Next Article in Journal
Nuclear Actin and Lamins in Viral Infections
Next Article in Special Issue
Ready, Set, Fuse! The Coronavirus Spike Protein and Acquisition of Fusion Competence
Previous Article in Journal / Special Issue
Henipavirus Mediated Membrane Fusion, Virus Entry and Targeted Therapeutics
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Viruses
Volume 4
Issue 2
10.3390/v4020309
viruses-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Novel Approaches to Inhibit HIV Entry

by
Chukwuka A. Didigu
and
Robert W. Doms
*
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, 3610 Hamilton Walk, Philadelphia, PA 19104, USA
*
Author to whom correspondence should be addressed.
Viruses 2012, 4(2), 309-324; https://doi.org/10.3390/v4020309
Submission received: 16 December 2011 / Revised: 17 January 2012 / Accepted: 7 February 2012 / Published: 21 February 2012
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
Browse Figures
Versions Notes

Abstract

:
Human Immunodeficiency Virus (HIV) entry into target cells is a multi-step process involving binding of the viral glycoprotein, Env, to its receptor CD4 and a coreceptor—either CCR5 or CXCR4. Understanding the means by which HIV enters cells has led to the identification of genetic polymorphisms, such as the 32 base-pair deletion in the ccr5 gene (ccr5∆32) that confers resistance to infection in homozygous individuals, and has also resulted in the development of entry inhibitors—small molecule antagonists that block infection at the entry step. The recent demonstration of long-term control of HIV infection in a leukemic patient following a hematopoietic stem cell transplant using cells from a ccr5∆32 homozygous donor highlights the important role of the HIV entry in maintaining an established infection and has led to a number of attempts to treat HIV infection by genetically modifying the ccr5 gene. In this review, we describe the HIV entry process and provide an overview of the different classes of approved HIV entry inhibitors while highlighting novel genetic strategies aimed at blocking HIV infection at the level of entry.

1. Introduction

Since its identification as the etiologic agent of acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) has claimed the lives of millions around the world. Although the introduction of antiretroviral therapy (ART) has dramatically altered the disease course of treated HIV-infected individuals by delaying the progression to AIDS [1,2,3], often times for many years, the considerable morbidities associated with ART (reviewed in [4]) still drive efforts to develop a cure for HIV. As one of the most intensely studied pathogens of the last decade, much is known about the life cycle of HIV, which begins with entry of the virus into susceptible cells. To enter a cell, HIV must first bind to its primary receptor CD4, and then to one of two coreceptors—CCR5 or CXCR4 (Figure 1) [5,6,7,8,9,10,11,12,13]. The choice of coreceptor used by the virus is intimately linked to disease acquisition and pathogenesis as the majority of transmitted viruses use CCR5 to enter cells [14,15,16,17], while the appearance of viruses capable of using CXCR4 during infection is associated with a more rapid progression to AIDS [18,19,20,21]. Additionally, there is a naturally occurring mutation in ccr5 (ccr5∆32) that prevents expression of CCR5 on the cell surface, and individuals homozygous for this mutation are highly resistant to infection with viruses capable of using CCR5, although their cells remain susceptible to infection with CXCR4-using viruses [22,23,24]. Interest in a cure for HIV was recently reignited following the report of an HIV-infected male—the berlin patient—who developed acute myelogenous leukemia and received a hematopoietic stem cell (HSC) transplant using cells from a ccr5∆32 homozygous donor [25,26]. Following his transplant, he was taken off ART and his virus has remained undetectable for greater than four years, suggesting that long-term control and a possible functional cure of his disease have been achieved. This remarkable report highlights how our understanding of a very basic question—how a virus enters its host cell—has led to the development of new antiviral drugs and therapeutic approaches that have brought us a step closer to controlling the global HIV pandemic. In this review, we provide an overview of HIV entry and its impact on disease pathogenesis, and report on novel treatment approaches targeting the entry process.

