Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection with human immunodeficiency virus (HIV) results in progressive deterioration of the cell-mediated immune system characterized by T-helper-cell dysfunction and loss in the face of signs of generalized immune-system activation. The final stage of HIV disease, AIDS, has a myriad of opportunistic infections and malignancies as its hallmarks. The causal relationship between HIV and this complex disease pattern is clear but the mechanisms by which it occurs are not well understood. There are a number of new developments in our understanding of the natural history of HIV infection from a laboratory standpoint. Our review of this information raises further questions as to the validity of the conventional "cytopathic" model and all its direct descendants. In response to these conflicts, we have developed and present an alternative hypothesis in which AIDS pathogenesis, in all its manifestations, is seen as the outcome of one central process, excess immune activation generated by the interaction of virus with the CD4 receptor. The implications of this hypothesis on therapy of HIV infections are discussed.
 ...
PMID:The natural history and pathogenesis of HIV infection. 144 66

Transfection of the human CD4 molecule into mouse cells does not confer susceptibility to human immunodeficiency virus type 1 (HIV-1) infection. Expression of the human CD4 molecule in transgenic mice was seen to offer some new possibilities. However, transgenic mouse T cells expressing either the human CD4 receptor, or a hybrid human/mouse CD4 receptor alone or in conjunction with human major histocompatibility complex class I molecules, were refractory to in vitro HIV-1 infection. In addition, no infection was observed after in vivo HIV inoculation to mice of these various transgenic lines. Injection of recombinant gp160 viral protein to the transgenic mice did not alter their T and B cell populations. The existence of a dominant block in mouse cells that prevents HIV entry is discussed.
 ...
PMID:Expression of human CD4 in transgenic mice does not confer sensitivity to human immunodeficiency virus infection. 149 54

Anti-idiotypic antibodies were raised in rabbits against a panel of 11 murine mAb directed to the human CD4 receptor. Selection of mAb for vaccination was based on inhibition studies demonstrating that these mAb recognized CD4/V1 epitopes implicated in HIV-1-gp120 binding. Purified antisera showed high titer anti-Id activity and reacted specifically with Ag-combining site-related Id of the mAb used for their generation. Anti-Id either detected a private Id of the immunizing mAb or displayed a partial cross-reactivity with Id of other mAb to CD4. Eight anti-Id to six different mAb were shown to recognize determinants of recombinant HIV-1-gp120 or of HIV-1-gp160 as shown by ELISA and radioimmunoprecipitation assay. These anti-Id were capable of inhibiting HIV infection up to 100% in a MT-4 cell assay in vitro. In addition to neutralizing infectivity of cell-free virus, anti-Id to two mAb--the mAb IOT4a and 7.3F11--were also shown to inhibit HIV-induced syncytia formation up to 100%. Anti-Id to the mAb IOT4a, 7.3F11, and to the mAb anti-Leu3a interfered with rgp120 binding to cellular CD4 as assessed by flow cytometry. These results demonstrated that mAb specific for both CDR2- and CDR3-like regions of CD4 were capable of inducing HIV-1-gp120 cross-reacting anti-Id neutralizing HIV-1 in vitro. These studies may have implications for the development of a gp120 internal image based vaccine against HIV.
 ...
PMID:Neutralization of HIV-1 by anti-idiotypes to monoclonal anti-CD4. Potential for idiotype immunization against HIV. 150 Jul 24

