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J C Chermann

Publications and source records attributed to J C Chermann.

At least 37 records · Page 2Linked to original sources
PubMed1998

Sexual and mother-to-child transmission of the human immunodeficiency virus type 1: a review.

PROBLEM: Sexual and mother-to-child transmission of the human immunodeficiency virus (HIV) type 1 occurs only with a low percentage of infection. Many instances of sexual intercourse result in no transmission, and only 20% of children are infected from seropositive mothers (3% in mothers treated with azidothymidine). METHOD OF STUDY: We analyzed the presence of HIV in various ejaculates of the same HIV-infected patients, as well as in the cervico-vaginal fluid. We have studied the mechanism of transmission from mother to child, by analyzing the cell-to-cell transmission in the trophoblast. RESULTS: Some ejaculates collected at different times from the same HIV-infected males are free of virus, explaining the low rate of sexual transmission. We never found HIV in mobile spermatozoa. The trophoblast can be infected by HIV with a strain dependence and also transiently. By analyzing the tissue of the fetus, it was found that only some organs are infected, confirming the cell-to-cell transmission between the mother and child and not a true vertical transmission through the germinal lines. CONCLUSIONS: HIV is not always present in the genital secretion, explaining the low rate of sexual transmission. Mother-to-child transmission occurs during pregnancy but often after the second trimester and at delivery after cell-to-cell or blood transmission, respectively.

Female↗
PubMed1998

Design, synthesis and structure relationships of new N,N',N",N"'-tetrakis (omega-amino alkyl) tetraazamacrocycles.

A number of N,N',N",N"'-tetrakis (omega-aminoalkyl) tetraazamacrocycles and related compounds were synthesized and evaluated for their inhibitory effects on human immunodeficiency virus type 1 (HIV-1) and duck hepatitis B virus (DHBV) replication. The activity of these compounds was found to be highly dependent upon structural features: (i) the length of the alkyl linker connecting the nitrogen atoms of the macrocyclic ring to the exocyclic nitrogen atoms of the terminal amino groups (five methylenes favoured antiviral activity); (ii) substitution of the terminal amino groups of the linker reduced antiviral activity; and (iii) the size of the tetraazamacrocyclic ring (14 or 15 atoms) did not markedly affect the antiviral activity. Some analogues were potent inhibitors of HIV-1 replication, with anti-HIV activity similar to that of biscyclam (JM 2763). In contrast, other analogues were found to be highly toxic in duck hepatocyte primary culture, the 2.2.15 cell line and to a lesser extent in MT-4 cells. Structural parameters, macrocyclic ring size and metal-chelating ability have been used to develop a structure-activity relationship model in order to aid the design of antiviral molecules derived from N,N',N",N"'-tetrakis (omega-aminoalkyl) tetraazamacrocycles.

Animals↗
PubMed1997

Circulating cell adhesion molecules in HIV1-infected patients as indicator markers for AIDS progression.

Cell adhesion molecules play an important role during immune responses. Circulating (c) forms of these molecules have been used as monitors of disease progression. In this study, we have investigated serum levels of ICAM1, ICAM2, ICAM3 and VCAM1 in HIV-infected patients. Our results showed that levels of cICAMs and cVCAM1 are increased during HIV infection. Among an HIV-infected population, the cICAM2 level was higher in the asymptomatic group compared to the AIDS group. In contrast, the cICAM1 level was higher in the AIDS group compared to the asymptomatic group. No difference between the two groups was observed in cICAM3 and cVCAM1 levels. A significant correlation was found between cICAM1, cICAM2 and cVCAM1 in both populations. We also showed that the cICAM1/cICAM2 ratio was correlated with the increase in the c beta 2 microglobulin level and the decrease in CD4 T-cell counts in the AIDS group. These results indicate that serum cCAM1 and cICAM2 in HIV infection could be additional markers to discriminate between asymptomatic and progressor patients.

Acquired Immunodeficiency Syndrome↗
PubMed1997

In vitro study of Seraspenide on HIV-induced inhibition of granulopoiesis.

Soluble(s) factor(s) produced by HIV-infected cells have been implicated in bone marrow dysfunction observed in AIDS patients. We have shown previously that infected macrophage but not CBMC-derived conditioned medium inhibited the differentiation of purified CD34+ cells, suggesting that accessory cells play a crucial role in granulopoiesis inhibition induced indirectly by HIV. In order to prevent this inhibition we tested the potential protective effect of Seraspenide, a reversible inhibitor of hematopoietic progenitors. We showed that 20 h pretreatment of mononuclear cells with Seraspenide at 10(-10) mol/l prevents CFU-GM inhibition induced by HIV-infected cell-derived conditioned medium.

Antigens, CD34↗
PubMed1997

Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals.

