An entirely new finding.

Comments by J. C. Spencer

We know that the HIV cannot replicate on its own and must rely on the host cell to reproduce. HIV infects helper T cells with a protein embedded in its envelope called gp120. The gp 120 protein binds to a molecule called CD4 on the surface of the helper T cell. This process initiates a complex set of reactions that transfers the HIV genetic code into the host cell.

Because this is such an important discovery in glycomics, I am following the article with a number of abstracts on the gp 120 protein envelope.

Now the article:

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Pathologists Believe They Have Pinpointed Achilles Heel Of HIV

Human Immunodeficiency Virus (HIV) researchers at The University of Texas Medical School at Houston believe they have uncovered the Achilles heel in the armor of the virus that continues to kill millions.

The weak spot is hidden in the HIV envelope protein gp120. This protein is essential for HIV attachment to host cells, which initiate infection and eventually lead to Acquired Immunodeficiency Syndrome or AIDS. Normally the body�s immune defenses can ward off viruses by making proteins called antibodies that bind the virus. However, HIV is a constantly changing and mutating virus, and the antibodies produced after infection do not control disease progression to AIDS. For the same reason, no HIV preventative vaccine that stimulates production of protective antibodies is available.

The Achilles heel, a tiny stretch of amino acids numbered 421-433 on gp120, is now under study as a target for therapeutic intervention. Sudhir Paul, Ph.D., pathology professor in the UT Medical School, said, �Unlike the changeable regions of its envelope, HIV needs at least one region that must remain constant to attach to cells. If this region changes, HIV cannot infect cells. Equally important, HIV does not want this constant region to provoke the body�s defense system. So, HIV uses the same constant cellular attachment site to silence B lymphocytes - the antibody producing cells. The result is that the body is fooled into making abundant antibodies to the changeable regions of HIV but not to its cellular attachment site. Immunologists call such regions superantigens. HIV�s cleverness is unmatched. No other virus uses this trick to evade the body�s defenses.�

Paul is the senior author on a paper about this theory in a June issue of the journal Autoimmunity Reviews. Additional data supporting the theory are to be presented at the XVII International AIDS Conference Aug. 3-8 in Mexico City in two studies titled �Survivors of HIV infection produce potent, broadly neutralizing IgAs directed to the superantigenic region of the gp120 CD4 binding site� and �Prospective clinical utility and evolutionary implication of broadly neutralizing antibody fragments to HIV gp120 superantigenic epitope.�

First reported in the early 1980s, HIV has spread across the world, particularly in developing countries. In 2007, 33 million people were living with AIDS, according to a report by the World Health Organization and the United Nations.

Paul�s group has engineered antibodies with enzymatic activity, also known as abzymes, which can attack the Achilles heel of the virus in a precise way. �The abzymes recognize essentially all of the diverse HIV forms found across the world. This solves the problem of HIV changeability. The next step is to confirm our theory in human clinical trials," Paul said.

Unlike regular antibodies, abzymes degrade the virus permanently. A single abzyme molecule inactivates thousands of virus particles. Regular antibodies inactivate only one virus particle, and their anti-viral HIV effect is weaker.

�The work of Dr. Paul�s group is highly innovative. They have identified antibodies that, instead of passively binding to the target molecule, are able to fragment it and destroy its function. Their recent work indicates that naturally occurring catalytic antibodies, particularly those of the IgA subtype, may be useful in the treatment and prevention of HIV infection,� said Steven J. Norris, Ph.D., holder of the Robert Greer Professorship in the Biomedical Sciences and vice chair for research in the Department of Pathology and Laboratory Medicine at the UT Medical School at Houston.

