Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sulfated polyesters (SP) that inhibit HIV infection interact with both the gp120 binding region of CD4 molecules and with the v3 domain loop of gp120 molecules (gp120/v3) but the contributions of these interactions to the inhibition of HIV env-mediated fusion are presently unclear. In order to characterize the molecular mechanisms by which SP inhibit HIV env-mediated fusion, we studied the effect of SP treatment on env-mediated fusion of CD4+ cells driven by recombinant vaccinia virus (vPE-16) and on the binding of anti-HIV MAbs to cellular gp120 or purified, rgp120. SP were more effective than neutralizing anti-gp120/v3 MAbs in inhibiting env-mediated fusion. In addition, SP interacted with the v3 loop of gp120 to inhibit the binding of the neutralizing MAb 9284 but not the binding of 9305, a neutralizing anti-gp120/v3 MAb that binds to an adjacent epitope. Because SP are polyanions, we compared the chemical properties of the SP-gp120/v3 and SP-CD4 interactions. Whereas the ability of SP to inhibit the binding of MAb 9284 and rgp120 was relatively independent of NaCl concentrations, the ability of SP to interfere with rCD4-rgp120 binding depended on the NaCl concentration and was maximal at low NaCl concentrations. In addition, the SP-gp120 interaction was found to be reversible, in contrast to the SP-rCD4 interaction which was previously shown to be relatively irreversible at low salt. These data are consistent with the notions that the interaction of SP with CD4 is primarily electrostatic, but that the interaction of SP with gp120 has complex characteristics that implicate a role for protein conformation.
AIDS Res Hum Retroviruses 1992 Sep
PMID:Sulfated polyester interactions with the CD4 molecule and with the third variable loop domain (v3) of gp120 are chemically distinct. 145 6

Mutations within the principal neutralizing determinant (the V3 loop) of the HIV-1 surface envelope glycoprotein gp120 block or greatly reduce the ability of the HIV-1 envelope glycoprotein to induce cell fusion in CD4+ HeLa T4 cells while keeping its CD4 binding ability. However, when either cysteine or both cysteines forming the V3 disulfide bridge were mutated, the resultant glycoprotein could not mediate cell fusion, undergo proteolytic processing, or bind CD4. To investigate the role that the V3 loop plays in gp160 processing and CD4 binding, we deleted the entire V3 loop region of the HIV-1 env gene. The resultant glycoprotein could not mediate cell fusion in the HeLa T4 cell line and no proteolytic processing of gp160 or CD4 binding could be detected. To test whether any domain of the V3 loop is involved in attaining the proper envelope glycoprotein conformation required for proteolytic processing and CD4 binding, we introduced a series of deletions into the coding region of the V3 loop. Most of the residues within the V3 loop could be removed while retaining gp160 processing and CD4 binding. Our results indicate that the cysteines that form the V3 loop or the disulfide bond itself are important for proper envelope glycoprotein folding and processing. Because many of the mutants constructed in this study do not contain the type-specific neutralizing determinant of HIV-1, they may be potential reagents to bind group-specific neutralizing antibodies or to elicit a group-specific neutralizing response against HIV-1.
AIDS Res Hum Retroviruses 1992 Sep
PMID:Studies on the role of the V3 loop in human immunodeficiency virus type 1 envelope glycoprotein function. 145 7