Human immunodeficiency virus type 1 (HIV-1) genomes present in peripheral blood mononuclear cells (PBMCs) of infected persons or in lymphocytes infected in vitro were studied by long-distance PCR (LD-PCR) using primers localized in the HIV-1 long terminal repeats. The full-length 9-kb DNA was the only LD-PCR product obtained in peripheral and cord blood lymphocytes from seronegative donors infected in vitro. However, a high proportion (27% to 66%) of distinct populations of extensively deleted HIV-1 genomes of variable size was detected in PBMCs of 15 of 16 HIV-1-infected persons. Physical mapping of defective genomes showed that the frequency of deletions is proportional to their proximity to the central part of HIV-1 genome, which is consistent with a deletion mechanism involving a single polymerase jump during reverse transcription. Sequencing of deletion junctions revealed the presence of short direct repeats of three or four nucleotides. The number of defective HIV-1 genomes decreased after in vitro activation of PBMCs. Persistence of full-length and deleted genomes in in vitro activated PBMCs correlated with isolation of an infectious virus. Our results represent the first quantitative assessment of intragenomic rearrangements in HIV-1 genomes in PBMCs of infected persons and demonstrate that, in contrast to in vitro infection, defective genomes accumulate in PBMCs of infected persons.

Adult↗
PubMed1997

[Study of HIV localization in sperm].

The aim of the study was to investigate the presence and the localization of HIV in human ejaculate and its different components. Sixty-three ejaculates from 19 HIV-positive patients have been studied. By using cellular as well as molecular biology methods, we never detected HIV in living and mobile spermatozoa although we sometime found the virus in seminal liquid and in nuclear fractions. Up to date, frozen sperms free of HIV particles from 11 HIV-positive male partners were used to inseminate safely and with success the 11 HIV-negative female partners (no female partner as well as babies contamination). In conclusion, our procedure of HIV-free spermatozoa screening allowed discordant couples to have HIV-negative descendants. In contrast to the natural coïtus in ovulated period or to insemination with washed spermatozoa that are really "Russian roulette", our procedure ensure a total security of no contamination for the pregnant mother.

Adult↗
PubMed1996

Genetic control of infection of primary macrophages with T-cell-tropic strains of HIV-1.

Human immunodeficiency virus type 1 (HIV-1) NDK, a Zairian subtype D virus highly cytopathic for CD4-positive lymphocytes, and the prototype subtype B virus HIV-1 LAV are about 10(4) and 10(5) times more infectious, respectively, for T lymphocytes than for blood-derived macrophages (BDM). Recombinant viruses derived from HIV-1 LAV and HIV-1 NDK were used to determine the genetic control and the step of the virus/cell cycle responsible for infection of BDM with T-cell-tropic viruses. We found that recombinants bearing the envelope glycoprotein of HIV-1 NDK are able to enter more efficiently into BDM than recombinants with HIV-1 LAV envelope glycoprotein. We also found that a genetic region outside of the env gene is responsible for production of HIV-1 NDK infectious progeny from BDM. This region consists of the vif gene and the C- and N-terminal portions of pol and vpr genes, respectively. Our results suggest that productive infection of primary macrophages with T-cell-tropic strains of HIV-1 is determined by two different genetic mechanisms: one effective at the virus/cell entry, controlled by the env gene, and the second after entry, controlled by genes vif and vpr. In comparison with HIV-1 LAV, HIV-1 NDK has been able to more easily overcome both restriction mechanisms.

Cell Line↗
PubMed1995

Interface peptides as structure-based human immunodeficiency virus reverse transcriptase inhibitors.

Reverse transcriptases from both human immunodeficiency viruses type 1 and 2 are obligatory dimers. A tryptophan-rich repeat motif that is highly conserved between these proteins, as well as in the reverse transcriptase from simian immunodeficiency virus, has been postulated to be involved in hydrophobic subunit interactions. A synthetic 19-mer peptide covering part of this tryptophan repeat motif was recently shown to inhibit human immunodeficiency viruses type 1 reverse transcriptase subunit dimerization (Divita, G., Restle, T., Goody, R. S., Chermann, J.-C., and Baillon, J. G. (1994) J. Biol. Chem. 269, 13080-13083). In the present study, we show that the same peptide can also inhibit human immunodeficiency virus type 2 reverse transcriptase subunit dimerization, suggesting that the same inhibitors might be used as agents against both viruses as well as against variants of human immunodeficiency virus type 1 that differ from the variant against which they were developed. Under appropriate experimental conditions, e.g. at acidic pH, this peptide is also able to induce the dissociation of the enzyme from human immunodeficiency virus type 1.

Amino Acid Sequence↗
PubMed1995

Fusogenic determinants of highly cytopathic subtype D Zairian isolate HIV-1 NDK.