The noncovalent association of the gp120 and gp41 envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) is disrupted by soluble CD4 binding, resulting in shedding of the gp120 exterior envelope glycoprotein. This observation has led to the speculation that interaction of gp120 with the CD4 receptor triggers shedding of the exterior envelope glycoprotein, allowing exposure of gp41 domains necessary for membrane fusion steps involved in virus entry or syncytium formation. To test this hypothesis, a set of HIV-1 envelope glycoprotein mutants were used to examine the relationship of soluble CD4-induced shedding of the gp120 glycoprotein to envelope glycoprotein function in syncytium formation and virus entry. All mutants with a threefold or greater reduction in CD4-binding ability exhibited marked decreases in gp120 shedding in response to soluble CD4, even though several of these mutants exhibited significant levels of envelope glycoprotein function. Conversely, most fusion-defective mutants with wild-type gp120-CD4 binding affinity, including those with changes in the V3 loop, efficiently shed gp120 following soluble CD4 binding. Thus, soluble CD4-induced shedding of gp120 is not a generally useful marker for conformational changes in the HIV-1 envelope glycoproteins necessary for the virus entry or syncytium formation processes. Some gp120 mutants, despite being expressed on the cell surface and capable of efficiently binding soluble CD4, exhibited decreased gp120 shedding. These mutants were still sensitive to neutralization by soluble CD4, indicating that, for envelope glycoproteins exhibiting high affinity for soluble CD4, competitive inhibition may be more important than gp120 shedding for the antiviral effect.
 ...
PMID:Lack of correlation between soluble CD4-induced shedding of the human immunodeficiency virus type 1 exterior envelope glycoprotein and subsequent membrane fusion events. 150 Dec 86

This summary describes current studies in antiviral targeting as reported at the Frontiers in HIV Therapy conference, November 3-7, 1991, in San Diego, California. In parallel with the progressive steps in HIV-1 replication, the meeting covered potential antiviral targets starting from the time HIV-1 docks with the CD4 receptor to virus release. The summary concludes with current research trends to block HIV-1 growth.
 ...
PMID:Frontiers in HIV-1 Therapy: fourth conference of the NIAID National Cooperative Drug Discovery Groups-HIV. 151 17

The replication cycle of human immunodeficiency virus type 1 (HIV-1) consists of four distinct stages, each of which can be targeted for specific antiviral chemotherapy. The stages are (1) the attachment of virus to the CD4 receptor at the cell surface; (2) the uncoating of viral nucleic acid and its conversion via viral reverse transcriptase activity to DNA; (3) cellular multiplication, accompanied by the replication of integrated proviral DNA and production of viral RNA and proteins; and (4) the assembly and liberation of progeny virus from the cell and the potential reinitiation of the replication cycle in previously uninfected cells. Since each of these steps represents a potential target for anti-HIV chemotherapy, it is apparent that the rationale for the use of antiviral drugs is not dissimilar from the manner in which antineoplastic agents are targeted to specific stages in the replication cycle of tumor cells. As in the case of anticancer chemotherapy, it is hoped that combinations of drugs, which act against different steps in the viral replication cycle, might have synergistic potential. AZT or zidovudine is the most widely used drug to date to impede the replication of HIV-1; it is significant that this compound was designed initially with anticancer chemotherapy in mind. Although AZT therapy has been reasonably successful, this drug has had important toxic side effects. As in the case of many cancer chemotherapeutic agents, drug resistance to AZT is likely to be an important problem, and there have been several reports of the isolation of drug-resistant variants of HIV-1.
 ...
PMID:Strategies in the treatment of AIDS and related diseases: the lessons of cancer chemotherapy. 155 Oct 24

The European collaborative study of HIV-infected pregnant women in Europe now indicates a 13% risk of fetal HIV infection (originally thought to be about 30%, and possibly higher in some countries). Several reports suggest trans-placental passage. However, the detailed mechanisms associated with such vertical transmission have not yet been clarified. We have examined the possibility that HIV enters placental tissue from maternal blood via binding to CD4 and Fc receptors (FcR) at the trophoblast level, allowing intraplacental infection. Here we report the detection of several FcR with distinct localization in the placental villus as well as CD4 surface expression on human trophoblast cells. In addition, we show that trophoblastic cells interact specifically with the gp120/gp160 viral envelope protein. By their tissue localization, these receptors could be responsible for the entry of HIV into the fetal placental cells. Furthermore, purified placental cells can be directly infected by HIV in vitro, and the infection is inhibited by soluble CD4. This suggests a crucial role of the CD4 receptor but an additional way of entry cannot be excluded. Such an in vitro model may be suitable for further studies concerning placental HIV transmission and its prevention.
 ...
PMID:Human trophoblast cells express CD4 and are permissive for productive infection with HIV-1. 156 94