2. HIV Entry: The Basics

Entry of HIV into target cells is mediated by the type I integral membrane viral glycoprotein Env. Env is synthesized as a polypeptide precursor termed gp160 which undergoes several of modifications within the cell as it is transported to the cell surface, including extensive N-linked glycosylation, and cleavage by cellular proteases into the extracellular gp120 and the membrane-spanning gp41 subunits [27,28,29]. The extensive glycosylation of Env contributes to its ability to evade humoral immune responses, as the carbohydrate moieties covering its surface are poorly immunogenic and may shield potentially antigenic epitopes on the glycoprotein from recognition by the immune system [30,31,32]. Following gp160 cleavage—an event required for subsequent membrane fusion—gp120 and gp41 maintain their association via non-covalent interactions and are transported to the cell surface where they exist as a trimer of heterodimers that is ultimately incorporated into the viral membrane. Prior to CD4 binding—the first essential step in HIV entry—a number of cell-surface molecules are capable of mediating Env-dependent attachment of the virion to target cells. One such attachment factor is the C-type lectin CD209 or dendritic cell-specific intercellular adhesion molecule (ICAM) grabbing non-integrin (DC-SIGN). Expressed on dendritic cells, DC-SIGN and several other lectins are capable of binding Env and boosting infection in vitro by facilitating trans-infection of surrounding CD4 T cells by dendritic cell-bound virions (reviewed in [33]). More recently, monomeric gp120 from some HIV strains has been shown to bind the gut homing integrin α4ß7 [34,35], which is expressed on activated CD4 T cells. This finding is of particular interest as the depletion of CD4 T cells in the gut-associated lymphoid tissue (GALT) early in infection is a hallmark of HIV disease [36,37,38] and ß7 integrins mediate trafficking of lymphocytes to the gut mucosa [39]. However, it is not clear whether α4ß7 supports binding of trimeric Env on the surface of virions, and thus its relevance to the gut pathology associated with HIV infection remains unknown. Further, while interactions with these and other attachment factors influence HIV infection in vitro, little is known regarding their significance in vivo.
Viruses 04 00309 g001 1024
Figure 1. The HIV Entry Process. The figure below outlines a model for HIV Entry. The entry process begins with binding of gp120 (red) to its primary cellular receptor CD4 (green). CD4 binding results in conformational changes that allow binding of gp120 to the coreceptor-either CCR5 or CXCR4. Coreceptor binding results in triggering of the fusion machinery and formation of the six-helix bundle required to drive fusion of the viral and host cell membranes. Also pictured are the two main steps that have been successfully targeted (coreceptor binding and viral fusion—approved therapeutics appear in parentheses) along with the primary target of most genetic therapies aimed at preventing HIV entry—the HIV coreceptors (in red). Adapted from Antiviral Research Vol 85, Tilton J.C. and Doms R.W, “Entry inhibitors in the treatment of HIV-1 infection,” 91-100, Copyright 2009, with permission from Elsevier.
Figure 1. The HIV Entry Process. The figure below outlines a model for HIV Entry. The entry process begins with binding of gp120 (red) to its primary cellular receptor CD4 (green). CD4 binding results in conformational changes that allow binding of gp120 to the coreceptor-either CCR5 or CXCR4. Coreceptor binding results in triggering of the fusion machinery and formation of the six-helix bundle required to drive fusion of the viral and host cell membranes. Also pictured are the two main steps that have been successfully targeted (coreceptor binding and viral fusion—approved therapeutics appear in parentheses) along with the primary target of most genetic therapies aimed at preventing HIV entry—the HIV coreceptors (in red). Adapted from Antiviral Research Vol 85, Tilton J.C. and Doms R.W, “Entry inhibitors in the treatment of HIV-1 infection,” 91-100, Copyright 2009, with permission from Elsevier.
Viruses 04 00309 g001
The gp120 subunit of Env is composed of five relatively conserved (C1–C5) and five more variable (V1–V5) domains [40]. The conserved regions form the proximal core of gp120 while intrachain disulfide bonds in the variable regions of gp120 result in the formation of five variable ‘loop’ structures that make up the most exterior portion of the gp120 ectodomain [41]. The CD4 binding site on gp120 is a well conserved cavity formed at the interface of the inner and outer domains of the glycoprotein [42]. Following binding of gp120 to CD4, a series of conformational changes occur including the rearrangement of two pairs of ß-sheets from the gp120 inner and outer domains that come together to form a four-stranded ß-sheet structure termed the bridging sheet. The bridging sheet links the inner and outer domains of gp120 and interacts with the viral coreceptor, be it CCR5 or CXCR4 [42,43]. gp120 binding to CD4 also results in enhanced exposure and reorientation of the V1/V2 and V3 loops of gp120, outward rotation of each gp120 monomer to reveal the gp41 stalk, and hinge-like movements in CD4 that are thought to bring the viral membrane in close proximity to the target cell [42,44,45]. Together, all of these events culminate in the creation and exposure of the coreceptor-binding site.
The HIV coreceptors belong to the family of chemokine receptors—seven-transmembrane G-protein coupled receptors with prominent roles in immune cell trafficking. These receptors have three extracellular and intracellular loops, extracellular N-termini, and intracellular C-termini. While several different chemokine receptors are capable of mediating HIV entry in vitro, current evidence suggests that the CCR5 and CXCR4 chemokine receptors are the most frequently utilized in vivo [46,47,48]. Viruses capable of utilizing CCR5 alone, CXCR4 alone, or both coreceptors, are labeled R5-tropic, X4-tropic, and RX54 or dual-tropic viruses respectively. CCR5 is the primary coreceptor for the majority of HIV-1 isolates and is expressed on CD4+ T-cell subsets, macrophages and dendritic cells, while CXCR4 is less commonly used, but is expressed on a wide variety of cells both within and outside the immune system [49]. For reasons that remain unclear, the majority of transmitted viruses utilize CCR5 irrespective of the route of transmission and despite the availability of target cells expressing CXCR4 [17,50,51]. Multiple lines of evidence including mutational analyses, studies of small molecule inhibitors, and inhibition by coreceptor-specific blocking antibodies suggest that both the second extracellular loop (ECL2) and sulfated tyrosines within the N-terminus of the coreceptor interact with the V3 loop of gp120 and mediate coreceptor binding [52,53,54,55,56,57]. The V3 loop is also known to be a key determinant of coreceptor preference as the presence of positively charged amino acids at positions 11 and or 24/25 of V3 is correlated with CXCR4 usage [58,59].
The HIV fusion machinery is contained within the gp41 subunit of Env, which is comprised of a large cytoplasmic domain, a membrane-spanning segment, and an ectodomain that maintains contact with gp120. The ectodomain contains a typical fusion peptide—a stretch of hydrophobic amino acids at the N-terminus [60,61]—along with two α-helical heptad repeats (HR), the N-terminal HR1 and the C-terminal HR2 repeats [62,63]. The current model of gp41-mediated fusion is based on studies performed using HIV fusion inhibitors, crystal structures, and structural similarities between gp41 and other well-characterized type I membrane fusion proteins including the influenza virus glycoprotein, hemagglutinin (HA) [63,64,65,66]. In this model, the sequential interaction of Env with CD4 and a coreceptor results in exposure of the fusion peptide, which then inserts into the plasma membrane of the host cell, causing gp41 to physically link both membranes. Subsequently, the three HR1 domains of the Env trimer interact with one another to form a coiled coil, and the three HR2 segments fold back on the HR1 trimer creating a six-helix bundle that brings the viral and host cell membranes in close contact with one another, allowing for mixing of the two membranes and formation of the fusion pore. Fusion between Env and the host cell was long thought to occur at the plasma membrane as HIV entry occurs in a pH-independent manner [67] and Env is capable of mediating fusion between neighboring cells, provided that they express CD4 and an appropriate coreceptor [68]. However, recent work using trans dominant-negative mutants of proteins involved in clathrin-mediated endocytosis [69] along with elegant studies using single-virion imaging [70] have demonstrated a clear role for components of the endocytic pathway in HIV entry in a number of cell lines. These studies were performed using immortalized cell lines, and as such, the role of the endocytic pathway in HIV entry into relevant cell types in vivo will need to be determined.