Phenotypic characterization of subtype B strains of human immunodeficiency virus type 1 (HIV-1) indicates that the major determinants of their cytopathogenicity and tropism are contained in the gene coding for the envelope glycoprotein gp120, namely in its variable regions V1, V2, and V3. Recombinant viruses derived from HIV-1 LAV, the subtype B prototype virus, and HIV-1 NDK, the Zairian subtype D virus highly cytopathic for CD4-positive lymphocytes, were used to elucidate genetic control of fusogenic functions in subtype D viruses. Our data demonstrate that multigenic determination of fusogenic properties is more complex in the subtype D than in clade B viruses. Variability in three regions of HIV-1 NDK genome correlated with formation of large syncytia. These regions consisted of the matrix protein, the C-terminal portion of vpr up to the C1 region of gp120, and the V1-V3 regions of gp120. Variability in the envelope glycoprotein but not in other regions of the HIV-1 genome was related to enhanced resistance of HIV-1 NDK to treatment of target cells with OKT4-A anti-CD4 MAb. Therefore, a different genetic control affects two aspects of HIV-1 fusogenicity: (i) variability in the envelope glycoprotein itself is sufficient to influence a virus-to-cell fusion at the virus/cell entry, and (ii) a more complex genetic function including genes of matrix protein and envelope glycoprotein is related to variability of cell-to-cell fusion during formation of syncytium.

Antibodies, Monoclonal↗
PubMed1995

Neutralizing antibodies against highly cytopathic Zairian human immunodeficiency type-1 virus (HIV-1) NDK are present in sera outside Africa.

The prototype virus HIV-1 LAV and highly cytopathic Zairian virus HIV-1 NDK belong to the genetic subtypes B and D and represent low and highly cytopathic phenotypes, respectively. Their neutralization pattern and serotype were studied with respect to differences in their genotypes and phenotypes. Sera from HIV-1-infected persons living in four geographically distant areas, Philadelphia (USA), Ribeirao Preto (Brazil), Marseille (France) and Kinshasa (Zaire), were tested for the presence of type-specific and group-specific cross-reacting neutralizing antibodies against HIV-1 LAV and HIV-1 NDK in a continuous cell line MT4. The majority of type-specific antibodies were directed against HIV-1 LAV in Philadelphia, Ribeirao Preto and Marseille, and against HIV-1 NDK in Kinshasa. However, some sera with an HIV-1 NDK type-specific neutralization pattern were also found in Philadelphia, Ribeirao Preto and Marseille. These results indicate that strains with an HIV-1 NDK-like serotype could be found outside Africa. The presence of type-specific neutralizing antibodies against HIV-1 NDK in sera from North and South America and Europe should be taken into account during attempts to serotype HIV as well as in the course of selection of HIV-1 candidate strains for an AIDS vaccine.

Amino Acid Sequence↗
PubMed1995

Lectin-mediated effects on HIV type 1 infection in vitro.

Lectins with specificity for terminal mannose residues and anti-mannan antibodies neutralize HIV-1 infection in vitro. This is assumed to be caused by binding of the agents to the viral glycoproteins. In this study we show that one such agent, the Galanthus nivalis lectin (GNA), also blocks infection at the target cell level. To explore the effect of GNA on HIV infection we used the two HIV-1 isolates LAV and NDK, representing in the first case a prototype virus and in the latter case a highly cytopathic virus, which spreads preferentially via cell-to-cell contact. MT-4 cells were used as target cells and infection was determined from the occurrence of syncytia. Cell-to-cell infection was studied with CEM cells persistently infected with the two virus isolates. GNA, at concentrations in the nanogram per milliliter range, neutralized the HIV-1 isolates LAV, NDK, and MN as well as HIV-2ROD. Pretreatment of cells with the lectin, before addition of virus, or of infected cells, also blocked infection. This effect was more pronounced with HIV-1NDK than with HIV-1LAV. Mannosidase treatment of the target cells abolished the GNA effect on HIV-1NDK infection. It is concluded that GNA inhibits infection of several HIV isolates. It neutralizes infection by binding to the virion but also blocks infection at the target cell level. The latter effect may be different for different virus isolates. Mannosyl residuals at the cell surface are targets for GNA modulation of infection with the cytopathic HIV-1NDK. These do not represent essential virus receptors.

Antiviral Agents↗
PubMed1995

HIV Tat protein potentiates in vitro granulomonocytic progenitor cell growth.

The direct involvement of hematopoietic progenitor cells in AIDS which results in dysregulated hematopoiesis, probably due to regulatory factors yet to be determined, has been reported by us and others. In this study we demonstrate that the HIV-2 Tat gene product is released in supernatant of HIV-2-infected long-term bone marrow cultures (LTBMC). These Tat-containing supernatants specifically enhanced growth of CFU-GM in agar culture system and this promoting activity was specifically neutralized with anti-Tat antibodies. The use of different recombinant Tat proteins confirmed that Tat has been responsible for enhanced in vitro growth of CFU-GM after HIV-2 infection of LTBMC. Moreover, limiting dilution analysis showed that Tat acts directly on the CD34+ cell population in which it increases the frequency of IL3-responding cells.

