Combination antiretroviral therapy for HIV-1 infection introduced in the last half-decade has resulted in dramatic control of viremia in most patients and remarkable improvement in morbidity and mortality. A sizable proportion of infected individuals, however, fail to benefit from these agents or experience only temporary benefit because of the emergence of resistant strains, unacceptable drug toxicity, or difficulties with compliance. Although any step in the viral replication cycle is a potential target for therapeutic intervention, currently available drugs target only two of these steps: reverse transcriptase inhibitors block the stage early after viral entry when the viral RNA genome is copied into DNA, and protease inhibitors block the protein processing step carried out by the viral protease enzyme late in the replication cycle as virus leave the host cell. New strategies that target other steps of infection are critically needed. The last several years have yielded exciting advances in the understanding of how HIV-1 enters its target cell, which have led to the development of promising agents that block viral entry and are likely to be the next group of antiretroviral drugs to become clinically available. This article addresses new insights into the mechanism of HIV-1 entry, and focuses on prototype agents under study as representative approaches that target specific steps of the entry process. More detailed information of the structural biology and mechanisms of entry may be found in several excellent recent reviews [
- Doms R.W.
- Moore J.P.
HIV-1 membrane fusion: targets of opportunity.
J Cell Biol. 2000; 151: F9-F13
- Eckert D.M.
- Kim P.S.
Mechanisms of viral membrane fusion and its inhibition.
Annu Rev Biochem. 2001; 70: 777-810
- LaBranche C.C.
- Galasso G.
- Moore J.P.
- et al.
HIV fusion and its inhibition.
Antiviral Res. 2001; 50: 95-115
- Zimmerberg J.
- Chernomordik L.V.
Adv Drug Deliv Rev. 1999; 38: 197-205
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.
Content published before 2002 is available via pay-per-view purchase only.
Subscribe:Subscribe to Clinics in Laboratory Medicine
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- HIV-1 membrane fusion: targets of opportunity.J Cell Biol. 2000; 151: F9-F13
- Mechanisms of viral membrane fusion and its inhibition.Annu Rev Biochem. 2001; 70: 777-810
- HIV fusion and its inhibition.Antiviral Res. 2001; 50: 95-115
- Membrane fusion.Adv Drug Deliv Rev. 1999; 38: 197-205
- Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody.Nature. 1998; 393: 648-659
- A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding.Science. 1998; 280: 1949-1953
- The antigenic structure of the HIV gp120 envelope glycoprotein.Nature. 1998; 393: 705-711
- Human immunodeficiency virus type 1 gp120 envelope glycoprotein regions important for association with the gp41 transmembrane glycoprotein.J Virol. 1991; 65: 2119-2123
- Core structure of gp41 from the HIV envelope glycoprotein.Cell. 1997; 89: 263-273
- Mutational analysis of the interaction between CD4 and class II MHC: class II antigens contact CD4 on a surface opposite the gp120-binding site.Cell. 1991; 66: 1037-1049
- Crystal structure of an HIV-binding recombinant fragment of human CD4.Nature. 1990; 348 ([abstr]): 419-426
- Chemokines and chemokine receptors: biology and clinical relevance in inflammation and AIDS.Annu Rev Med. 1999; 50: 425-440
- 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
- Will multiple coreceptors need to be targeted by inhibitors of human immunodeficiency virus type 1 entry?.J Virol. 1999; 73: 3443-3448
- CD4-independent binding of SIV gp120 to rhesus CCR5.Science. 1997; 278: 1470-1473
- Shared usage of the chemokine receptor CXCR4 by the feline and human immunodeficiency viruses.J Virol. 1997; 71: 6407-6415
- Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding.J Virol. 1995; 69: 5723-5733
- Conformational changes in cell surface HIV-1 envelope glycoproteins are triggered by cooperation between cell surface CD4 and co-receptors.J Biol Chem. 1998; 273: 404-409
- Characterization of the sequence of interactions of the fusion domain of the simian immunodeficiency virus with membranes: role of the membrane dipole potential.J Biol Chem. 1999; 274: 29951-29959