3. Inhibition of HIV Entry

The multi-step process by which HIV enters cells provides a series of unique targets for interventions to prevent viral entry including receptor and coreceptor binding, and membrane fusion. Efforts to inhibit these steps have led to the discovery of a new class of anti-HIV drugs—the HIV entry inhibitors (reviewed in [71]). A number of CCR5 inhibitors have been developed and display anti-HIV activity both in vitro and in vivo. These drugs are believed to work by binding to CCR5 at a site distinct from the gp120-binding site and subsequently alter the conformation of the CCR5 extracellular loops required for entry of R5-tropic HIV variants. One such CCR5 antagonist, maraviroc, is licensed for use in the United States and in Europe [43,72]. A variety of CXCR4 antagonists have also been developed, and while they exhibit potent anti-HIV activity in vitro (against X4 but not R5 virus strains), administration of these drugs in vivo results in mobilization of HSCs from the bone marrow to the peripheral blood, highlighting the important role of CXCR4 in HSC homing [73,74,75]. Although this side effect limits their use in HIV-infected individuals, the CXCR4 antagonist plerixafor, is currently used to mobilize HSCs for subsequent autologous transfer in patients with non-Hodgkin’s lymphoma and multiple myeloma [76].
gp41-mediated membrane fusion presents another drug target in the HIV entry process. Synthetic peptides based on the sequence of HR2 display significant antiviral activity against HIV in vitro but for many years, the mechanism of this antiviral activity remained unknown [77]. However, both the observation that these peptides display higher antiviral activity as dimers, and the elucidation of the structure of the gp41 fusion machinery have led to a model for their mechanism of action [63,64,78]. These drugs are now believed to act in a dominant negative fashion by competing with the HR1 and HR2 domains of gp41 and ultimately preventing the formation of the six-helix bundle required for membrane fusion. One such peptide, enfuvirtide, is the only FDA-approved HIV fusion inhibitor, and is indicated for use in combination with standard antiretroviral therapy. However, the twice-daily subcutaneous dosing schedule of the drug makes it an unattractive choice for many patients and care providers.
As is the case for most anti-HIV drugs, viral variants resistant to all of the entry inhibitors have been identified. The appearance of maraviroc resistant viruses in vitro is a well-established phenomenon and these viruses either adapt to recognize the drug-bound conformation of CCR5, or more commonly, acquire the ability to use CXCR4 in addition to CCR5 (reviewed in [79]). In vivo, resistance to maraviroc most commonly results from outgrowth of pre-existing X4 or R5X4 variants that are sometimes present at very low levels prior to the onset of therapy. As such, tropism testing is indicated prior to administration of maraviroc. In the case of enfuvirtide, mutations within HR1 and HR2 rapidly select for viruses with a dramatically decreased sensitivity to the drug [80,81]. HIV drug resistance is not unique to entry inhibitors, but is a widespread problem seen with all classes of HIV chemotherapeutics, and while ART increases survival in HIV-infected individuals, the problems of drug resistance, impaired immune function despite ART, long-term financial cost and drug-associated toxicities of ART continue to fuel the search for curative therapies for HIV infection. Although the search for a cure has long been met with an aura of skepticism, the success of the berlin patient has provided hope that a cure is indeed achievable. After living with HIV for at least 10 years, and experiencing control of viremia on ART for 4 years, the berlin patient developed acute myelogenous leukemia and received a HSC transplant using cells from a ccr5∆32 homozygous donor. His ART was stopped 1 day before the transplant and despite being able to detect proviral HIV DNA for up to 60 days post-transplant, he never experienced a rebound of his viral load [26]. In the 4 years that have followed this transplant, his viral load has remained undetectable as determined by viral RNA and DNA assays of multiple tissues including the gut, bone marrow, peripheral blood and brain. He has also experienced a repopulation of his gut mucosa CD4+ T cells along with a decrease in antibodies directed against HIV.
The Berlin patient received two interventions—conditioning chemotherapy and radiation, and an infusion of HIV resistant cells—all of which of which could have contributed to his dramatic control of the infection. However, as similar chemotherapy regimens and HSC transplants using cells from normal donors have always been followed by a recrudescence of infection following cessation of ART (reviewed in [82]), the control of infection seen in the Berlin patient was clearly dependent upon the genetic absence of CCR5, reinforcing the important role of HIV entry in the maintenance of an established infection. Despite the urgent need for a cure for HIV infection, the risks associated with chemotherapy and radiation, and the relatively low frequency of ccr5∆32 homozygous individuals, makes it unlikely that allogeneic HSC transplants using cells from ccr5∆32 homozygous donors will become a widespread treatment option, and has prompted attempts to mimic the genetic knockout of CCR5 that was achieved in the Berlin patient.

4. Genetic Knockout of CCR5

Several studies have successfully decreased expression of CCR5 in primary human HSCs, CD4 T cells and macrophages in vitro using a variety of unique genetic approaches. Dominant negative forms of CCR5, anti-CCR5 intracellular antibodies (intrabodies), and a number of RNA-based approaches including RNA interference (RNAi), short-hairpin RNAs (shRNA), and ribozymes have been all been shown to decrease CCR5 expression [83,84,85,86,87,88]. In one recent study, the investigators took a combinatorial approach by simultaneously targeting CCR5, the viral genes tat and rev, and the viral trans-activating region (TAR) [83]. Using this approach, the authors successfully introduced an shRNA construct targeting a tat/rev exon, a TAR decoy that localized to the nucleolus, and a CCR5-targeting ribozyme into human HSCs ex vivo using a lentiviral vector, and showed that the cells expressing the construct—dubbed Triple-R—were protected from infection in vitro and provided protection from infection in a humanized mouse model of HIV infection. Following this promising pre-clinical study, Triple-R was tested in a Phase I trial where four patients with AIDS-related lymphoma who were scheduled to receive autologous HSC transplants had a fraction of their infused stem cells modified by the Triple-R construct [89]. The gene-modified cells engrafted in all four patients, and were readily detectable at a consistently low level for up to 24 months. While these cells did not have any detectable effect on infection, possibly due to the low number of gene-modified cells, the study was successfully completed without any toxicity related to the genetic modification of HSCs suggesting that modification of these long-term progenitor cells is a safe and viable option for future genetic therapies aimed at eliminating HIV infection.
As with most gene therapy approaches, achieving lasting expression of the transgene of interest in progenitor cell populations such as HSCs is a challenge, and there remains a need for the development of vector systems that will allow for stable transgene expression in different cell populations over long periods of time. A limitation of a number of these studies has been the need for repeated administration of many of these agents due to their transient effects. As such, recent work has sought to introduce somatic mutations into the ccr5 gene with the ultimate goal of phenocopying the natural ccr5∆32 mutation by rendering a fraction of cells ccr5 negative. These mutations were introduced using zinc finger nucleases (ZFNs)—chimeric proteins composed of a DNA-binding zinc-finger protein (ZFP) fused to the catalytic domain of a FokI restriction endonuclease (Figure 2) [90]. Following binding of a ZFN pair to the intended target sequence, the nuclease domains of the ZFN pair dimerize and introduce a double stranded break (DSB) in the DNA molecule. This break is repaired by the error-prone cellular non-homologous end joining (NHEJ) machinery and typically results in the introduction of insertions and deletions that render the gene product non-functional [91,92,93]. As the ZFP domain of a ZFN can be engineered to bind unique DNA sequences, a pair of ZFNs that recognize the portion of the ccr5 gene encoding the first transmembrane segment were designed and shown to specifically modify 20–40% of the CCR5 alleles in human CD4 T cells in vitro [94]. These gene-modified cells appeared indistinguishable from wildtype cells in culture, but following challenge with an R5-tropic virus, the gene-modified cells had a selective growth advantage as they were protected from infection. In vivo experiments using a humanized mouse model of HIV infection also showed that CCR5-modified CD4 T cells engrafted into the animals at levels similar to unmodified CD4 cells, and are capable of controlling viral load and maintaining CD4 counts following infection with R5-tropic viruses. More recently, CCR5-specific ZFNs have been shown to be capable of disrupting the CCR5 gene in human HSCs ex vivo, with CCR5-modified HSCs displaying normal multi-lineage differentiation into a variety of CCR5-negative hematopoietic cell subsets that recapitulate the protective phenotype seen in the in vitro and humanized mouse studies using CCR5-modified CD4 T cells [95]. The ultimate goal of ZFN therapy is the ex vivo modification of CD4 T cells and HSCs from HIV infected individuals, with the hope that after reinfusion, these cells will control HIV infection in the absence of ART. To this end, the safety and tolerability of CCR5-ZFN modified CD4 T cells is currently being tested in two ongoing human clinical trials (NCT00842634, NCT01044654; Clinicaltrials.gov) and preliminary results presented at the 2011 Conference on Retroviruses and Opportunistic Infections (CROI) suggest that infusion of ZFN-modified CD4 T cells into patients currently on ART is safe, and these gene modified cells appear to initially expand and persist at a stable level over time. While these human studies provide evidence for the safety of this approach and its ability to be scaled up, the effect of infusing CCR5-ZFN modified cells on HIV disease can only be assessed in the absence of ART. As such, structured treatment interruptions, where patients are taken off ART following infusions of CCR5-ZFN modified cells, have been built into the human trials. One of the benefits of the ZFN approach is the permanent modification of the ccr5 gene in a subset of cells, thereby getting around the problem of longevity that is intrinsic to approaches targeting CCR5 at the level of RNA. Additionally, the ex vivo modification step bypasses the need for systemic in vivo delivery of the gene therapy vector and thus potentially limits toxicity while ensuring that only the intended cells receive the CCR5 ZFN.
Viruses 04 00309 g002 1024
Figure 2. Zinc Finger Nucleases (ZFNs) bind and cleave DNA. A ZFN consists of a DNA-binding zinc finger protein (ZFP) domain fused to the catalytic domain of a FokI endonuclease. Each ZFP array in the image (ZFP left & right) contacts 12bp of DNA for a total DNA specificity of 24 base pairs. The members of the ZFN pair depicted are separated by a 5 to 6 base pair spacer and concomitant binding of each ZFN results in dimerization of the nuclease domains and the introduction of a double stranded break. Adapted by permission from Macmillian Publishers Ltd: Nature Biotechnology. Miller, J.C.; Holmes, M.C.; Wang, J.; Guschin, D.Y.; Lee, Y.-L.; Rupniewski, I.; Beausejour, C.M.; Waite, A.J.; Wang, N.S.; Kim, K.A.; et al. An improved zinc-finger nuclease architecture for highly specific genome editing. Nature biotechnology 2007, 25, 778-785. Copyright 2007.
Figure 2. Zinc Finger Nucleases (ZFNs) bind and cleave DNA. A ZFN consists of a DNA-binding zinc finger protein (ZFP) domain fused to the catalytic domain of a FokI endonuclease. Each ZFP array in the image (ZFP left & right) contacts 12bp of DNA for a total DNA specificity of 24 base pairs. The members of the ZFN pair depicted are separated by a 5 to 6 base pair spacer and concomitant binding of each ZFN results in dimerization of the nuclease domains and the introduction of a double stranded break. Adapted by permission from Macmillian Publishers Ltd: Nature Biotechnology. Miller, J.C.; Holmes, M.C.; Wang, J.; Guschin, D.Y.; Lee, Y.-L.; Rupniewski, I.; Beausejour, C.M.; Waite, A.J.; Wang, N.S.; Kim, K.A.; et al. An improved zinc-finger nuclease architecture for highly specific genome editing. Nature biotechnology 2007, 25, 778-785. Copyright 2007.
Viruses 04 00309 g002

