Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) plays a major role in the down-regulation of its receptor, CD4. This down-regulation, at least in part, is caused by the formation of gp160-CD4 intracellular complexes which fail to transport out of the endoplasmic reticulum (ER). In this report, we have evaluated the ability of envelope glycoproteins from various isolates to block CD4 transport within the endoplasmic reticulum. Using a recombinant vaccinia virus expression system in HeLa cells, we expressed different HIV-1 and HIV-2 envelope glycoproteins with CD4. Pulse-chase labeling followed by immunoprecipitation demonstrated that envelope glycoproteins from primary and lab-adapted isolates were capable of forming intracellular complexes with CD4, resulting in the partial inhibition of CD4 transport to the Golgi. Although the efficiency of CD4 modulation was variable, these differences did not correlate with the type of isolate from which the HIV-1 glycoprotein was derived. However, we did find that the HIV-2 ST envelope glycoprotein (gp150) was not as efficient at blocking CD4 as the glycoprotein (gp140) derived from HIV-2 ROD. The decreased ability of ST gp150 to block CD4 within the ER was associated with an increased efficiency of ST gp150 transport and cleavage. Thus, differences in the ability of HIV envelope glycoproteins to block CD4 transport do exist, and these differences may be determined by envelope glycoprotein transport kinetics.
 ...
PMID:Receptor interference mediated by the envelope glycoproteins of various HIV-1 and HIV-2 isolates. 889 48

We evaluated the cytotoxic effects of various human immunodeficiency virus (HIV-1) reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, stavudine, and nevirapine) on HIV-1-infected and uninfected T cell lines. Among the compounds, only stavudine (not the others) proved to be more cytotoxic to MOLT-4/IIIB cells (MOLT-4 cells chronically infected with HIV-1) than to uninfected MOLT-4 cells. Its 50% cytotoxic concentrations were 59.8 and 2.2 microM for MOLT-4 and MOLT-4/IIIB cells, respectively. Stavudine was also more cytotoxic to CEM/ROD (CEM cells chronically infected with HIV type 2) than to uninfected CEM cells. Microscopic analysis revealed that stavudine induced apoptosis in MOLT-4/IIIB cells. Apparent chromatin condensation in the nucleus was observed by electron microscopy. Furthermore, a DNA fragmentation ladder was detected by agarose gel electrophoresis. Addition of thymidine to the culture medium could rescue the cells from stavudine-induced apoptosis. The expression of anti-apoptotic protein Bcl-2 was partially downregulated in MOLT-4/IIIB cells after treatment with stavudine. This downregulation was not identified in MOLT-4 cells. These results indicate that stavudine selectively induces apoptosis in HIV-1-infected T cells and may have potential as a novel strategy for effective chemotherapy of the acquired immune deficiency syndrome (AIDS).
 ...
PMID:Stavudine selectively induces apoptosis in HIV type 1-infected cells. 900 5

A clade B strain of human immunodeficiency virus type 1 (HIV-1(LAI)) could infect CD4+ cells expressing human CXCR-4 (fusin) or its rat homolog with similar efficacy. By contrast, cells expressing rat CXCR-4 were not permissive to HIV-1(NDK) (clade D), HIV-2(ROD), or HIV-1(LAI) with chimeric envelope protein gp120 bearing the V3 domain from HIV-1(NDK). The reciprocal chimeric gp120 (HIV-1(NDK) with V3 from HIV-1(LAI)) could mediate infection of cells expressing either human or rat CXCR-4. Genetically divergent HIV strains have different requirements for interaction with the CXCR-4 coreceptor, and the gp120 V3 domain seems to be involved in this interaction.
 ...
PMID:Human immunodeficiency virus strains differ in their ability to infect CD4+ cells expressing the rat homolog of CXCR-4 (fusin). 906 Jun 91

The human immunodeficiency virus type 2 (HIV-2) strain ROD/B can efficiently use the 7tm chemokine receptor CXCR-4 as a primary receptor to enter CD4-negative cells. We have stably expressed CXCR-4 on mink lung Mv-1-lu and feline kidney CCC cells (normally restrictive to HIV entry) and have shown efficient fusion, entry, and replication of ROD/B. Mutation of the two N-linked glycosylation sites on CXCR-4 (N11-->I, and N176-->Q) or pretreatment of CCC or Mv-1-lu cells expressing wild-type CXCR-4 with the glycosylation inhibitor tunicamycin increased fusion and entry by ROD/B. Deletion of portions of the N terminus of CXCR-4 resulted in a 3- to 10-fold decrease in cell-free infection by ROD/B and complete inhibition of cell-cell fusion by both ROD/B and another HIV-2 strain, CBL23. These data suggest that the N-terminal domain of CXCR-4 is involved in but is not essential for the efficient fusion of ROD/B with CD4-negative cells. Deletion of the C-terminal (intracellular) domain of CXCR-4 did not significantly affect entry by ROD/B, indicating that intracellular signalling through this domain does not play a significant role in entry by HIV-2.
 ...
PMID:CD4-independent infection by human immunodeficiency virus type 2 strain ROD/B: the role of the N-terminal domain of CXCR-4 in fusion and entry. 915 32