- Role of the membrane-proximal domain in the initial stages of human immunodeficiency virus type 1 envelope glycoprotein-mediated membrane fusion.J Virol. 1999; 73: 6089-6092
- Atomic structure of the ectodomain from HIV-1 gp41.Nature. 1997; 387: 426-430
- Dilation of the human immunodeficiency virus-1 envelope glycoprotein fusion pore revealed by the inhibitory action of a synthetic peptide from gp41.J Cell Biol. 1998; 140: 315-323
- Early intermediates in HIV-1 envelope glycoprotein-mediated fusion triggered by CD4 and co-receptor complexes.J Biol Chem. 2001; 276: 30335-30341
- CC-KR5: A RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1.Science. 1996; 272: 1955-1958
- The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates.Cell. 1996; 85: 1135-1148
- 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
- HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor.Science. 1996; 272: 872-876
- HIV-1 tropism for mononuclear phagocytes can be determined by regions of gp120 outside the CD4-binding domain.Nature. 1990; 348: 69-73
- Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission.J Clin Invest. 1994; 94: 2060-2067
- Genotypic and phenotypic characterization of HIV-1 in patients with primary infection.Science. 1993; 261: 1179-1181
- Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection.Cell. 1996; 86: 367-377
- Resistance to HIV-1 infection of Caucasian individuals bearing mutant alleles of the CCR5 chemokine receptor gene.Nature. 1996; 382: 722-725
- A 32-bp deletion within the CCR5 locus protects against transmission of parenterally acquired human immunodeficiency virus but does not affect progression to AIDS-defining illness.J Infect Dis. 1998; 178: 1163-1166
- Monocytotropic human immunodeficiency virus type 1 (HIV-1) variants detectable in all stages of HIV-1 infection lack T-cell line tropism and syncytium-inducing ability in primary T-cell culture.J Virol. 1991; 65: 356-363
- A cross-sectional comparison of persons with syncytium- and non-syncytium-inducing human immunodeficiency virus.J Infect Dis. 1993; 168: 1374-1379
- Change in coreceptor use correlates with disease progression in HIV-1-infected individuals.J Exp Med. 1997; 185: 621-628
- In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression.Nat Med. 1997; 3: 1259-1265
- Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates.J Virol. 1989; 63: 2118-2125
- Heterogeneous spectrum of coreceptor usage among variants within a dualtropic human immunodeficiency virus type 1 primary-isolate quasispecies.J Virol. 2000; 74: 10229-10235
- A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection.J Exp Med. 2001; 193: 671-678
- Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses.Cell. 2000; 100: 575-585
- DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells.Cell. 2000; 100: 587-597
- DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans.Proc Natl Acad Sci USA. 2001; 98: 2670-2675
- DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13.J Immunol. 2000; 165: 2937-2942
- Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques.J Exp Med. 1996; 183: 215-225
- Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120.Proc Natl Acad Sci USA. 1992; 89: 8356-8360
- Extensive repertoire of membrane-bound and soluble dendritic cell-specific ICAM-3-grabbing nonintegrin 1 (DC-SIGN1) and DC-SIGN2 isoforms. Inter-individual variation in expression of DC-SIGN transcripts.J Biol Chem. 2001; 276: 33196-33212
- Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR.Science. 2001; 294: 2163-2166
- Expression of DC-SIGN by dendritic cells of intestinal and genital mucosae in humans and rhesus macaques.J Virol. 2002; 76: 1866-1875
- Placental expression of DC-SIGN may mediate intrauterine vertical transmission of HIV.J Pathol. 2001; 195: 586-592
- Involvement of a leukocyte adhesion receptor (LFA-1) in HIV-induced syncytium formation.Science. 1989; 244: 1075-1078
- Interaction between virion-bound host intercellular adhesion molecule-1 and the high-affinity state of lymphocyte function-associated antigen-1 on target cells renders R5 and X4 isolates of human immunodeficiency virus type 1 more refractory to neutralization.Virology. 2000; 268: 493-503