Antigens, CD↗
PubMed1994

Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate- and phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates.

The synthesis of potential "combined prodrugs" where phosphonoformic acid (PFA) or phosphonoacetic acid (PAA) was attached to the 5'-O or N4 position of 2',3'-dideoxy-3'-thiacytidine (BCH-189) is described. The anti-HIV-1 activity of 11 analogues which included carboxylic ester or phosphoric ester linkages of PFA or PAA to BCH-189 was determined in MT-4 cells. Of these compounds, the IC50 of analogues 3, 4, 6, and 7 ranged from 0.2 to 100 microM, while IC50 for BCH-189 in this system was 0.1 microM. In vitro hydrolysis of the various esters or amides in human plasma indicated that these agents were relatively stable in the presence of plasma esterases with t1/2 values of up to 120 min. Moreover, lipophilicity of these compounds (partition coefficient) was determined in order to establish correlation between lipophilicity and diffusion of BCH-189 analogues into the cells. The active compounds may exert their effects by extracellular or intracellular hydrolysis to the corresponding antiviral agent BCH-189, but intrinsic anti-HIV-1 activity of some of PAA and PFA adducts, themselves, may also be involved.

Antiviral Agents↗
PubMed1994

Lectin effects on HIV-1 infectivity.

Lectins with specificity for terminal mannose residues and anti-mannan antibodies are assumed to neutralize HIV-1 by binding to the viral glycoproteins. In this report we demonstrate that one such agents, the lectin from Galanthus nivalis (GNA), blocks infection also at the target cell level.

Carbohydrate Sequence↗
PubMed1994

Inhibition of human immunodeficiency virus type 1 reverse transcriptase dimerization using synthetic peptides derived from the connection domain.

Based on presently available information on the structure of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, peptides have been synthesized which correspond to the sequence of a particular region of the protein involved in formation of the active heterodimeric form of the enzyme. Several peptides that are 15-19 amino acids long and that are derived from the so-called connection domain of the reverse transcriptase are able to inhibit dimerization of the enzyme and thus inhibit development of its enzymatic activities. In particular, a tryptophan-rich 19-mer corresponding to residues 389-407 was relatively efficient, showing an apparent dissociation constant in the micromolar range for one or both of the subunits. The sequence of this region is identical for both subunits, since one (molecular mass of 51 kDa) is the proteolytic product of the other (molecular mass of 66 kDa). Dissociation of the preformed heterodimer could not be induced by the peptides, but increasing concentrations reduced the rate of dimerization in a concentration-dependent manner until it became immeasurable at high concentrations. The results suggest that inhibition of dimerization of reverse transcriptase is an attractive approach to chemotherapeutic intervention in HIV infection and that further development of peptide-based inhibition strategies is worth pursuing.

Amino Acid Sequence↗
PubMed1994

Synthesis and antiviral activity of new carbonylphosphonate 2',3'-dideoxy-3'-thiacytidine conjugates.

The synthesis of new potential PFA-BCH-189 conjugate analogues is described and their molecular structure clearly identified through NMR and mass spectra techniques. The anti-HIV-1 activity was determined according to the inhibition of syncytium formation in MT-4 cells, while the anti-HBV activity was determined in infected duck hepatocytes. Both antiviral activities of the PFA-BCH-189 conjugates were much lower than those of the parent BCH-189 (2',3'-dideoxy-3'-thiacytidine) (1). Whereas a prodrug effect, following cleavage and release of the free BCH-189 and PFA, cannot be ruled out, poor cellular permeation of the drug seems to be the most likely reason for the reduced activities against HIV and DHBV. The presence of the PFA moiety appears to be detrimental for both the anti-HIV and anti-DHBV activity of PFA-BCH-189 cases.

Animals↗
PubMed1994

Humoral response in rabbits immunized with calcium phosphate adjuvanted HIV-1 gp160 antigen.

Rabbits were immunized with either calcium phosphate adjuvanted purified HIV-1 gp160 or a fluid preparation. Circulating antibodies were detected by ELISA, RIPA and Western Blot tests. Sera of rabbits immunized with the adjuvanted preparation contained high levels of anti-gp160 antibodies, as well as antibodies recognizing p55, p25 and p18. On the contrary, rabbits immunized with the fluid preparation contained only anti-p18 antibodies. Neutralizing antibodies were also detected. It is concluded that the calcium phosphate adjuvant could be used for preparation of candidate anti-HIV vaccines, since it permits one to induce high levels of circulating antibodies, in the absence of untoward reactions as observed when aluminium adjuvants or water in oil emulsions are used.

Animals↗