The abzymes are derived from HIV negative people with the autoimmune disease lupus and a small number of HIV positive people who do not require treatment and do not get AIDS. Stephanie Planque, lead author and UT Medical School at Houston graduate student, said, �We discovered that disturbed immunological events in lupus patients can generate abzymes to the Achilles heel of HIV. The human genome has accumulated over millions of years of evolution a lot of viral fragments called endogenous retroviral sequences. These endogenous retroviral sequences are overproduced in people with lupus, and an immune response to such a sequence that resembles the Achilles heel can explain the production of abzymes in lupus. A small minority of HIV positive people also start producing the abzymes after decades of the infection. The immune system in some people can cope with HIV after all.�

Carl Hanson, Ph.D., who heads the Retrovirus Diagnostic Section of the Viral and Rickettsial Disease Laboratory of the California Department of Public Health, has shown that the abzymes neutralize infection of human blood cells by diverse strains of HIV from various parts of the world. Human blood cells are the only cells that HIV infects.

�This is an entirely new finding. It is a novel antibody that appears to be very effective in killing the HIV virus. The main question now is if this can be applied to developing vaccine and possibly used as a microbicide to prevent sexual transmission,� said David C. Montefiori, Ph.D., director of the Laboratory for AIDS Vaccine Research & Development at Duke University Medical Center. The abzymes are now under development for HIV immunotherapy by infusion into blood. They could also be used to guard against sexual HIV transmission as topical vaginal or rectal formulations.

�HIV is an international priority because we have no defense against it,� Paul said. �Left unchecked, it will likely evolve into even more virulent forms. We have learned a lot from this research about how to induce the production of the protective abzymes on demand. This is the Holy Grail of HIV research -- development of a preventative HIV vaccine.�

Major contributors to the research from the UT Medical School include Yasuhiro Nishiyama, Ph.D., and Hiroaki Taguchi, Ph.D., both with the Department of Pathology and Laboratory Medicine, and Miguel Escobar, M.D., of the Department of Pediatrics. Maria Salas and Hanson, both with the Viral and Rickettsial Disease Laboratory, contributed.

The research was funded by the National Institutes of Health and the Texas Higher Education Coordinating Board.

ScienceDaily - July 16, 2008
http://www.sciencedaily.com/releases/2008/07/080715165520.htm

Related papers supported by BioInfoBank Library

HIV Envelope Protein gp120 :: chemistry

Paper:
Biomed Khim. ;52 (5):448-57 17180919 (P,S,E,B) Favorite:1
[Study of conformational homology for the HIV-1 gpi20 V3 loop. structural analysis of the HIV-RF and HIV-Thailand viral strains]
A M Andrianov A conformation of the H-IV-RF gp120 V3 loop giving rise to the virus principal neutralizing determinant as well as determinants of cell tropism and syncytium formation was built by computer modeling methods using NMR spectroscopy data. The elements of the HIV-RF V3 loop secondary structure and conformational states of its irregular stretches were determined. The structural elements preserved in two viral strains, were identified using the comparative analysis of simulated structure with that of homologous site for the HIV-Thailand gp120 V3 loop. Conservative structure elements of the HIV-1 V3 loop are considered to be promising targets for deriving its chemically modified forms characterized by the enhanced immunogenicity and cross-reactivity of neutralizing antibodies, as well as for the antiviral drug design resulting from these researches. Mesh-terms: AIDS Vaccines :: chemistry; AIDS Vaccines :: immunology; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: immunology; HIV-1 :: chemistry; HIV-1 :: immunology; Models, Molecular; Protein Structure, Secondary;

Most cited papers:
Nature. 1998 Jun 18;393 (6686):648-59 9641677 (P,S.E,B) Cited:255
Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody.