HIV-2ALT is a highly divergent HIV-2-related isolate that is genetically equidistant to the prototypic HIV-2 strains, defined by HIV-2ROD, and to the simian immunodeficiency viruses SIVmac and SIVsm. We have now cloned and sequenced the envelope region of HIV-2ALT, thus completing the analysis of the whole viral genome. The sequences of env and nef and of the second exons of tat and rev were compared with those of the other viruses of the HIV-2/SIVsm/SIVmac group. Despite of the high degree of variation of HIV-2ALT, functional domains of the genes are conserved. Although in env, the overall pattern of constant and variable domains is maintained, many single amino acid exchanges exist at positions previously thought to be constant in HIV-2 strains. In addition, when compared with a broader spectrum of immunodeficiency viruses, which includes SIVMND from mandrill and SIVAGM from African green monkey, HIV-2ALT Env has a high percentage of amino acid exchanges, which are unique to this strain. This underlines the separate branch of HIV-2ALT within the phylogenetic tree and makes obvious the inclusion of such divergent strains in preventive and therapeutic programs.
AIDS Res Hum Retroviruses 1992 Sep
PMID:Analysis of the envelope region of the highly divergent HIV-2ALT isolate extends the known range of variability within the primate immunodeficiency viruses. 145 8

Infectious HIV-1 particles containing replication-defective vectors that express the hygromycin B phosphotransferase gene were generated by transient complementation in COS-1 cells. A defective vector dependent only on trans-complementation with an env gene and a small vector containing a deletion of almost all of the trans region were used to examine pseudotyping of HIV-1 by an amphotropic murine retrovirus. Although pseudotyping by the heterologous envelope glycoprotein occurred with efficiency, no pseudotyping at the RNA level was observed. Genetic complementation was used to rapidly analyze the effect of env mutations in the V3, proteolytic processing site, fusion domain, and cytoplasmic tail on viral infectivity. Mutations decreasing syncytium formation usually also lowered infectivity. However, a mutation in the cytoplasmic tail and a separate mutation adjacent to the fusion domain dramatically decreased viral particle infectivity but did not appreciably decrease envelope glycoprotein-mediated cell-to-cell fusion. These results may indicate that these regions of the transmembrane peptide are necessary for acquisition of envelope glycoprotein by budding virus particles or for virus entry.
AIDS Res Hum Retroviruses 1992 Sep
PMID:Analysis of HIV-1 envelope mutants and pseudotyping of replication-defective HIV-1 vectors by genetic complementation. 145 11

The lysis of infected host cells by virus-specific cytolytic T lymphocytes (CTL) is an important factor in host resistance to viral infection. An optimal vaccine against human immunodeficiency virus type 1 (HIV-1) would elicit virus-specific CTL as well as neutralizing antibodies. The induction by a vaccine of HIV-1-specific CD8+ CTL in humans has not been previously reported. In this study, CTL responses were evaluated in HIV-1-seronegative human volunteers participating in a phase I acquired immune deficiency syndrome (AIDS) vaccine trial involving a novel vaccine regimen. Volunteers received an initial immunization with a live recombinant vaccinia virus vector carrying the HIV-1 env gene and a subsequent boost with purified env protein. An exceptionally strong env-specific CTL response was detected in one of two vaccine recipients, while modest but significant env-specific CTL activity was present in the second vaccinee. Cloning of the responding CTL gave both CD4+ and CD8+ env-specific CTL clones, permitting a detailed comparison of critical functional properties of these two types of CTL. In particular, the potential antiviral effects of these CTL were evaluated in an in vitro system involving HIV-1 infection of cultures of normal autologous CD4+ lymphoblasts. At extremely low effector-to-target ratios, vaccine-induced CD8+ CTL clones lysed productively infected cells present within these cultures. When tested for lytic activity against target cells expressing the HIV-1 env gene, CD8+ CTL were 3-10-fold more active on a per cell basis than CD4+ CTL. However, when tested against autologous CD4+ lymphoblasts acutely infected with HIV-1, CD4+ clones lysed a much higher fraction of the target cell population than did CD8+ CTL. CD4+ CTL were shown to recognize not only the infected cells within these acutely infected cultures but also noninfected CD4+ T cells that had passively taken up gp120 shed from infected cells and/or free virions. These results were confirmed in studies in which CD4+ lymphoblasts were exposed to recombinant gp120 and used as targets for gp120-specific CD4+ and CD8+ CTL clones. gp120-pulsed, noninfected targets were lysed in an antigen-specific fashion by CD4+ but not CD8+ CTL clones. Taken together, these observations demonstrate that in an in vitro HIV-1 infection, sufficient amounts of gp120 antigen are produced and shed by infected cells to enable uptake by cells that are not yet infected, resulting in the lysis of these noninfected cells by gp120-specific, CD4+ CTL.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Comparative clonal analysis of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ and CD8+ cytolytic T lymphocytes isolated from seronegative humans immunized with candidate HIV-1 vaccines. 146 Apr 17