- Contribution of virion ICAM-1 to human immunodeficiency virus infectivity and sensitivity to neutralization.J Virol. 1997; 71: 4847-4851
- Cyclophilin A is required for an early step in the life cycle of human immunodeficiency virus type 1 before the initiation of reverse transcription.J Virol. 1996; 70: 3551-3560
- Specific incorporation of cyclophilin A into HIV-1 virions.Nature. 1994; 372: 359-362
- Host cyclophilin A mediates HIV-1 attachment to target cells via heparans.EMBO J. 1999; 18: 6771-6785
- CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A.Proc Natl Acad Sci USA. 2001; 98: 6360-6365
- Antibody-dependent enhancement of infection and the pathogenesis of viral disease.Clin Infect Dis. 1994; 19: 500-512
- Antibody-dependent enhancement of human immunodeficiency virus type 1 infection.Lancet. 1988; 11: 790-794
- Antibody-enhanced infection by HIV-1 via Fc receptor-mediated entry.Science. 1988; 242: 580-583
- The Fc and not CD4 receptor mediates antibody enhancement of HIV infection in human cells.Science. 1989; 244: 1357-1360
- Two receptors are required for antibody-dependent enhancement of human immunodeficiency virus type 1 infection: CD4 and FcgR.J Virol. 1990; 64: 5605-5610
- Strong correlation between the complement-mediated antibody-dependent enhancement of HIV-1 infection and plasma viral load.AIDS. 1999; 13: 1841-1849
- Cholesterol and sphingolipid enhance the Triton X-100 insolubility of glycosylphosphatidylinositol-anchored proteins by promoting the formation of detergent-insoluble ordered membrane domains.J Biol Chem. 1998; 273: 1150-1157
- Segregation of CD4 and CXCR4 into distinct lipid microdomains in T lymphocytes suggests a mechanism for membrane destabilization by human immunodeficiency virus.J Virol. 2002; 76: 1802-1815
- Membrane raft microdomains mediate lateral assemblies required for HIV-1 infection.EMBO Rep. 2000; 1: 190-196
- Lipid rafts and HIV pathogenesis: host membrane cholesterol is required for infection by HIV type 1.AIDS Res Hum Retroviruses. 2001; 17: 1009-1019
- Evidence for budding of human immunodeficiency virus type 1 selectively from glycolipid-enriched membrane lipid rafts.J Virol. 2000; 74: 3264-3272
- A soluble form of CD4 (T4) protein inhibits AIDS virus infection.Nature. 1988; 331: 82-84
- A soluble CD4 protein selectively inhibits HIV replication and syncytium formation.Nature. 1988; 331: 78-81
- Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen.Science. 1987; 238: 1704-1707
- High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates.Proc Natl Acad Sci USA. 1990; 87: 6574-6578
- Quantitative model of antibody- and soluble CD4-mediated neutralization of primary isolates and T-cell line-adapted strains of human immunodeficiency virus type 1.J Virol. 1996; 70: 3668-3677
- Expression and characterization of CD4-IgG2, a novel heterotetramer that neutralizes primary HIV type 1 isolates.AIDS Res Hum Retroviruses. 1995; 11: 533-539
- A human monoclonal antibody to a complex epitope in the V3 region of gp120 of human immunodeficiency virus type 1 has broad reactivity within and outside clade B.J Virol. 1995; 69: 122-130
- Structural flexibility and functional valence of CD4-IgG2 (PRO 542): potential for cross-linking human immunodeficiency virus type 1 envelope spikes.J Virol. 2001; 75: 6682-6686
- Single-dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults.J Infect Dis. 2000; 182: 326-329
- Recombinant CD4-IgG2 in human immunodeficiency virus type 1-infected children: phase 1/2 study. The Pediatric AIDS Clinical Trials Group Protocol 351 Study Team.J Infect Dis. 2000; 182 ([abstract]): 1774-1779
- Role of CCR5 in infection of primary macrophages and lymphocytes by M-tropic strains of HIV: resistance to patient-derived and prototype isolates resulting from the Δccr5 mutation.J Virol. 1997; 71: 3219-3227
- Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CCR5 structural gene.Science. 1996; 273: 1856-1862
- Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells.Science. 1995; 270: 1811-1815
- Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist.Science. 1997; 276: 276-279
- A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity.Proc Natl Acad Sci USA. 1999; 96: 5698-5703