P D Kwong, R Wyatt, J Robinson, R W Sweet, J Sodroski, W A Hendrickson The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. These interactions initiate a fusion of the viral and cellular membranes. Although gp120 can elicit virus-neutralizing antibodies, HIV eludes the immune system. We have solved the X-ray crystal structure at 2.5 A resolution of an HIV-1 gp120 core complexed with a two-domain fragment of human CD4 and an antigen-binding fragment of a neutralizing antibody that blocks chemokine-receptor binding. The structure reveals a cavity-laden CD4-gp120 interface, a conserved binding site for the chemokine receptor, evidence for a conformational change upon CD4 binding, the nature of a CD4-induced antibody epitope, and specific mechanisms for immune evasion. Our results provide a framework for understanding the complex biology of HIV entry into cells and should guide efforts to intervene. Mesh-terms: Amino Acid Sequence; Animals; Antigens, CD4 :: chemistry; Antigens, CD4 :: immunology; Antigens, CD4 :: metabolism; CHO Cells; Cricetulus; Crystallography, X-Ray; Glycosylation; HIV Antibodies :: chemistry; HIV Antibodies :: immunology; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: immunology; HIV Envelope Protein gp120 :: metabolism; HIV Envelope Protein gp41 :: metabolism; Hamsters; Human; Immunoglobulin Fragments :: chemistry; Immunoglobulin Fragments :: immunology; Membrane Fusion; Models, Molecular; Molecular Sequence Data; Neutralization Tests; Protein Conformation; Receptors, CCR5 :: metabolism; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Science. 1993 Aug 27;261 (5125):1179-81 8356453 (P,S,E,B) Cited:167
Genotypic and phenotypic characterization of HIV-1 patients with primary infection.

T Zhu, H Mo, N Wang, D S Nam, Y Cao, R A Koup, D D Ho Aaron Diamond AIDS Research Center, New York University School of Medicine, NY 10016. Better characterization of human immunodeficiency virus-type 1 (HIV-1) in patients with primary infection has important implications for the development of an acquired immunodeficiency syndrome (AIDS) vaccine because vaccine strategies should target viral isolates with the properties of transmitted viruses. In five HIV-1 seroconverters, the viral phenotype was found to be uniformly macrophage-tropic and non-syncytium-inducing. Furthermore, the viruses were genotypically homogeneous within each patient, but a common signature sequence was not discernible among transmitted viruses. In the two cases where the sexual partners were also studied, the sequences of the transmitted viruses matched best with minor variants in the blood of the transmitters. There was also a stronger pressure to conserve sequences in gp120 than in gp41, nef, and p17, suggesting that a selective mechanism is involved in transmission. Mesh-terms: Amino Acid Sequence; Base Sequence; Cell Line; Female; Gene Products, gag :: chemistry; Gene Products, gag :: genetics; Genes, Viral; Genotype; Giant Cells :: physiology; HIV Antigens :: chemistry; HIV Antigens :: genetics; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: genetics; HIV Envelope Protein gp41 :: chemistry; HIV Envelope Protein gp41 :: genetics; HIV Infections :: microbiology; HIV Infections :: transmission; HIV Seropositivity :: microbiology; HIV-1 :: chemistry; HIV-1 :: genetics; HIV-1 :: physiology; Human; Macrophages; Male; Molecular Sequence Data; Phenotype; Sequence Alignment; Sexual Partners; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Virus Replication; Nature. 1998 Jun 18;393 (6686):705-11 9641684 (P,S,E,B) Cited:146

The antigenic structure of the HIV gp120 envelope glycoprotein.

R Wyatt, P D Kwong, E Desjardins, R W Sweet, J Robinson, W A Hendrickson, J G Sodroski The human immunodeficiency virus HIV-1 establishes persistent infections in humans which lead to acquired immunodeficiency syndrome (AIDS). The HIV-1 envelope glycoproteins, gp120 and gp41, are assembled into a trimeric complex that mediates virus entry into target cells. HIV-1 entry depends on the sequential interaction of the gp120 exterior envelope glycoprotein with the receptors on the cell, CD4 and members of the chemokine receptor family. The gp120 glycoprotein, which can be shed from the envelope complex, elicits both virus-neutralizing and non-neutralizing antibodies during natural infection. Antibodies that lack neutralizing activity are often directed against the gp120 regions that are occluded on the assembled trimer and which are exposed only upon shedding. Neutralizing antibodies, by contrast, must access the functional envelope glycoprotein complex and typically recognize conserved or variable epitopes near the receptor-binding regions. Here we describe the spatial organization of conserved neutralization epitopes on gp120, using epitope maps in conjunction with the X-ray crystal structure of a ternary complex that includes a gp120 core, CD4 and a neutralizing antibody. A large fraction of the predicted accessible surface of gp120 in the trimer is composed of variable, heavily glycosylated core and loop structures that surround the receptor-binding regions. Understanding the structural basis for the ability of HIV-1 to evade the humoral immune response should assist in the design of a vaccine. Mesh-terms: Antibody Formation; Antigens, CD4 :: immunology; Crystallography, X-Ray; Epitopes, B-Lymphocyte :: chemistry; Epitopes, B-Lymphocyte :: immunology; Glycosylation; HIV Antibodies :: chemistry; HIV Antibodies :: immunology; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: immunology; HIV-1 :: chemistry; HIV-1 :: immunology; Human; Immunoglobulins, Fab :: chemistry; Immunoglobulins, Fab :: immunology; Models, Molecular; Neutralization Tests; Protein Conformation; SIV :: chemistry; SIV :: immunology; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Science. 1998 Jun 19;280 (5371):1949-53 9632396 (P,S,E,B) Cited:140