5. Future Directions

Despite their promise, genetic approaches targeting CCR5 are currently incapable of achieving the complete genetic knockout of CCR5 that exists in ccr5∆32 homozygous individuals and was accomplished in the Berlin patient. Whether the incomplete ablation of CCR5 provided by these genetic approaches will be able to provide long-term, or indeed, any control of established HIV infection remains to be seen. Additionally, it is unclear how the virus will respond to the partial ablation of one of its primary coreceptors. One possible outcome is a switch from R5 to X4-tropism or an outgrowth of a pre-existing X4-tropic virus reservoir following removal of ccr5. As the coreceptor switch correlates with an accelerated disease progression, a possible coreceptor switch following the removal of ccr5 may be minimized by performing tropism testing to exclude patients with detectable levels of X4-tropic virus prior to administering treatments that reduce levels of CCR5 expression, or by the use of approaches that simultaneously target both coreceptors [96]. However, this latter goal may prove challenging because of the important role of CXCR4 in immune cell trafficking. Additionally, HIV is capable of using a number of other chemokine receptors in vitro, and recent reports have identified variants of the closely related simian immunodeficiency virus (SIVsmm) that utilizes CCR5 but not CXCR4 in vitro, yet still infects sooty mangabeys lacking functional CCR5—suggesting in vivo usage of coreceptors other than CCR5 and CXCR4 [97]. This raises the possibility that another potential mechanism of escape from therapies involving the genetic ablation of the major coreceptors is viral evolution to use some of the less commonly utilized alternative coreceptors. Although a number of questions remain regarding the feasibility, efficacy, and long-term toxicities of these approaches to genetically modify the HIV coreceptors, as well as their effects on viral evolution, genetic ablation of the entry factor CCR5 remains the only proven means of providing long-term control of infection in the absence of ART and as such, continues to provides hope that a cure for HIV can be achieved.

Acknowledgments

Funding for this work was provided by NIH R01 40880 and NIH UU19 AI082628. We are thankful to Craig B. Wilen for helpful comments during the preparation of this manuscript.

Conflict of Interest

The authors declare no conflict of interest.

