV drugs. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Figures

Open AccessReview Multi-Faceted Post-Transcriptional Functions of HIV-1 Rev
Biology 2012, 1(2), 165-174; doi:10.3390/biology1020165
Received: 20 June 2012 / Revised: 15 July 2012 / Accepted: 16 July 2012 / Published: 23 July 2012
Cited by 4 | PDF Full-text (224 KB) | HTML Full-text | XML Full-text
Abstract
Post-transcriptional regulation of HIV-1 gene expression is largely governed by the activities of the viral Rev protein. In this minireview, the multiple post-transcriptional activities of Rev in the export of partially spliced and unspliced HIV-1 RNAs from the nucleus to the cytoplasm, in
[...] Read more.
Post-transcriptional regulation of HIV-1 gene expression is largely governed by the activities of the viral Rev protein. In this minireview, the multiple post-transcriptional activities of Rev in the export of partially spliced and unspliced HIV-1 RNAs from the nucleus to the cytoplasm, in the translation of HIV-1 transcripts, and in the packaging of viral genomic RNAs are reviewed in brief. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessReview Breaking Barriers to an AIDS Model with Macaque-Tropic HIV-1 Derivatives
Biology 2012, 1(2), 134-164; doi:10.3390/biology1020134
Received: 16 May 2012 / Revised: 14 June 2012 / Accepted: 18 June 2012 / Published: 5 July 2012
Cited by 7 | PDF Full-text (285 KB) | HTML Full-text | XML Full-text
Abstract
The development of an animal model of human immunodeficiency virus type 1 (HIV-1)/AIDS that is suitable for preclinical testing of antiretroviral therapy, vaccines, curative strategies, and studies of pathogenesis has been hampered by the human-specific tropism of HIV-1. Although simian immunodeficiency virus (SIV)
[...] Read more.
The development of an animal model of human immunodeficiency virus type 1 (HIV-1)/AIDS that is suitable for preclinical testing of antiretroviral therapy, vaccines, curative strategies, and studies of pathogenesis has been hampered by the human-specific tropism of HIV-1. Although simian immunodeficiency virus (SIV) or HIV-1/SIV chimeric viruses (SHIVs)-rhesus macaque models are excellent surrogates for AIDS research, the genetic differences between SIV or SHIV and HIV-1 limit their utility as model systems. The identification of innate retroviral restriction factors has increased our understanding about blockades to HIV-1 replication in macaques and provided a guide for the construction of macaque-tropic HIV-1 clones. However, while these viruses replicate in macaque cells in vitro, they are easily controlled and have not caused AIDS in host animals, indicating that we may not fully understand the restrictive barriers of innate immunity. In this review, we discuss recent findings regarding HIV-1 restriction factors, particularly as they apply to cross-species transmission of primate lentiviruses and the development of a macaque model of HIV-1/AIDS. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessReview Dynamic Post-Transcriptional Regulation of HIV-1 Gene Expression
Biology 2012, 1(2), 116-133; doi:10.3390/biology1020116
Received: 11 May 2012 / Revised: 15 June 2012 / Accepted: 18 June 2012 / Published: 3 July 2012
Cited by 2 | PDF Full-text (187 KB) | HTML Full-text | XML Full-text
Abstract
Gene expression of the human immunodeficiency virus type 1 (HIV-1) is a highly regulated process. Basal transcription of the integrated provirus generates early transcripts that encode for the viral products Tat and Rev. Tat promotes the elongation of RNA polymerase while Rev mediates
[...] Read more.