A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding.

C D Rizzuto, R Wyatt, N Hern�ndez-Ramos, Y Sun, P D Kwong, W A Hendrickson, J Sodroski The entry of primate immunodeficiency viruses into target cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors, CD4 and members of the chemokine receptor family. The gp120 third variable (V3) loop has been implicated in chemokine receptor binding, but the use of the CCR5 chemokine receptor by diverse primate immunodeficiency viruses suggests the involvement of an additional, conserved gp120 element. Through the use of gp120 mutants, a highly conserved gp120 structure was shown to be critical for CCR5 binding. This structure is located adjacent to the V3 loop and contains neutralization epitopes induced by CD4 binding. This conserved element may be a useful target for pharmacologic or prophylactic intervention in human immunodeficiency virus (HIV) infections. Mesh-terms: Amino Acid Substitution; Animals; Antigens, CD4 :: metabolism; Binding Sites; Crystallization; HIV Antibodies :: immunology; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: genetics; HIV Envelope Protein gp120 :: immunology; HIV Envelope Protein gp120 :: metabolism; HIV-1 :: chemistry; HIV-1 :: immunology; Human; Models, Molecular; Peptide Fragments :: chemistry; Protein Conformation; Protein Structure, Secondary; Receptors, CCR5 :: metabolism; Recombinant Proteins :: metabolism; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; J Exp Med. 1991 Aug 1;174:407-15 1713252 (P,S,E,B) Cited:133

Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding.

Q J Sattentau, J P Moore Academic Department of Genito-Urinary Medicine, University College and Middlesex School of Medicine, London, United Kingdom. The human immunodeficiency virus (HIV) binds to the surface of T lymphocytes and other cells of the immune system via a high affinity interaction between CD4 and the HIV outer envelope glycoprotein, gp120. By analogy with certain other enveloped viruses, receptor binding by HIV may be followed by exposure of the hydrophobic NH2 terminus of its transmembrane glycoprotein, gp41, and fusion of the virus and cell membranes. A similar sequence of events is thought to take place between HIV-infected and uninfected CD4+ cells, resulting in their fusion to form syncytia. In this study, we have used a soluble, recombinant form of CD4 (sCD4) to model events taking place after receptor binding by the HIV envelope glycoproteins. We demonstrate that the complexing of sCD4 with gp120 induces conformational changes within envelope glycoprotein oligomers. This was measured on HIV-1-infected cells by the increased binding of antibodies to the gp120/V3 loops, and on the surface of virions by increased cleavage of this loop by an exogenous proteinase. At 37 degrees C, these conformational changes are coordinate with the dissociation of gp120/sCD4 complexes from gp41, and the increased exposure of gp41 epitopes. At 4 degrees C, gp120 dissociation from the cell surface does not occur, but increased exposure of both gp120/V3 and gp41 epitopes is detected. We propose that these events occurring after CD4 binding are integral components of the membrane fusion reaction between HIV or HIV-infected cells and CD4+ cells. Mesh-terms: Antibodies, Monoclonal :: metabolism; Antigens, CD4 :: metabolism; Blotting, Western; Epitopes :: immunology; Flow Cytometry; Fluorescent Antibody Technique; HIV Antibodies :: metabolism; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: metabolism; HIV Envelope Protein gp41 :: metabolism; HIV-1 :: metabolism; Human; Protein Conformation; Receptors, HIV; Recombinant Proteins :: metabolism; Support, Non-U.S. Gov't; T-Lymphocytes :: microbiology; Virion; Nature. 2003 Mar 20;422 (6929):307-12 12646921 (P,S,E,B) Cited:86