References and Notes

  1. Detels, R.; Munoz, A.; McFarlane, G.; Kingsley, L.A.; Margolick, J.B.; Giorgi, J.; Schrager, L.K.; Phair, J.P. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. JAMA 1998, 280, 1497–1503. [Google Scholar]
  2. Gulick, R.M.; Meibohm, A.; Havlir, D.; Eron, J.J.; Mosley, A.; Chodakewitz, J.A.; Isaacs, R.; Gonzalez, C.; McMahon, D.; Richman, D.D.; et al. Six-year follow-up of HIV-1-infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine, and lamivudine. AIDS 2003, 17, 2345–2349. [Google Scholar]
  3. Palella, F.J., Jr.; Delaney, K.M.; Moorman, A.C.; Loveless, M.O.; Fuhrer, J.; Satten, G.A.; Aschman, D.J.; Holmberg, S.D. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N. Engl. J. Med. 1998, 338, 853–860. [Google Scholar] [CrossRef]
  4. Deeks, S.G. HIV Infection, Inflammation, Immunosenescence, and Aging. Annu. Rev. Med. 2011, 62, 141–155. [Google Scholar] [CrossRef]
  5. Maddon, P.J.; Dalgleish, A.G.; McDougal, J.S.; Clapham, P.R.; Weiss, R.A.; Axel, R. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 1986, 47, 333–348. [Google Scholar]
  6. McDougal, J.S.; Maddon, P.J.; Dalgleish, A.G.; Clapham, P.R.; Littman, D.R.; Godfrey, M.; Maddon, D.E.; Chess, L.; Weiss, R.A.; Axel, R. The T4 glycoprotein is a cell-surface receptor for the AIDS virus. Cold Spring Harb. Symp. Quant. Biol. 1986, 51, 703–711. [Google Scholar]
  7. Alkhatib, G.; Combadiere, C.; Broder, C.C.; Feng, Y.; Kennedy, P.E.; Murphy, P.M.; Berger, E.A. CC CKR5: A RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 1996, 272, 1955–1958. [Google Scholar]
  8. Choe, H.; Farzan, M.; Sun, Y.; Sullivan, N.; Rollins, B.; Ponath, P.D.; Wu, L.; Mackay, C.R.; LaRosa, G.; Newman, W.; et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 1996, 85, 1135–1148. [Google Scholar]
  9. Deng, H.; Liu, R.; Ellmeier, W.; Choe, S.; Unutmaz, D.; Burkhart, M.; Di Marzio, P.; Marmon, S.; Sutton, R.E.; Hill, C.M.; et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996, 381, 661–666. [Google Scholar]
  10. Doranz, B.J.; Rucker, J.; Yi, Y.; Smyth, R.J.; Samson, M.; Peiper, S.C.; Parmentier, M.; Collman, R.G.; Doms, R.W. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 1996, 85, 1149–1158. [Google Scholar] [CrossRef]
  11. Dragic, T.; Litwin, V.; Allaway, G.P.; Martin, S.R.; Huang, Y.; Nagashima, K.A.; Cayanan, C.; Maddon, P.J.; Koup, R.A.; Moore, J.P.; et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996, 381, 667–673. [Google Scholar]
  12. Feng, Y.; Broder, C.C.; Kennedy, P.E.; Berger, E.A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996, 272, 872–877. [Google Scholar]
  13. Oberlin, E.; Amara, A.; Bachelerie, F.; Bessia, C.; Virelizier, J.L.; Arenzana-Seisdedos, F.; Schwartz, O.; Heard, J.M.; Clark-Lewis, I.; Legler, D.F.; et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 1996, 382, 833–835. [Google Scholar]
  14. Schuitemaker, H.; Koot, M.; Kootstra, N.A.; Dercksen, M.W.; de Goede, R.E.; van Steenwijk, R.P.; Lange, J.M.; Schattenkerk, J.K.; Miedema, F.; Tersmette, M. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J. Virol. 1992, 66, 1354–1360. [Google Scholar]
  15. Roos, M.T.; Lange, J.M.; de Goede, R.E.; Coutinho, R.A.; Schellekens, P.T.; Miedema, F.; Tersmette, M. Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection. J Infect Dis 1992, 165, 427–432. [Google Scholar]
  16. Zhu, T.; Mo, H.; Wang, N.; Nam, D.S.; Cao, Y.; Koup, R.A.; Ho, D.D. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 1993, 261, 1179–1181. [Google Scholar]
  17. Keele, B.F.; Giorgi, E.E.; Salazar-Gonzalez, J.F.; Decker, J.M.; Pham, K.T.; Salazar, M.G.; Sun, C.; Grayson, T.; Wang, S.; Li, H.; et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 7552–7557. [Google Scholar]
  18. Connor, R.I.; Sheridan, K.E.; Ceradini, D.; Choe, S.; Landau, N.R. Change in coreceptor use correlates with disease progression in HIV-1—Infected individuals. J. Exp. Med. 1997, 185, 621–628. [Google Scholar]
  19. Hunt, P.W.; Harrigan, P.R.; Huang, W.; Bates, M.; Williamson, D.W.; McCune, J.M.; Price, R.W.; Spudich, S.S.; Lampiris, H.; Hoh, R.; et al. Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected patients with detectable viremia. J. Infect. Dis. 2006, 194, 926–930. [Google Scholar]
  20. Hoffmann, C. The epidemiology of HIV coreceptor tropism. Eur. J. Med. Res. 2007, 12, 385–390. [Google Scholar]
  21. Koot, M.; Keet, I.P.; Vos, A.H.; de Goede, R.E.; Roos, M.T.; Coutinho, R.A.; Miedema, F.; Schellekens, P.T.; Tersmette, M. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann. Intern. Med. 1993, 118, 681–688. [Google Scholar]
  22. Huang, Y.; Paxton, W.A.; Wolinsky, S.M.; Neumann, A.U.; Zhang, L.; He, T.; Kang, S.; Ceradini, D.; Jin, Z.; Yazdanbakhsh, K.; et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat. Med. 1996, 2, 1240–1243. [Google Scholar]
  23. Liu, R.; Paxton, W.A.; Choe, S.; Ceradini, D.; Martin, S.R.; Horuk, R.; MacDonald, M.E.; Stuhlmann, H.; Koup, R.A.; Landau, N.R. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996, 86, 367–377. [Google Scholar]
  24. Samson, M.; Libert, F.; Doranz, B.J.; Rucker, J.; Liesnard, C.; Farber, C.M.; Saragosti, S.; Lapoumeroulie, C.; Cognaux, J.; Forceille, C.; et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996, 382, 722–725. [Google Scholar]
  25. Allers, K.; Hutter, G.; Hofmann, J.; Loddenkemper, C.; Rieger, K.; Thiel, E.; Schneider, T. Evidence for the cure of HIV infection by CCR5 32/ 32 stem cell transplantation. Blood 2011, 117, 2791–2799. [Google Scholar]
  26. H\utter, G.; Nowak, D.; Mossner, M.; Ganepola, S.; M\ussig, A.; Allers, K.; Schneider, T.; Hofmann, J.o.; Kucherer, C.; Blau, O.; et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N. Engl. J. Med. 2009, 360, 692–698. [Google Scholar]
