scholarly journals Increased Neutralization Sensitivity and Reduced Replicative Capacity of Human Immunodeficiency Virus Type 1 after Short-Term In Vivo or In Vitro Passage through Chimpanzees

2000 ◽  
Vol 74 (17) ◽  
pp. 7699-7707 ◽  
Author(s):  
Tim Beaumont ◽  
Silvia Broersen ◽  
Ad van Nuenen ◽  
Han G. Huisman ◽  
Ana-Maria de Roda Husman ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Short Term ◽  
Neutralization Sensitivity ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Development of disease is extremely rare in chimpanzees when inoculated with either T-cell-line-adapted neutralization-sensitive or primary human immunodeficiency virus type 1 (HIV-1), at first excluding a role for HIV-1 neutralization sensitivity in the clinical course of infection. Interestingly, we observed that short-term in vivo and in vitro passage of primary HIV-1 isolates through chimpanzee peripheral blood mononuclear cells (PBMC) resulted in a neutralization-sensitive phenotype. Furthermore, an HIV-1 variant reisolated from a chimpanzee 10 years after experimental infection was still sensitive to neutralization by soluble CD4, the CD4 binding site recognizing antibody IgG1b12 and autologous chimpanzee serum samples, but had become relatively resistant to neutralization by polyclonal human sera and neutralizing monoclonal antibodies. The initial adaptation of HIV-1 to replicate in chimpanzee PBMC seemed to coincide with a selection for viruses with low replicative kinetics. Neither coreceptor usage nor the expression level of CD4, CCR5, or CXCR4 on chimpanzee PBMC compared to human cells could explain the phenotypic changes observed in these chimpanzee-passaged viruses. Our data suggest that the increased neutralization sensitivity of HIV-1 after replication in chimpanzee cells may in part contribute to the long-term asymptomatic HIV-1 infection in experimentally infected chimpanzees.

scholarly journals Separation of Human Immunodeficiency Virus Type 1 Replication from nef-Mediated Pathogenesis in the Human Thymus

2001 ◽  
Vol 75 (8) ◽  
pp. 3916-3924 ◽  
Author(s):  
Karen M. Duus ◽  
Eric D. Miller ◽  
Jonathan A. Smith ◽  
Grigoriy I. Kovalev ◽  
Lishan Su
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
In Vivo Model ◽  
Immunodeficiency Virus ◽  
Pathogenic Activity ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) is frequently attenuated after long-term culture in vitro. The attenuation process probably involves mutations of functions required for replication and pathogenicity in vivo. Analysis of attenuated HIV-1 for replication and pathogenicity in vivo will help to define these functions. In this study, we examined the pathogenicity of an attenuated HIV-1 isolate in a laboratory worker accidentally exposed to a laboratory-adapted HIV-1 isolate. Using heterochimeric SCID-hu Thy/Liv mice as an in vivo model, we previously defined HIV-1 env determinants (HXB/LW) that reverted to replicate in vivo (L. Su, H. Kaneshima, M. L. Bonyhadi, R. Lee, J. Auten, A. Wolf, B. Du, L. Rabin, B. H. Hahn, E. Terwilliger, and J. M. McCune, Virology 227:46–52, 1997). Here we further demonstrate that HIV-1 replication in vivo can be separated from its pathogenic activity, in that the HXB/LW virus replicated to high levels in SCID-hu Thy/Liv mice, with no significant thymocyte depletion. Restoration of the nef gene in the recombinant HXB/LW genome restored its pathogenic activity, with no significant effect on HIV-1 replication in the thymus. Our results suggest that in vitro-attenuated HIV-1 lacks determinants for pathogenicity as well as for replication in vivo. Our data indicate that (i) the replication defect can be recovered in vivo by mutations in the envgene, without an associated pathogenic phenotype, and (ii)nef can function in the HXB/LW clone as a pathogenic factor that does not enhance HIV-1 replication in the thymus. Furthermore, the HXB/LW virus may be used to study mechanisms of HIV-1nef-mediated pathogenesis in vivo.

scholarly journals How Many Human Immunodeficiency Virus Type 1-Infected Target Cells Can a Cytotoxic T-Lymphocyte Kill?