Antibody neutralization and escape by HIV-1.

Xiping Wei, Julie M Decker, Shuyi Wang, Huxiong Hui, John C Kappes, Xiaoyun Wu, Jesus F Salazar-Gonzalez, Maria G Salazar, J Michael Kilby, Michael S Saag, Natalia L Komarova, Martin A Nowak, Beatrice H Hahn, Peter D Kwong, George M Shaw Howard Hughes Medical Institute, University of Alabama at Birmingham, 720 South 20th Street, KAUL 816, Birmingham, Alabama 35294-0024, USA. Neutralizing antibodies (Nab) are a principal component of an effective human immune response to many pathogens, yet their role in HIV-1 infection is unclear. To gain a better understanding of this role, we examined plasma from patients with acute HIV infection. Here we report the detection of autologous Nab as early as 52 days after detection of HIV-specific antibodies. The viral inhibitory activity of Nab resulted in complete replacement of neutralization-sensitive virus by successive populations of resistant virus. Escape virus contained mutations in the env gene that were unexpectedly sparse, did not map generally to known neutralization epitopes, and involved primarily changes in N-linked glycosylation. This pattern of escape, and the exceptional density of HIV-1 envelope glycosylation generally, led us to postulate an evolving 'glycan shield' mechanism of neutralization escape whereby selected changes in glycan packing prevent Nab binding but not receptor binding. Direct support for this model was obtained by mutational substitution showing that Nab-selected alterations in glycosylation conferred escape from both autologous antibody and epitope-specific monoclonal antibodies. The evolving glycan shield thus represents a new mechanism contributing to HIV-1 persistence in the face of an evolving antibody repertoire. Mesh-terms: Amino Acid Sequence; Antibodies, Monoclonal :: immunology; Antibody Specificity; Antigens, CD4 :: immunology; Epitopes :: chemistry; Epitopes :: genetics; Epitopes :: immunology; Glycosylation; HIV Antibodies :: immunology; HIV Antigens :: chemistry; HIV Antigens :: genetics; HIV Antigens :: immunology; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: genetics; HIV Envelope Protein gp120 :: immunology; HIV Envelope Protein gp41 :: chemistry; HIV Envelope Protein gp41 :: genetics; HIV Envelope Protein gp41 :: immunology; HIV Infections :: immunology; HIV Infections :: virology; HIV-1 :: chemistry; HIV-1 :: genetics; HIV-1 :: immunology; HIV-1 :: physiology; Human; Humans; Immune Sera :: immunology; Models, Biological; Molecular Sequence Data; Mutagenesis; Neutralization Tests; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Time Factors; Nat Struct Biol. 1995 Dec ;2 (12):1075-82 8846219 (P,S,E,B) Cited:86

A trimeric structural domain of the HIV-1 transmembrane glycoprotein.