  27. Earl, P.L.; Moss, B.; Doms, R.W. Folding, interaction with GRP78-BiP, assembly, and transport of the human immunodeficiency virus type 1 envelope protein. J. Virol. 1991, 65, 2047–2055. [Google Scholar]
  28. Willey, R.L.; Bonifacino, J.S.; Potts, B.J.; Martin, M.A.; Klausner, R.D. Biosynthesis, cleavage, and degradation of the human immunodeficiency virus 1 envelope glycoprotein gp160. PNAS 1988, 85, 9580–9584. [Google Scholar]
  29. Hallenberger, S.; Bosch, V.; Angliker, H.; Shaw, E.; Klenk, H.D.; Garten, W. Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160. Nature 1992, 360, 358–361. [Google Scholar]
  30. Reitter, J.N.; Means, R.E.; Desrosiers, R.C. A role for carbohydrates in immune evasion in AIDS. Nat. Med. 1998, 4, 679–684. [Google Scholar]
  31. Quinones-Kochs, M.I.; Buonocore, L.; Rose, J.K. Role of N-linked glycans in a human immunodeficiency virus envelope glycoprotein: Effects on protein function and the neutralizing antibody response. J. Virol. 2002, 76, 4199–4211. [Google Scholar]
  32. Fenouillet, E.; Jones, I.; Powell, B.; Schmitt, D.; Kieny, M.P.; Gluckman, J.C. Functional role of the glycan cluster of the human immunodeficiency virus type 1 transmembrane glycoprotein (gp41) ectodomain. J. Virol. 1993, 67, 150–160. [Google Scholar]
  33. Pohlmann, S.; Baribaud, F.; Doms, R.W. DC-SIGN and DC-SIGNR: Helping hands for HIV. Trends Immun. 2001, 22, 643–646. [Google Scholar]
  34. Arthos, J.; Cicala, C.; Martinelli, E.; Macleod, K.; Van Ryk, D.; Wei, D.; Xiao, Z.; Veenstra, T.D.; Conrad, T.P.; Lempicki, R.A. HIV-1 envelope protein binds to and signals through integrin α4β7, the gut mucosal homing receptor for peripheral T cells. Nature Immun. 2008, 9, 301–309. [Google Scholar]
  35. Cicala, C.; Martinelli, E.; McNally, J.P.; Goode, D.J.; Gopaul, R.; Hiatt, J.; Jelicic, K.; Kottilil, S.; Macleod, K.; O'Shea, A.; et al. The integrin alpha4beta7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1. Proc. Natl. Acad. Sci. USA 2009, 106, 20877–20882. [Google Scholar]
  36. Veazey, R.S.; DeMaria, M.; Chalifoux, L.V.; Shvetz, D.E.; Pauley, D.R.; Knight, H.L.; Rosenzweig, M.; Johnson, R.P.; Desrosiers, R.C.; Lackner, A.A. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 1998, 280, 427–431. [Google Scholar]
  37. Schneider, T.; Ullrich, R.; Zeitz, M. Immunopathology of human immunodeficiency virus infection in the gastrointestinal tract. Springer Semin. Immun. 1997, 18, 515–533. [Google Scholar]
  38. Clayton, F.; Snow, G.; Reka, S.; Kotler, D.P. Selective depletion of rectal lamina propria rather than lymphoid aggregate CD4 lymphocytes in HIV infection. Clin. Exp. Immun. 1997, 107, 288–292. [Google Scholar]
  39. Wagner, N.; Lohler, J.; Kunkel, E.J.; Ley, K.; Leung, E.; Krissansen, G.; Rajewsky, K.; Muller, W. Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. Nature 1996, 382, 366–370. [Google Scholar]
  40. Starcich, B.R.; Hahn, B.H.; Shaw, G.M.; McNeely, P.D.; Modrow, S.; Wolf, H.; Parks, E.S.; Parks, W.P.; Josephs, S.F.; Gallo, R.C.; et al. Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS. Cell 1986, 45, 637–648. [Google Scholar] [Green Version]
  41. Leonard, C.K.; Spellman, M.W.; Riddle, L.; Harris, R.J.; Thomas, J.N.; Gregory, T.J. Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. J. Biol. Chem. 1990, 265, 10373–10382. [Google Scholar]
  42. Kwong, P.D.; Wyatt, R.; Robinson, J.; Sweet, R.W.; Sodroski, J.; Hendrickson, W.A. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998, 393, 648–659. [Google Scholar]
  43. DHS NDA 22-128 approval. Available online: http://www.accessdata.fda.gov/drugsatfda_docs /appletter/2007/022128s000ltr.pdf (accessed on 16 January 2012).
  44. Wu, L.; Gerard, N.P.; Wyatt, R.; Choe, H.; Parolin, C.; Ruffing, N.; Borsetti, A.; Cardoso, A.A.; Desjardin, E.; Newman, W.; et al. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 1996, 384, 179–183. [Google Scholar]
  45. Liu, J.; Bartesaghi, A.; Borgnia, M.J.; Sapiro, G.; Subramaniam, S. Molecular architecture of native HIV-1 gp120 trimers. Nature 2008, 455, 109–113. [Google Scholar]
  46. Zhang, Y.J.; Dragic, T.; Cao, Y.; Kostrikis, L.; Kwon, D.S.; Littman, D.R.; KewalRamani, V.N.; Moore, J.P. Use of Coreceptors Other Than CCR5 by Non-Syncytium-Inducing Adult and Pediatric Isolates of Human Immunodeficiency Virus Type 1 Is Rare In Vitro. J. Virol. 1998, 72, 9337–9344. [Google Scholar]
  47. Edinger, A.L.; Clements, J.E.; Doms, R.W. Chemokine and orphan receptors in HIV-2 and SIV tropism and pathogenesis. Virology 1999, 260, 211–221. [Google Scholar]
  48. Jiang, C.; Parrish, N.F.; Wilen, C.B.; Li, H.; Chen, Y.; Pavlicek, J.W.; Berg, A.; Lu, X.; Song, H.; Tilton, J.C.; et al. Primary infection by a human immunodeficiency virus with atypical coreceptor tropism. J. Virol. 2011, 85, 10669–10681. [Google Scholar]
  49. Bleul, C.C.; Wu, L.; Hoxie, J.A.; Springer, T.A.; Mackay, C.R. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc. Natl. Acad. Sci. USA 1997, 94, 1925–1930. [Google Scholar]
  50. van't Wout, A.B.; Kootstra, N.A.; Mulder-Kampinga, G.A.; Albrecht-van Lent, N.; Scherpbier, H.J.; Veenstra, J.; Boer, K.; Coutinho, R.A.; Miedema, F.; Schuitemaker, H. Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. The Journal of clinical investigation 1994, 94, 2060–2067. [Google Scholar] [CrossRef]
  51. Margolis, L.; Shattock, R. Selective transmission of CCR5-utilizing HIV-1: The 'gatekeeper' problem resolved? Nat. Rev. Microbiol. 2006, 4, 312–317. [Google Scholar] [CrossRef]
  52. Doranz, B.J.; Lu, Z.H.; Rucker, J.; Zhang, T.Y.; Sharron, M.; Cen, Y.H.; Wang, Z.X.; Guo, H.H.; Du, J.G.; Accavitti, M.A.; et al. Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1. J. Virol. 1997, 71, 6305–6314. [Google Scholar]