- A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5.Proc Natl Acad Sci USA. 2000; 97: 5639-5644
- SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo.Proc Natl Acad Sci USA. 2001; 98: 12718-12723
- HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use.Proc Natl Acad Sci USA. 2002; 99: 395-400
- Anti-human immunodeficiency virus type 1 activity of an oligocationic compound mediated via gp120 V3 interactions.J Virol. 1996; 70: 2825-2831
- A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor.J Exp Med. 1997; 186: 1395-1400
- HIV-1 entry: an expanding portal for drug discovery.Drug Discov Today. 2000; 5: 183-194
- Safe use of the CXCR4 inhibitor ALX40–4C in humans.AIDS Res Hum Retroviruses. 2001; 17: 475-486
- Multi-branched peptides based on the HIV-1 V3 loop consensus motif inhibit HIV-1 and HIV-2 infection in CD4+ and CD4− cells.C R Acad Sci III. 1993; 316: 1381-1387
- Relationships between the anti-HIV V(3)-derived peptide SPC(3) and lymphocyte membrane properties involved in virus entry: SPC(3) interferes with CXCR(4).FEMS Microbiol Lett. 2000; 183: 235-240
- Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100.Antimicrob Agents. 1994; 38: 668-674
- Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event.Proc Natl Acad Sci USA. 1992; 89: 5286-5290
- Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4.J Exp Med. 1997; 186: 1383-1388
- Antiviral efficacy in vivo of the anti-human immunodeficiency virus bicyclam SDZ SID 791 (JM 3100), an inhibitor of infectious cell entry.Antimicrob Agents Chemother. 1996; 40: 750-754
- Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers.Antimicrob Agents Chemother. 2000; 44: 1667-1673
- Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice.Proc Natl Acad Sci USA. 1998; 95: 9448-9453
- The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract.Nature. 1998; 393: 591-594
- Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development.Nature. 1998; 393: 595-599
- A molecular clasp in the human immunodeficiency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion.J Virol. 1995; 69: 3771-3777
- Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120.J Virol. 2000; 74: 8358-8367
- Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry.Nat Med. 1998; 4: 1302-1307
- T20/DP178, an ectodomain peptide of human immunodeficiency virus type 1 gp41, is an activator of human phagocyte N-formyl peptide receptor.Blood. 1999; 93: 3885-3892
- Protein design of an HIV-1 entry inhibitor.Science. 2001; 291: 884-888
- Inhibition of HIV-1 infection by down-regulation of the CXCR4 co-receptor using an intracellular single chain variable fragment against CXCR4.Gene Ther. 2001; 8: 408-418
- Functional deletion of the CCR5 receptor by intracellular immunization produces cells that are refractory to CCR5-dependent HIV-1 infection and cell fusion.Proc Natl Acad Sci USA. 2000; 97: 805-810
- Multivalent anti-CCR ribozymes for stem cell-based HIV type 1 gene therapy.AIDS Res Hum Retroviruses. 2001; 17: 385-399
- Down-regulation of the CCR5 beta-chemokine receptor and inhibition of HIV-1 infection by stable VA1-ribozyme chimeric transcripts.Antisense Nucleic Acid Drug Dev. 2000; 10: 251-261
- Inactivation of HIV-1 chemokine co-receptor CXCR-4 by a novel intrakine strategy.Nat Med. 1997; 3: 1110-1116
- Phenotypic knockout of HIV type 1 chemokine coreceptor CCR-5 by intrakines as potential therapeutic approach for HIV-1 infection.Proc Natl Acad Sci USA. 1997; 94: 11567-11572
- Membrane-anchored peptide inhibits human immunodeficiency virus entry.J Virol. 2001; 75: 3038-3042
- Differential regulation of HIV-1 fusion cofactor expression by CD28 costimulation of CD4+ T cells.Science. 1997; 276: 273-276
- Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection.Nat Med. 2002; 8: 47-53
- Strong in vitro synergy between the fusion inhibitor T-20 and the CXCR4 blocker AMD-3100.J Acquir Immune Defic Syndr Hum Retrovirol. 2000; 25: 99-102
- Human immunodeficiency virus type 1 entry inhibitors PRO 542 and T-20 are potently synergistic in blocking virus-cell and cell-cell fusion.J Infect Dis. 2001; 183: 1121-1125
☆This work was supported by grants AI 07632, AI 35502, and MH 61139 from the National Institutes of Health.
© 2002 Elsevier Science (USA). Published by Elsevier Inc. All rights reserved.