Serosurveys conducted prior to 1988 indicated a very low level of HIV-1 infection in Thailand, even among high-risk groups. The Ministry of Health has reported a dramatic increase in HIV-1 infection during the last three years. The geographic and demographic distribution of the epidemic is broad, involving multiple provinces and risk groups. Foci of higher incidence and prevalence have been noted in the urban center of Bangkok and in the northern provinces of Chiang Mai and Chiang Rai. Here we report the results of genetic characterization of 16 HIV-1 isolates from Thailand using a combination of polymerase chain reaction (PCR) typing and DNA sequencing. The complete sequence of gp160 (env) of five isolates, partial env sequence of six additional isolates, and the gag gene of two isolates were determined. Two highly distinct HIV-1 variants were found. One variant resembled those prevalent in North America and Europe; five of the isolates were of this type. The remaining eleven isolates were very similar to one another and represented a variant unlike any previously described. Phylogenetic tree analysis of complete env and gag genes placed the two variants on widely separated branches. Protein sequence comparisons indicate both general and specific features that distinguish the Northern Thailand variant both from the Bangkok variant and from virtually all previously sequenced HIV-1 isolates. A simple PCR test for distinguishing the two variants has been developed for use in epidemiologic surveys.
AIDS Res Hum Retroviruses 1992 Nov
PMID:Genetic variants of HIV-1 in Thailand. 148 77

Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Encoded by the HIV genome are several precursor proteins that undergo proteolytic cleavage to yield functional proteins. The env precursor protein is cleaved by a cellular protease. The gag precursor protein of HIV (p55), however, is cleaved by a virally encoded aspartate protease (HIV Protease). Cleavage of p55 is required for viral maturation and infectivity. There are also several host cell aspartate proteases that serve important homeostatic functions. Cathepsins D and E are lysosomal aspartate proteases which are believed to play an important role in macrophage function, and it has been suggested that inhibition of these enzymes by an HIV protease inhibitor may exacerbate immunosuppression in AIDS patients. We have studied the effect of SK&F 107461 (a hydroxyethylene dipeptide isostere inhibitor of HIV protease), on various host defense functions of human monocytes. Pepstatin A (an inhibitor of most aspartate proteases) and leupeptin (an inhibitor of serine and cysteine proteases) were included as controls. Although less potent than the prototypic aspartate protease inhibitor pepstatin, SK&F 107461 inhibited partially purified cathepsin D in vitro. However, in cell-based assays, SK&F 107461 had no effect on the degradation of hemoglobin, antigen processing of the protein antigen streptokinase, or secretion of 17-kD IL-1 beta by monocytes at concentrations which inhibit maturation of intracellular virus in HIV infected monocytes. Furthermore, SK&F 107461 had no effect on constitutive candidacidal activity. In contrast, leupeptin and pepstatin A partially inhibited accessory cell function of monocytes in the proliferative response to the recall antigen streptokinase. In addition, leupeptin partially inhibited degradation of hemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)
AIDS Res Hum Retroviruses 1992 Dec
PMID:Effect of a human immunodeficiency virus protease inhibitor on human monocyte function. 149 45