  53. Wu, L.; LaRosa, G.; Kassam, N.; Gordon, C.J.; Heath, H.; Ruffing, N.; Chen, H.; Humblias, J.; Samson, M.; Parmentier, M.; et al. Interaction of chemokine receptor CCR5 with its ligands: multiple domains for HIV-1 gp120 binding and a single domain for chemokine binding. J. Exp. Med. 1997, 186, 1373–1381. [Google Scholar]
  54. Trkola, A.; Ketas, T.J.; Nagashima, K.A.; Zhao, L.; Cilliers, T.; Morris, L.; Moore, J.P.; Maddon, P.J.; Olson, W.C. Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. J. Viro. 2001, 75, 579–588. [Google Scholar]
  55. Laakso, M.M.; Lee, F.-H.; Haggarty, B.; Agrawal, C.; Nolan, K.M.; Biscone, M.; Romano, J.; Jordan, A.P.O.; Leslie, G.J.; Meissner, E.G.; et al. V3 loop truncations in HIV-1 envelope impart resistance to coreceptor inhibitors and enhanced sensitivity to neutralizing antibodies. PLoS Pathog. 2007, 3, e117. [Google Scholar]
  56. Cormier, E.G.; Dragic, T. The crown and stem of the V3 loop play distinct roles in human immunodeficiency virus type 1 envelope glycoprotein interactions with the CCR5 coreceptor. J. Virol. 2002, 76, 8953–8957. [Google Scholar]
  57. Huang, C.-C.; Lam, S.N.; Acharya, P.; Tang, M.; Xiang, S.-H.; Hussan, S.S.-U.; Stanfield, R.L.; Robinson, J.; Sodroski, J.; Wilson, I.A.; et al. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 2007, 317, 1930–1934. [Google Scholar]
  58. Fouchier, R.A.; Groenink, M.; Kootstra, N.A.; Tersmette, M.; Huisman, H.G.; Miedema, F.; Schuitemaker, H. Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J. Virol. 1992, 66, 3183–3187. [Google Scholar]
  59. De Jong, J.J.; De Ronde, A.; Keulen, W.; Tersmette, M.; Goudsmit, J. Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: analysis by single amino acid substitution. J. Virol. 1992, 66, 6777–6780. [Google Scholar]
  60. Bosch, M.L.; Earl, P.L.; Fargnoli, K.; Picciafuoco, S.; Giombini, F.; Wongstaal, F.; Franchini, G. Identification of the fusion peptide of primate immunodeficiency viruses. Science 1989, 244, 694–697. [Google Scholar]
  61. Freed, E.O.; Delwart, E.L.; Buchschacher, G.L.; Panganiban, A.T. A mutation in the human immunodeficiency virus type 1 transmembrane glycoprotein gp41 dominantly interferes with fusion and infectivity. Proc. Natl. Acad. Sci. USA 1992, 89, 70–74. [Google Scholar]
  62. Tan, K.; Liu, J.; Wang, J.; Shen, S.; Lu, M. Atomic structure of a thermostable subdomain of HIV-1 gp41. Proc. Natl. Acad. Sci. USA 1997, 94, 12303–12308. [Google Scholar]
  63. Weissenhorn, W.; Dessen, A.; Harrison, S.C.; Skehel, J.J.; Wiley, D.C. Atomic structure of the ectodomain from HIV-1 gp41. Nature 1997, 387, 426–430. [Google Scholar]
  64. Chan, D.C.; Fass, D.; Berger, J.M.; Kim, P.S. Core structure of gp41 from the HIV envelope glycoprotein. Cell 1997, 89, 263–273. [Google Scholar]
  65. Furuta, R.A.; Wild, C.T.; Weng, Y.; Weiss, C.D. Capture of an early fusion-active conformation of HIV-1 gp41. Nat. Struct. Biol. 1998, 5, 276–279. [Google Scholar]
  66. Markosyan, R.M.; Cohen, F.S.; Melikyan, G.B. HIV-1 envelope proteins complete their folding into six-helix bundles immediately after fusion pore formation. Mol. Biol. Cell 2003, 14, 926–938. [Google Scholar]
  67. McClure, M.O.; Marsh, M.; Weiss, R.A. Human immunodeficiency virus infection of CD4-bearing cells occurs by a pH-independent mechanism. EMBO J. 1988, 7, 513. [Google Scholar]
  68. Lifson, J.D.; Feinberg, M.B.; Reyes, G.R.; Rabin, L.; Banapour, B.; Chakrabarti, S.; Moss, B.; Wong-Staal, F.; Steimer, K.S.; Engleman, E.G. Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein. Nature 1986, 323, 725–728. [Google Scholar]
  69. Daecke, J.; Fackler, O.T.; Dittmar, M.T.; Krausslich, H.-G. Involvement of clathrin-mediated endocytosis in human immunodeficiency virus type 1 entry. J. Virol. 2005, 79, 1581–1594. [Google Scholar]
  70. Miyauchi, K.; Kim, Y.; Latinovic, O.; Morozov, V.; Melikyan, G.B. HIV enters cells via endocytosis and dynamin-dependent fusion with endosomes. Cell 2009, 137, 433–444. [Google Scholar]
  71. Tilton, J.C.; Doms, R.W. Entry inhibitors in the treatment of HIV-1 infection. Antiviral Res. 2010, 85, 91–100. [Google Scholar]
  72. EMEA EPAR summary for Celsentri (Maraviroc). Available online: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_summary_for_the_public/human/000811 /WC500022191.pdf.
  73. Broxmeyer, H.E.; Orschell, C.M.; Clapp, D.W.; Hangoc, G.; Cooper, S.; Plett, P.A.; Liles, W.C.; Li, X.; Graham-Evans, B.; Campbell, T.B.; et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J. Exp. Med. 2005, 201, 1307–1318. [Google Scholar]
  74. Lack, N.A.; Green, B.; Dale, D.C.; Calandra, G.B.; Lee, H.; MacFarland, R.T.; Badel, K.; Liles, W.C.; Bridger, G. A pharmacokinetic-pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100. Clin. Pharmacol. Ther. 2005, 77, 427–436. [Google Scholar]
  75. Liles, W.C.; Rodger, E.; Broxmeyer, H.E.; Dehner, C.; Badel, K.; Calandra, G.; Christensen, J.; Wood, B.; Price, T.H.; Dale, D.C. Augmented mobilization and collection of CD34+ hematopoietic cells from normal human volunteers stimulated with granulocyte-colony-stimulating factor by single-dose administration of AMD3100, a CXCR4 antagonist. Transfusion 2005, 45, 295–300. [Google Scholar]
  76. Brave, M.; Farrell, A.; Ching Lin, S.; Ocheltree, T.; Pope Miksinski, S.; Lee, S.L.; Saber, H.; Fourie, J.; Tornoe, C.; Booth, B.; et al. FDA review summary: Mozobil in combination with granulocyte colony-stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation. Oncology 2010, 78, 282–288. [Google Scholar]
  77. Wild, C.; Greenwell, T.; Matthews, T. A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. AIDS Res. Hum. Retroviruses 1993, 9, 1051–1053. [Google Scholar]