The CXCR-4 chemokine receptor and CD4 behave as coreceptors for cell line-adapted human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and for dual-tropic HIV strains, which also use the CCR-5 coreceptor. The cell line-adapted HIV-1 strains LAI and NDK and the dual-tropic HIV-2 strain ROD were able to infect CD4+ cells expressing human CXCR-4, while only LAI was able to infect cells expressing the rat homolog of CXCR-4. This strain selectivity was addressed by using human-rat CXCR-4 chimeras. All chimeras tested mediated LAI infection, but only those containing the third extracellular domain (e3) of human CXCR-4 mediated NDK and ROD infection. The e3 domain might be required for the functional interaction of NDK and ROD, but not LAI, with CXCR-4. Alternatively, LAI might also interact with e3 but in a different way. Monoclonal antibody 12G5, raised against human CXCR-4, did not stain cells expressing rat CXCR-4. Chimeric human-rat CXCR-4 allowed us to map the 12G5 epitope in the e3 domain. The ability of 12G5 to neutralize infection by certain HIV-1 and HIV-2 strains is also consistent with the role of e3 in the coreceptor activity of CXCR-4. The deletion of most of the amino-terminal extracellular domain (e1) abolished the coreceptor activity of human CXCR-4 for ROD and NDK but not for LAI. These results indicate that HIV strains have different requirements for their interaction with CXCR-4. They also suggest differences in the interaction of dual-tropic HIV with CCR-5 and CXCR-4.
 ...
PMID:Role of the first and third extracellular domains of CXCR-4 in human immunodeficiency virus coreceptor activity. 915 68

A stretch of purine residues, the polypurine tract (PPT), is found in all retroviruses and is used to initiate plus-strand DNA synthesis. While the PPT of most lentiviruses is a homogeneous sequence of purine residues, the PPT of some isolates of the human and simian immunodeficiency viruses is interrupted with a single pyrimidine residue. The ROD strain of human immunodeficiency virus type 2 (HIV-2) has such a pyrimidine-containing variant PPT. Virus generated from an infectious molecular clone, pROD10, was used to infect two CD4-positive T-cell lines, H9 and CEM. The sequence of the PPT was determined after two passages. From both cell lines, the variant PPT was retained, demonstrating that the presence of a pyrimidine in the PPT was fully functional and that there was no strong selection for an all-purine PPT.
 ...
PMID:Maintenance of an unusual polypurine tract in HIV-2: stability to passage in culture. 929 33

The effects of the C-C chemokines RANTES (regulation upon activation normal T-cell expressed and secreted) and MCP-3 (monocyte chemotactic protein 3) on human immunodeficiency virus (HIV) replication in normal human peripheral blood mononuclear cells (PBMC) activated in vitro with phytohemagglutinin (PHA) were investigated. The following T-cell line-tropic (T-tropic) HIV strains were tested: HIV type 1 (HIV-1) SF-2, HIV-1 IIIB, HIV-1 MN, HIV-1 NDK, HIV-1 HE, HIV-1 NL4-3, HIV-2 ROD, and HIV-2 EHO. The strain most sensitive to the antiviral effects of RANTES and MCP-3 appeared to be HIV-1 SF-2. A 50% inhibitory concentration for HIV-1 SF-2 of 4 ng of RANTES per ml was obtained, and that of MCP-3 was about 1 ng/ml. However, MCP-3 was inactive at 100 ng/ml. Other HIV-1 strains, such as MN and HE, were less sensitive to the antiviral effects of RANTES and MCP-3, whereas all the other HIV strains tested were insensitive. Although the ratio of CD3+ CD4+ to CD3+ CD8+ T cells was the same in HIV-infected PBMC cultures treated or untreated with the chemokines, RANTES and MCP-3 interfered with the binding of monoclonal antibody (MAb) OKT4 to the CD4 receptor on T cells but not with the binding of MAb OKT4A. Therefore, RANTES and MCP-3 not only interfere with the HIV-induced fusion process but also have some modulating effect on the CD4 cell receptor. The chemokines did not affect HIV-1 binding to PHA-stimulated PBMC. Taken together, our observations point to the important role that both RANTES and MCP-3 may play in inhibiting HIV-1 replication of certain T-tropic strains in primary PBMC cultures. This may have important implications for immunotherapeutic strategies designed to slow down disease progression in AIDS.
 ...
PMID:RANTES and MCP-3 inhibit the replication of T-cell-tropic human immunodeficiency virus type 1 strains (SF-2, MN, and HE). 931 6