2005 ◽  
Vol 79 (21) ◽  
pp. 13579-13586 ◽  
Author(s):  
W. David Wick ◽  
Otto O. Yang ◽  
Lawrence Corey ◽  
Steven G. Self
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Target Cells ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT The antiviral role of CD8+ cytotoxic T lymphocytes (CTLs) in human immunodeficiency virus type 1 (HIV-1) infection is poorly understood. Specifically, the degree to which CTLs reduce viral replication by killing HIV-1-infected cells in vivo is not known. Here we employ mathematical models of the infection process and CTL action to estimate the rate that CTLs can kill HIV-1-infected cells from in vitro and in vivo data. Our estimates, which are surprisingly consistent considering the disparities between the two experimental systems, demonstrate that on average CTLs can kill from 0.7 to 3 infected target cells per day, with the variability in this figure due to epitope specificity or other factors. These results are compatible with the observed decline in viremia after primary infection being primarily a consequence of CTL activity and have interesting implications for vaccine design.

scholarly journals TRIM5 genotypes in cynomolgus monkeys primarily influence inter-individual diversity in susceptibility to monkey-tropic human immunodeficiency virus type 1

2013 ◽  
Vol 94 (6) ◽  
pp. 1318-1324 ◽  
Author(s):  
Akatsuki Saito ◽  
Masako Nomaguchi ◽  
Ken Kono ◽  
Yasumasa Iwatani ◽  
Masaru Yokoyama ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cynomolgus Monkeys ◽  
Gene Variation ◽  
Immunodeficiency Virus ◽  
Hiv 1

TRIM5α restricts human immunodeficiency virus type 1 (HIV-1) infection in cynomolgus monkey (CM) cells. We previously reported that a TRIMCyp allele expressing TRIM5–cyclophilin A fusion protein was frequently found in CMs. Here, we examined the influence of TRIM5 gene variation on the susceptibility of CMs to a monkey-tropic HIV-1 derivative (HIV-1mt) and found that TRIMCyp homozygotes were highly susceptible to HIV-1mt not only in vitro but also in vivo. These results provide important insights into the inter-individual differences in susceptibility of macaques to HIV-1mt.

scholarly journals Viral Entry through CXCR4 Is a Pathogenic Factor and Therapeutic Target in Human Immunodeficiency Virus Type 1 Disease

2000 ◽  
Vol 74 (1) ◽  
pp. 184-192 ◽  
Author(s):  
Birgit Schramm ◽  
Michael L. Penn ◽  
Roberto F. Speck ◽  
Stephen Y. Chan ◽  
Erik De Clercq ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Disease Progression ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Lymphoid Tissues ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The chemokine receptors CCR5 and CXCR4 function as the principal coreceptors for human immunodeficiency virus type 1 (HIV-1). Coreceptor function has also been demonstrated for a variety of related receptors in vitro. The relative contributions of CCR5, CXCR4, and other putative coreceptors to HIV-1 disease in vivo have yet to be defined. In this study, we used sequential primary isolates and recombinant strains of HIV-1 to demonstrate that CXCR4-using (X4) viruses emerging in association with disease progression are highly pathogenic in ex vivo lymphoid tissues compared to CXCR4-independent viruses. Furthermore, synthetic receptor antagonists that specifically block CXCR4-mediated entry dramatically suppressed the depletion of CD4+ T cells by recombinant and clinically derived X4 HIV-1 isolates. Moreover, in vitro specificity for the additional coreceptors CCR3, CCR8, BOB, and Bonzo did not augment cytopathicity or diminish sensitivity toward CXCR4 antagonists in lymphoid tissues. These data provide strong evidence to support the concept that adaptation to CXCR4 specificity in vivo accelerates HIV-1 disease progression. Thus, therapeutic intervention targeting the interaction of HIV-1 gp120 with CXCR4 may be highly valuable for suppressing the pathogenic effects of late-stage viruses.

scholarly journals Autoantibodies directed against CD43 molecules with an altered glycosylation status on human immunodeficiency virus type 1 (HIV-1)- infected CEM cells are found in all HIV-1+ individuals

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2302-2311 ◽  
Author(s):  
V Giordanengo ◽  
M Limouse ◽  
L Desroys du Roure ◽  
J Cottalorda ◽  
A Doglio ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Autoimmune Response ◽  
Immunodeficiency Virus ◽  
Altered Glycosylation ◽  
Hiv 1