  78. Jiang, S.; Lin, K.; Strick, N.; Neurath, A.R. HIV-1 inhibition by a peptide. Nature 1993, 365, 113–113. [Google Scholar]
  79. Moore, J.P.; Kuritzkes, D.R. A piece de resistance: How HIV-1 escapes small molecule CCR5 inhibitors. Curr. Opin. HIV and AIDS 2009, 4, 118–124. [Google Scholar]
  80. Rimsky, L.T.; Shugars, D.C.; Matthews, T.J. Determinants of human immunodeficiency virus type 1 resistance to gp41-derived inhibitory peptides. J. Virol. 1998, 72, 986–993. [Google Scholar]
  81. Melby, T.; Sista, P.; DeMasi, R.; Kirkland, T.; Roberts, N.; Salgo, M.; Heilek-Snyder, G.; Cammack, N.; Matthews, T.J.; Greenberg, M.L. Characterization of Envelope Glycoprotein gp41 Genotype and Phenotypic Susceptibility to Enfuvirtide at Baseline and on Treatment in the Phase III Clinical Trials TORO-1 and TORO-2. AIDS Res. Hum. Retroviruses 2006, 22, 375–385. [Google Scholar]
  82. H\utter, G.; Zaia, J.A. Allogeneic haematopoietic stem cell transplantation in patients with human immunodeficiency virus: The experiences of more than 25 years. Clin. Exp. Immunol. 2011, 163, 284–295. [Google Scholar]
  83. Anderson, J.; Li, M.-J.; Palmer, B.; Remling, L.; Li, S.; Yam, P.; Yee, J.-K.; Rossi, J.; Zaia, J.; Akkina, R. Safety and Efficacy of a Lentiviral Vector Containing Three Anti-HIV Genes—CCR5 Ribozyme, Tat-rev siRNA, and TAR Decoy—in SCID-hu Mouse–Derived T Cells. Mol. Ther. 2007, 15, 1182–1188. [Google Scholar]
  84. Anderson, J.S.; Javien, J.; Nolta, J.A.; Bauer, G. Preintegration HIV-1 Inhibition by a Combination Lentiviral Vector Containing a Chimeric TRIM5α Protein, a CCR5 shRNA, and a TAR Decoy. Mol. Ther. 2009, 17, 2103–2114. [Google Scholar] [CrossRef]
  85. Liang, M.; Kamata, M.; Chen, K.N. Inhibition of HIV-1 infection by a unique short hairpin RNA to chemokine receptor 5 delivered into macrophages through hematopoietic progenitor cell transduction. J. Gene Med. 2010, 12, 1521–2254. [Google Scholar]
  86. Kim, S.-S.; Peer, D.; Kumar, P.; Subramanya, S.; Wu, H.; Asthana, D.; Habiro, K.; Yang, Y.-G.; Manjunath, N.; Shimaoka, M.; et al. RNAi-mediated CCR5 Silencing by LFA-1-targeted Nanoparticles Prevents HIV Infection in BLT Mice. Mol. Ther. 2009, 18, 370–376. [Google Scholar]
  87. Swan, C.H.; Buhler, B.; Steinberger, P.; Tschan, M.P.; Barbas, C.F., 3rd; Torbett, B.E. T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery. Gene Ther. 2006, 13, 1480–1492. [Google Scholar]
  88. Luis Abad, J.; Gonzalez, M.A.; del Real, G.; Mira, E.; Manes, S.; Serrano, F.; Bernad, A. Novel interfering bifunctional molecules against the CCR5 coreceptor are efficient inhibitors of HIV-1 infection. Mol. Ther. 2003, 8, 475–484. [Google Scholar]
  89. DiGiusto, D.L.; Krishnan, A.; Li, L.; Li, H.; Li, S.; Rao, A.; Mi, S.; Yam, P.; Stinson, S.; Kalos, M.; et al. RNA-Based Gene Therapy for HIV with Lentiviral Vector-Modified CD34+ Cells in Patients Undergoing Transplantation for AIDS-Related Lymphoma. Sci. Transl. Med. 2010, 2, 36–43. [Google Scholar]
  90. Mani, M.; Kandavelou, K.; Dy, F.J.; Durai, S.; Chandrasegaran, S. Design, engineering, and characterization of zinc finger nucleases. Biochem. Biophys. Res. Commun. 2005, 335, 447–457. [Google Scholar]
  91. Podhajska, A.J.; Szybalski, W. Conversion of the FokI endonuclease to a universal restriction enzyme: cleavage of phage M13mp7 DNA at predetermined sites. Gene 1985, 40, 175–182. [Google Scholar]
  92. Miller, J.C.; Holmes, M.C.; Wang, J.; Guschin, D.Y.; Lee, Y.-L.; Rupniewski, I.; Beausejour, C.M.; Waite, A.J.; Wang, N.S.; Kim, K.A.; et al. An improved zinc-finger nuclease architecture for highly specific genome editing. Nature Biotechn. 2007, 25, 778–785. [Google Scholar]
  93. Durai, S.; Mani, M.; Kandavelou, K.; Wu, J.; Porteus, M.H.; Chandrasegaran, S. Zinc finger nucleases: custom-designed molecular scissors for genome engineering of plant and mammalian cells. Nucleic. Acids. Res. 2005, 33, 5978–5990. [Google Scholar]
  94. Perez, E.E.; Wang, J.; Miller, J.C.; Jouvenot, Y.; Kim, K.A.; Liu, O.; Wang, N.; Lee, G.; Bartsevich, V.V.; Lee, Y.-L.; et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nature Biotechn. 2008, 26, 808–816. [Google Scholar]
  95. Holt, N.; Wang, J.; Kim, K.; Friedman, G.; Wang, X.; Taupin, V.; Crooks, G.M.; Kohn, D.B.; Gregory, P.D.; Holmes, M.C.; et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nature Biotechn. 2010, 28, 839–847. [Google Scholar]
  96. Wilen, C.B.; Wang, J.; Tilton, J.C.; Miller, J.C.; Kim, K.A.; Rebar, E.J.; Sherrill-Mix, S.A.; Patro, S.C.; Secreto, A.J.; Jordan, A.P.O.; et al. Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases. PLoS Pathog. 2011, 7, e1002020. [Google Scholar]
  97. Riddick, N.E.; Hermann, E.A.; Loftin, L.M.; Elliott, S.T.; Wey, W.C.; Cervasi, B.; Taaffe, J.; Engram, J.C.; Li, B.; Else, J.G.; et al. A Novel CCR5 Mutation Common in Sooty Mangabeys Reveals SIVsmm Infection of CCR5-Null Natural Hosts and Efficient Alternative Coreceptor Use In Vivo. PLoS Pathog. 2010, 6, e1001064. [Google Scholar]

Share and Cite

MDPI and ACS Style

Didigu, C.A.; Doms, R.W. Novel Approaches to Inhibit HIV Entry. Viruses 2012, 4, 309-324. https://doi.org/10.3390/v4020309

AMA Style

Didigu CA, Doms RW. Novel Approaches to Inhibit HIV Entry. Viruses. 2012; 4(2):309-324. https://doi.org/10.3390/v4020309

Chicago/Turabian Style

Didigu, Chukwuka A., and Robert W. Doms. 2012. "Novel Approaches to Inhibit HIV Entry" Viruses 4, no. 2: 309-324. https://doi.org/10.3390/v4020309

APA Style

Didigu, C. A., & Doms, R. W. (2012). Novel Approaches to Inhibit HIV Entry. Viruses, 4(2), 309-324. https://doi.org/10.3390/v4020309

Article Metrics

Back to TopTop