M Lu, S C Blacklow, P S Kim Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge 02142, USA. Infection with HIV-1 is initiated by fusion of cellular and viral membranes. The gp41 subunit of the HIV-1 envelope plays a major role in this process, but the structure of gp41 is unknown. We have identified a stable, proteinase-resistant structure comprising two peptides, N-51 and C-43, derived from a recombinant protein fragment of the gp41 ectodomain. In isolation, N-51 is predominantly aggregated and C-43 is unfolded. When mixed, however, these peptides associate to form a stable, alpha-helical, discrete trimer of heterodimers. Proteolysis experiments indicate that the relative orientation of the N-51 and C-43 helices in the complex is antiparallel. We propose that N-51 forms an interior, parallel, homotrimeric, coiled-coil core, against which three C-43 helices pack in an antiparallel fashion. We suggest that this alpha-helical, trimeric complex is the core of the fusion-competent state of the HIV-1 envelope. Mesh-terms: Amino Acid Sequence; Cloning, Molecular; Endopeptidases :: chemistry; Giant Cells :: chemistry; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: ultrastructure; HIV-1 :: chemistry; HIV-1 :: ultrastructure; Membrane Glycoproteins :: chemistry; Membrane Glycoproteins :: ultrastructure; Molecular Sequence Data; Molecular Weight; Peptides :: chemistry; Proline :: chemistry; Protein Conformation; Recombinant Proteins :: chemistry; Support, Non-U.S. Gov't; Viral Envelope Proteins :: chemistry; Viral Envelope Proteins :: ultrastructure; Proc Natl Acad Sci U S A. 1991 Apr 15;88 (8):3097-101 2014229 (P,S.E,B) Cited:83

Identification of a determinant within the human immunodeficiency virus 1 surface envelope glycoprotein critical for productive infection of primary monocytes.

P Westervelt, H E Gendelman, L Ratner Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110. Profound differences exist in the replicative capacities of various human immunodeficiency virus 1 isolates in primary human monocytes. To investigate the molecular basis for these differences, recombinant full-length clones were constructed by reciprocal DNA fragment exchange between a molecular clone derived from a monocyte-tropic isolate (ADA) and portions of two full-length clones incapable of infection or replication in primary monocyte cultures (HXB2 and NL4-3). Virions derived from proviral clones that contained ADA sequences encoding vpu and the N and C termini of the surface envelope glycoprotein (gp120) were incapable of replication in monocytes. However, a 283-base-pair ADA sequence encoding amino acids 240-333 of the mature gp120 protein conferred the capacity for high-level virus replication in primary monocytes. The predicted amino acid sequence of this ADA clone differed from NL4-3 and HXB2 at 22 of 94 residues in this portion of gp120, which includes the entire third variable domain. Only 2 of 11 residues implicated in CD4 binding are located in this region of gp120 and are identical in HXB2, NL4-3, and ADA. Alignment of the ADA sequence with published amino acid sequences of three additional monocyte-replicative and three monocyte-nonreplicative clones indicates 6 discrete residues with potential involvement in conferring productive human immunodeficiency virus 1 infection of primary monocytes. Mesh-terms: Amino Acid Sequence; Comparative Study; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: physiology; HIV-1 :: pathogenicity; Human; In Vitro; Molecular Sequence Data; Monocytes :: microbiology; Structure-Activity Relationship; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.; J Virol. 1995 Sep ;69 (9):5723-33 7543586 (P,S,E,B) Cited:75

Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding.