We investigated the early interactions between HIV-1, HIV-2, and simian immunodeficiency virus (SIV) envelope glycoproteins gp120(IIIB), gp105(ROD), and gp120(mac251), and human and macaque cells of the lymphocytic series. Our results demonstrate that the soluble viral glycoproteins induce a specific phospholipase A2 (PLA2) activation in lymphocytes through CD4. This PLA2 activation was induced after envelope glycoprotein-CD4 interaction and, because of its local membrane-destabilizing effect, may have important implications for preparing the lymphocyte membrane for fusion with the viral particle. However, this effect is not sufficient to accomplish fusion. These data indicate that the specific step of fusion may be downstream from PLA2 activation.
 ...
PMID:HIV and SIV envelope glycoproteins induce phospholipase A2 activation in human and macaque lymphocytes. 937 18

We have previously reported on the generation of specific functional immune responses after inoculation of animals with expression vectors encoding HIV-1 genes. This article provides the details of the first application of this new technology to induce immune responses against HIV-2. This virus is molecularly and serologically distinct from HIV-1 and is in fact more closely related to the simian immunodeficiency virus (SIV). Anti-HIV-2 and SIV antibodies were induced in mice of three different haplotypes following a single intramuscular inoculation with an HIV-2/ROD envelope glycoprotein expression vector (pcEnv-2). Boosting of animals with pcEnv-2 induced both anti-HIV-2 neutralizing antibodies and T cell-proliferative responses against HIV-2 and SIVmac proteins. We compared the humoral and cellular immune responses of mice injected with pcEnv-2 and then boosted with either the homologous DNA construct or a recombinant Env protein. Animals boosted with pcEnv-2 generated B and T cell immune responses as strong as those of mice boosted with recombinant gp140 protein in adjuvant. Finally, cellular immune responses were significantly increased with the coadministration of pcEnv-2 and a plasmid expressing interleukin 12. We therefore conclude that DNA plasmid inoculation induces cross-reactive anti-HIV-2 and anti-SIVmac immune responses in mice. This technology should be further investigated as a potential vaccine component for this human pathogen.
 ...
PMID:An HIV type 2 DNA vaccine induces cross-reactive immune responses against HIV type 2 and SIV. 943 Feb 48

We report the development of a new group of nonnucleoside reverse transcriptase inhibitors (NNRTIs). One of the most active congeners of this series of 1,1,3-trioxo-2H,4H-thieno[3,4-e] [1,2,4]thiadiazine (TTD) derivatives, i.e., 2-(3-fluorobenzyl)-4-cyanomethylen-l,1,3-trioxo-2H,4H- thieno [3,4-e] [1,2,4] thiadiazine) (QM96639) was found to inhibit human immunodeficiency virus (HIV) type 1 [HIV-1 (IIIB)] replication in MT-4 cells at a concentration of 0.09 microM. This compound was toxic for the host cells only at a 1,400-fold higher concentration. The TTD derivatives proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3'-deoxythymidine (AZT), but not against HIV-2 (ROD) or simian immunodeficiency virus (SIV/ MAC251). HIV-1 strains containing the L100I, K103N, V106A, E138K, Y181C, or Y188H mutations in their reverse transcriptase (RT) displayed reduced sensitivity to the compounds. Their cross-resistance patterns correlated with that of nevirapine. 2-Benzyl-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e] [1,2,4]thiadiazine (QM96521) enhanced the anti-HIV-1 activity of AZT and didanosine in a subsynergistic manner. HIV-1-resistant virus containing the V179D mutation in the RT was selected after approximately six passages of HIV-1 (IIIB) in CEM cells in the presence of different concentrations of QM96521. From structure-activity relationship analysis of a wide variety of TTD derivatives, a number of restrictions appeared as to the chemical modifications that were compatible with anti-HIV activity. Modelling studies suggest that in contrast to most other NNRTIs, but akin to nevirapine, QM96521 does not act as a hydrogen bond donor in the RT-drug complex.
 ...
PMID:1,1,3-Trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (TTD) derivatives: a new class of nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors with anti-HIV-1 activity. 951 42


<< Previous 1 2 3 4 5 6 Next >>