Autoantibodies to lymphocytes have been detected in sera from human immunodeficiency virus type 1 (HIV-1)-infected individuals, and several autoantigens have been described. Among them, hyposialylated CD43 has been shown to be a target for autoantibodies in up to 47% of HIV+ individuals. However, the corresponding autoantigen (ie, the incompletely sialylated CD43) has not been isolated from blood cells of HIV-1-infected individuals. Recently, we have observed in vitro that HIV-1 productively or latently infected CEM cells (CEMLAI/NP) express CD43 molecules with modified glycosylation (mogly CD43). Using CEMLAI/NP cells, which do not express any structural viral antigen, we show now that all of the tested HIV+ sera from asymptomatic individuals, and up to 86% of those from subjects at the acquired immunodeficiency syndrome stage contain antibodies (mainly IgM and, to a lesser degree, IgG) that recognize the surface of CEMLAI/NP cells, and precipitate mogly CD43 molecules from the cells lysates. Taken together with our previous demonstration of altered glycosylation of CD43 from HIV-1-infected CEM cells in vitro, the constant antimogly CD43 autoimmune response observed from asymptomatic HIV-1+ subjects is likely to illustrate the occurrence of an altered glycosylation in vivo of the major lymphocyte surface CD43 glycoprotein, associated with HIV- 1 infection.

scholarly journals Functional Interactions of Human Immunodeficiency Virus Type 1 Integrase with Human and Yeast HSP60

2001 ◽  
Vol 75 (23) ◽  
pp. 11344-11353 ◽  
Author(s):  
Vincent Parissi ◽  
Christina Calmels ◽  
Vaea Richard De Soultrait ◽  
Anne Caumont ◽  
Michel Fournier ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nuclear Genome ◽  
Cellular Proteins ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Integration of human immunodeficiency virus type 1 (HIV-1) proviral DNA in the nuclear genome is catalyzed by the retroviral integrase (IN). In addition to IN, viral and cellular proteins associated in the high-molecular-weight preintegration complex have been suggested to be involved in this process. In an attempt to define host factors interacting with IN, we used an in vitro system to identify cellular proteins in interaction with HIV-1 IN. The yeast Saccharomyces cerevisiae was chosen since (i) its complete sequence has been established and the primary structure of all the putative proteins from this eucaryote has been deduced, (ii) there is a significant degree of homology between human and yeast proteins, and (iii) we have previously shown that the expression of HIV-1 IN in yeast induces a lethal phenotype. Strong evidences suggest that this lethality is linked to IN activity in infected human cells where integration requires the cleavage of genomic DNA. Using IN-affinity chromatography we identified four yeast proteins interacting with HIV-1 IN, including the yeast chaperonin yHSP60, which is the counterpart of human hHSP60. Yeast lethality induced by HIV-1 IN was abolished when a mutated HSP60 was coexpressed, therefore suggesting that both proteins interact in vivo. Besides interacting with HIV-1 IN, the hHSP60 was able to stimulate the in vitro processing and joining activities of IN and protected this enzyme from thermal denaturation. In addition, the functional human HSP60-HSP10 complex in the presence of ATP was able to recognize the HIV-1 IN as a substrate.

scholarly journals Coupled Integration of Human Immunodeficiency Virus Type 1 cDNA Ends by Purified Integrase In Vitro: Stimulation by the Viral Nucleocapsid Protein

1999 ◽  
Vol 73 (8) ◽  
pp. 6670-6679 ◽  
Author(s):  
Sandrine Carteau ◽  
Robert J. Gorelick ◽  
Frederic D. Bushman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
New Class ◽  
Immunodeficiency Virus ◽  
Viral Nucleocapsid ◽  
Hiv 1

ABSTRACT Integration of retroviral cDNA involves coupled joining of the two ends of the viral genome at precisely spaced positions in the host cell DNA. Correct coupled joining is essential for viral replication, as shown, for example, by the finding that viral mutants defective in coupled joining are defective in integration and replication. To date, reactions with purified human immunodeficiency virus type 1 (HIV-1) integrase protein in vitro have supported mainly uncoupled joining of single cDNA ends. We have analyzed an activity stimulating coupled joining present in HIV-1 virions, which led to the finding that the HIV-1 nucleocapsid (NC) protein can stimulate coupled joining more than 1,000-fold under some conditions. The requirements for stimulating coupled joining were investigated in assays with mutant NC proteins, revealing that mutations in the zinc finger domains can influence stimulation of integration. These findings (i) provide a means for assembling more authentic integrase complexes for mechanistic studies, (ii) reveal a new activity of NC protein in vitro, (iii) indicate a possible role for NC in vivo, and (iv) provide a possible method for identifying a new class of inhibitors that disrupt coupled joining.