R Wyatt, J Moore, M Accola, E Desjardin, J Robinson, J Sodroski Division of Human Retrovirology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. The binding of human immunodeficiency virus type 1 (HIV-1) to the cellular receptor CD4 has been suggested to induce conformational changes in the viral envelope glycoproteins that promote virus entry. Conserved, discontinuous epitopes on the HIV-1 gp120 glycoprotein recognized by the 17b, 48d, and A32 antibodies are preferentially exposed upon the binding of soluble CD4 (sCD4). The binding of the 17b and 48d antibodies to the gp120 glycoprotein can also be enhanced by the binding of the A32 antibody. Here we constructed HIV-1 gp120 mutants in which the variable segments of the V1/V2 and V3 structures were deleted, individually or in combination, while the 17b, 48d, and A32 epitopes were retained. The effects of the variable loop deletions on the function of the HIV-1 envelope glycoproteins and on the exposure of epitopes induced by sCD4 or A32 binding to the monomeric gp120 glycoprotein were examined. The variable-loop-deleted envelope glycoproteins were able to mediate virus entry, albeit at lower efficiencies than those of the wild-type glycoproteins. Thus, the V1/V2 and V3 variable sequences contribute to the efficiency of HIV-1 entry but are not absolutely required for the process. Neither the V1/V2 nor V3 loops were necessary for the increase in exposure of the 17b/48d epitopes induced by binding of the A32 monoclonal antibody. By contrast, induction of the 17b, 48d, and A32 epitopes by sCD4 binding apparently involves a movement of the V1/V2 loops, which in the absence of CD4 partially mask these epitopes on the native gp120 monomer. The results obtained with a mutant glycoprotein containing a deletion of the V1 loop alone indicated that the contribution of the V2 loop to these phenomena was more significant than that of the V1 sequences. These results suggest that the V1/V2 loops, which have been previously implicated in CD4-modulated, postattachment steps in HIV-1 entry, contribute to CD4-induced gp120 conformational changes detected by the 17b, 48d, and A32 antibodies. Mesh-terms: Amino Acid Sequence; Animals; Antigens, CD4 :: chemistry; Antigens, CD4 :: metabolism; Cell Line; Cercopithecus aethiops; Comparative Study; Enzyme-Linked Immunosorbent Assay; Epitopes :: chemistry; Genes, env; HIV Envelope Protein gp120 :: chemistry; HIV Envelope Protein gp120 :: immunology; HIV Envelope Protein gp120 :: metabolism; HIV-1 :: metabolism; Kidney; Kinetics; Models, Structural; Molecular Sequence Data; Mutagenesis; Protein Structure, Secondary; Receptors, Virus :: chemistry; Receptors, Virus :: metabolism; Recombinant Proteins :: chemistry; Recombinant Proteins :: isolation & purification; Recombinant Proteins :: metabolism; Sequence Deletion; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Transfection; Microbiol Rev. 1993 Mar ;57 (1):183-289 8464405 (P,S,E,B) Cited:67

Pathogenesis of human immunodeficiency virus infection.

J A Levy Department of Medicine, University of California School of Medicine, San Francisco 94143-0128. The lentivirus human immunodeficiency virus (HIV) causes AIDS by interacting with a large number of different cells in the body and escaping the host immune response against it. HIV is transmitted primarily through blood and genital fluids and to newborn infants from infected mothers. The steps occurring in infection involve an interaction of HIV not only with the CD4 molecule on cells but also with other cellular receptors recently identified. Virus-cell fusion and HIV entry subsequently take place. Following virus infection, a variety of intracellular mechanisms determine the relative expression of viral regulatory and accessory genes leading to productive or latent infection. With CD4+ lymphocytes, HIV replication can cause syncytium formation and cell death; with other cells, such as macrophages, persistent infection can occur, creating reservoirs for the virus in many cells and tissues. HIV strains are highly heterogeneous, and certain biologic and serologic properties determined by specific genetic sequences can be linked to pathogenic pathways and resistance to the immune response. The host reaction against HIV, through neutralizing antibodies and particularly through strong cellular immune responses, can keep the virus suppressed for many years. Long-term survival appears to involve infection with a relatively low-virulence strain that remains sensitive to the immune response, particularly to control by CD8+ cell antiviral activity. Several therapeutic approaches have been attempted, and others are under investigation. Vaccine development has provided some encouraging results, but the observations indicate the major challenge of preventing infection by HIV. Ongoing research is necessary to find a solution to this devastating worldwide epidemic. Mesh-terms: Amino Acid Sequence; Animals; Body Fluids :: microbiology; Female; HIV :: genetics; HIV :: immunology; HIV :: physiology; HIV Envelope Protein gp120 :: chemistry; HIV Infections :: drug therapy; HIV Infections :: etiology; HIV Infections :: immunology; HIV Infections :: transmission; Human; Infant, Newborn; Molecular Sequence Data; Pan troglodytes; Peptide Fragments :: chemistry; Pregnancy; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Virion :: genetics; Virion :: ultrastructure; Virus Replication;