Gene expression of the human immunodeficiency virus type 1 (HIV-1) is a highly regulated process. Basal transcription of the integrated provirus generates early transcripts that encode for the viral products Tat and Rev. Tat promotes the elongation of RNA polymerase while Rev mediates the nuclear export of viral RNAs that contain the Rev-responsive RNA element (RRE). These RNAs are exported from the nucleus to allow expression of Gag-Pol and Env proteins and for the production of full-length genomic RNAs. A balance exists between completely processed mRNAs and RRE-containing RNAs. Rev functions as an adaptor that recruits cellular factors to re-direct singly spliced and unspliced viral RNAs to nuclear export. The aim of this review is to address the dynamic regulation of this post-transcriptional pathway in light of recent findings that implicate several novel cellular cofactors of Rev function. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessReview Making a Short Story Long: Regulation of P-TEFb and HIV-1 Transcriptional Elongation in CD4+ T Lymphocytes and Macrophages
Biology 2012, 1(1), 94-115; doi:10.3390/biology1010094
Received: 15 May 2012 / Revised: 7 June 2012 / Accepted: 11 June 2012 / Published: 15 June 2012
Cited by 5 | PDF Full-text (573 KB) | HTML Full-text | XML Full-text
Abstract
Productive transcription of the integrated HIV-1 provirus is restricted by cellular factors that inhibit RNA polymerase II elongation. The viral Tat protein overcomes this by recruiting a general elongation factor, P-TEFb, to the TAR RNA element that forms at the 5’ end of
[...] Read more.
Productive transcription of the integrated HIV-1 provirus is restricted by cellular factors that inhibit RNA polymerase II elongation. The viral Tat protein overcomes this by recruiting a general elongation factor, P-TEFb, to the TAR RNA element that forms at the 5’ end of nascent viral transcripts. P-TEFb exists in multiple complexes in cells, and its core consists of a kinase, Cdk9, and a regulatory subunit, either Cyclin T1 or Cyclin T2. Tat binds directly to Cyclin T1 and thereby targets the Cyclin T1/P-TEFb complex that phosphorylates the CTD of RNA polymerase II and the negative factors that inhibit elongation, resulting in efficient transcriptional elongation. P-TEFb is tightly regulated in cells infected by HIV-1—CD4+ T lymphocytes and monocytes/macrophages. A number of mechanisms have been identified that inhibit P-TEFb in resting CD4+ T lymphocytes and monocytes, including miRNAs that repress Cyclin T1 protein expression and dephosphorylation of residue Thr186 in the Cdk9 T-loop. These repressive mechanisms are overcome upon T cell activation and macrophage differentiation when the permissivity for HIV-1 replication is greatly increased. This review will summarize what is currently known about mechanisms that regulate P-TEFb and how this regulation impacts HIV-1 replication and latency. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessReview The Surprising Role of Amyloid Fibrils in HIV Infection
Biology 2012, 1(1), 58-80; doi:10.3390/biology1010058
Received: 29 April 2012 / Revised: 19 May 2012 / Accepted: 23 May 2012 / Published: 29 May 2012
Cited by 8 | PDF Full-text (850 KB) | HTML Full-text | XML Full-text
Abstract
Despite its discovery over 30 years ago, human immunodeficiency virus (HIV) continues to threaten public health worldwide. Semen is the principal vehicle for the transmission of this retrovirus and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120)
[...] Read more.
Despite its discovery over 30 years ago, human immunodeficiency virus (HIV) continues to threaten public health worldwide. Semen is the principal vehicle for the transmission of this retrovirus and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2), assemble into amyloid fibrils that promote HIV infection. For example, PAP248-286 fibrils, termed SEVI (Semen derived Enhancer of Viral Infection), potentiate HIV infection by up to 105-fold. Fibrils enhance infectivity by facilitating virion attachment and fusion to target cells, whereas soluble peptides have no effect. Importantly, the stimulatory effect is greatest at low viral titers, which mimics mucosal transmission of HIV, where relatively few virions traverse the mucosal barrier. Devising a method to rapidly reverse fibril formation (rather than simply inhibit it) would provide an innovative and urgently needed preventative strategy for reducing HIV infection via the sexual route. Targeting a host-encoded protein conformer represents a departure from traditional microbicidal approaches that target the viral machinery, and could synergize with direct antiviral approaches. Here, we review the identification of these amyloidogenic peptides, their mechanism of action, and various strategies for inhibiting their HIV-enhancing effects. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)

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