scholarly journals Characterization of a Highly Replicative Intergroup M/O Human Immunodeficiency Virus Type 1 Recombinant Isolated from a Cameroonian Patient

1999 ◽  
Vol 73 (9) ◽  
pp. 7368-7375 ◽  
Author(s):  
Martine Peeters ◽  
Florian Liegeois ◽  
Ndongo Torimiro ◽  
Anke Bourgeois ◽  
Eitel Mpoudi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Antiviral Treatment ◽  
Biological Properties ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A Cameroonian patient with antibodies reacting simultaneously to human immunodeficiency virus type 1 (HIV-1) group O- and group M-specific V3-loop peptides was identified. In order to confirm that this patient was coinfected with both viruses, PCRs with O- and M-specific discriminating primers corresponding to different regions of the genome were carried out with both primary lymphocyte DNA and the corresponding viral strains isolated from three consecutive patient samples. The PCR data suggested that this patient is coinfected with a group M virus and a recombinant M/O virus. Indeed, only type Mgag sequences could be amplified, while for theenv region, both type M and O sequences were amplified, from plasma or from DNA extracted from primary lymphocytes. Sequence analysis of a complete recombinant genome isolated from the second sample (97CA-MP645 virus isolate) revealed two intergroup breakpoints, one in the vpr gene and the second in the long terminal repeat region around the TATA box. Comparison of the type M sequences shared by the group M and the recombinant M/O viruses showed that these sequences were closely related, with only 3% genetic distance, suggesting that the M virus was one of the parental viruses. In this report we describe for the first time a recombination event in vivo between viruses belonging to two different groups, leading to a replicative virus. Recombination between strains with such distant lineages (65% overall homology) may contribute substantially to the emergence of new HIV-1 variants. We documented that this virus replicates well and became predominant in vitro. At this time, group O viruses represent a minority of the strains responsible for the HIV-1 pandemic. If such recombinant intergroup viruses gained better fitness, inducing changes in their biological properties compared to the parental group O virus, the prevalences of group O sequences could increase rapidly. This will have important implications for diagnosis of HIV-1 infections by serological and molecular tests, as well as for antiviral treatment.

scholarly journals The Role of Pr55gag in the Annealing of tRNA3Lys to Human Immunodeficiency Virus Type 1 Genomic RNA

1999 ◽  
Vol 73 (5) ◽  
pp. 4485-4488 ◽  
Author(s):  
Shan Cen ◽  
Yue Huang ◽  
Ahmad Khorchid ◽  
Jean-Luc Darlix ◽  
Mark A. Wainberg ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Primer Binding Site ◽  
Genomic Rna ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT During human immunodeficiency virus type 1 (HIV-1) assembly, the primer tRNA for the reverse transcriptase-catalyzed synthesis of minus-strand strong-stop cDNA, tRNA3 Lys, is selectively packaged into the virus and annealed onto the primer binding site on the RNA genome. Annealing of tRNA3 Lys in HIV-1 is independent of polyprotein processing and is facilitated in vitro by p7 nucleocapsid (NCp7). We have previously shown that mutations in clusters of basic amino acids flanking the first Cys-His box in NC sequence inhibit annealing of tRNA3 Lys in vivo by 70 to 80%. In this report, we have investigated whether these NC mutations act through Pr55 gag or Pr160 gag-pol . In vivo placement of tRNA3 Lys is measured with total viral RNA as the source of primer tRNA-template in an in vitro reverse transcription assay. Cotransfection of COS cells with a plasmid coding for either mutant Pr55 gag or mutant Pr160 gag-pol , and with a plasmid containing HIV-1 proviral DNA, shows that only the NC mutations in Pr55 gag inhibit tRNA3 Lysplacement. The NC mutations in Pr55 gag reduce viral infectivity by 95% and are trans-dominant-negative, i.e., they inhibit genomic placement of tRNA3 Lys even in the presence of wild-type Pr55 gag . This dominant phenotype may indicate that the mutant Pr55 gag is disrupting an ordered Pr55 gag structure responsible for the annealing of tRNA3 Lys to genomic RNA.

Sign in / Sign up

Export Citation Format

Share Document