Human immunodeficiency virus type 1 (HIV-1), the agent of AIDS, frequently infects the central nervous system. We inoculated adult human brain cultures with chimeric viruses containing parts of the env gene of a cloned primary isolate from brain tissue, HIV-1 JRFl, inserted into the cloned DNA of a T-cell-tropic strain. A chimeric virus containing the carboxy-terminal portion of HIV-1 JRFl env did not replicate in these brain tissue cultures, while a chimera expressing an env-encoded protein containing 158 amino acids of HIV-1 JRFl gp120, including the V3 loop, replicated well in brain microglial cells, as it does in blood macrophages. Infection of brain microglial cells with such a chimera was blocked by an antibody to the V3 loop of gp 120. Thus, env determinants in the region of gp120, outside the CD4-binding site and comprising the V3 loop, are critical for efficient viral binding to and/or entry into human brain microglia.
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PMID:Human immunodeficiency virus type 1 tropism for brain microglial cells is determined by a region of the env glycoprotein that also controls macrophage tropism. 154 85

The generation of biologically active proviral DNA clones of simian immunodeficiency virus (SIV) that give rise to infectious virions has allowed the detailed examination of genetic variation in experimentally inoculated monkeys. Studies of nucleotide sequences derived directly from circulating leukocytes of infected monkeys show that the SIV genome undergoes rapid and dramatic variation during the course of infection. The env gene is a major site for variation, and within the Env protein, hypervariable regions analogous to those previously defined for the human immunodeficiency virus type 1 (HIV-1) env gene are apparent. A major exception is the region corresponding to the V3 domain in HIV-1, which has been highly conserved in all SIV studies to date. These data notwithstanding, the role of SIV genetic variation in the pathogenesis of AIDS in monkeys remains unclear. Genetic variation within the env gene does not appear to be sufficient for the development of AIDS since significant variation is observed in both pathogenic and nonpathogenic SIV infections. Furthermore, although it generally is believed that env gene variation might allow HIV and SIV to avoid recognition and elimination by host immune responses, this premise has not been rigorously proven. The use of molecularly cloned SIV in monkey models has provided important quantitative and qualitative information on in vivo sequence variation, and these data, in turn, have laid the groundwork for addressing the undoubtedly complex functional significance of this variation.
AIDS Res Hum Retroviruses 1992 Mar
PMID:Genetic variation of simian immunodeficiency viruses in nonhuman primates. 157 Nov 96

Simian immunodeficiency virus (SIV) is a designation for a group of related but unique lentiviruses identified in several primate species. A viral isolate from a rhesus macaque (i.e., SIVmac) causes a fatal AIDS-like disease in experimentally infected macaques, and several infectious molecular clones of this virus have been characterized. This report presents the complete nucleotide sequence of molecularly cloned SIVmac1A11, and comparisons are made with the sequence of molecularly cloned SIVmac239. SIVmac1A11 has delayed replication kinetics in lymphoid cells but replicates as well as uncloned SIVmac in macrophage cultures. Macaques infected with virus from the SIVmac1A11 clone develop antiviral antibodies, but virus does not persist in peripheral blood mononuclear cells and no disease signs are observed. SIVmac239 infects lymphoid cells, shows restricted replication in cultured macrophages, and establishes a persistent infection in animals that leads to a fatal AIDS-like disease. Both viruses are about 98% homologous at the nucleotide sequence level. In SIVmac1A11, the vpr gene as well as the transmembrane domain of env are prematurely truncated, whereas the nef gene of SIVmac239 is prematurely truncated. Sequence differences are also noted in variable region 1 (V1) in the surface domain of the env gene. The potential implications of these and other sequence differences are discussed with respect to the phenotypes of both viruses. This animal model is critically important for investigating the roles of specific viral genes in viral/host interactions that cannot be studied in individuals infected with the human immunodeficiency virus (HIV).
AIDS Res Hum Retroviruses 1992 Mar
PMID:Genetic and biological comparisons of pathogenic and nonpathogenic molecular clones of simian immunodeficiency virus (SIVmac). 157 Nov 98


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