The binding of HIV-1 envelope glycoprotein, gp120, to the CD4 receptor is an important step in productive infection. The development of agents which interrupt this binding phenomenon should be of therapeutic interest. The present study characterizes a whole cell gp120/CD4 radioligand binding assay (radioligand binding assay) modified for use in a high volume screening format. Modifications include the use of human CD4 receptor stably expressed in a Chinese hamster ovary cell line and the gentle fixation (paraformaldehyde) of the CD4 receptor just prior to assay. Binding of [125I]gp120 to fixed CD4 was of high affinity (KD = 6 nM), saturable, reversible, and specific. The kinetics of binding were identical to those of viable (non-fixed) CD4 receptor. [125I]gp120 binding was inhibited by unlabeled recombinant gp120, soluble CD4, and the anti-CD4 monoclonals OKT4A and LEU3A. A number of compounds reported to inhibit gp120 binding and/or gp120 induced syncytium formation were also active in this assay. This modified radioligand binding assay was developed to initiate a rational and extensive screening program to assist in the identification of potential chemotherapeutic agents based on their ability to inhibit gp120 binding to host cells.
 ...
PMID:Development and characterization of a whole-cell radioligand binding assay for [125I]gp120 of HIV-1. 156 13

Peptide T (H-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-OH), a fragment of HIV gp120, has been reported to inhibit binding of the virus to the CD4 receptor. The peptide assumes a beta-turn secondary structure, and stabilization of the conformation may increase the biological activity. We synthesized the octapeptide and its C-terminal pentapeptide fragment, unmodified and glycosylated, when monosaccharides were walked through the molecules. Incorporation of the sugar into the longer peptide resulted in the stabilization of the type I (III) beta-turn, as indicated by circular dichroism measurements. While N-terminal glycosylation of the shorter peptide also stabilized the type I (III) beta-turn, the circular dichroism spectra revealed slightly different type II beta-turn structures when the carbohydrate moiety was incorporated into mid-chain or C-terminal positions. Modification of biologically active reverse-turn structures by glycosylation offers a viable alternative to the peptide mimetics approach in drug design.
 ...
PMID:Chemical glycosylation of peptide T at natural and artificial glycosylation sites stabilizes or rearranges the dominant reverse turn structure. 157 31

Perinatal transmission of human immunodeficiency virus (HIV) from infected mothers to their children occurs at rates reported as 20-50%. The role of breast feeding in perinatal transmission of viral infections has not been well established. We studied 34 milk and colostral samples obtained from HIV-seropositive and HIV-seronegative women to determine if they contained anti-HIV activity. We found that all the samples contained a factor that inhibited the binding of HIV epitope-specific MAb to recombinant CD4 receptor molecules. The titers of inhibitory activity ranged from 1:200 to 1:10,000 and did not differ between HIV-seropositive and HIV-seronegative mothers. This milk factor also inhibited the binding of gp120 to CD4. Neither human sera nor bovine milk exhibited appreciable inhibitory activity. Fractionation of human milk indicated that the inhibitory activity was confined to the macromolecular fraction; little activity was found in isolated milk lipids or oligosaccharides. Chromatographic procedures indicated that the active macromolecule has an isoelectric point of 9.3-9.6. The active material did not bind to concanavalin A; however, the activity was partially destroyed by chemical and enzymatic treatments that removed sulfated residues. The active material may thus be a sulfated protein, glycoprotein, mucin, or glycosaminoglycan that inhibits the binding of CD4 to HIV envelope glycoproteins. The role of this factor in the natural history of HIV infection in infants and children should be the subject of additional investigations.
 ...
PMID:A human milk factor inhibits binding of human immunodeficiency virus to the CD4 receptor. 159 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>