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Virus isolates during acute and chronic human immunodeficiency virus type 1 infection show distinct patterns of sensitivity to entry inhibitors.

ABSTRACT: We studied the effect of entry inhibitors on 58 virus isolates derived during acute and chronic infection to validate these inhibitors in vitro and to probe whether viruses at early and chronic disease stages exhibit general differences in the interaction with entry receptors. We included members of all types of inhibitors currently identified: (i) agents that block gp120 binding to CD4 (CD4-IgG2 and monoclonal antibody [MAb] IgG1b12), (ii) compounds that block the interaction with CCR5 (the chemokine RANTES/CCL5, the small-molecule inhibitor AD101, and the anti-CCR5 antibody PRO 140), (iii) the fusion inhibitor enfuvirtide (T-20), and (iv) neutralizing antibodies directed against gp120 (MAb 2G12) and gp41 (MAbs 2F5 and 4E10). No differences between viruses from acute and chronic infections in the susceptibility to inhibitors targeting the CD4 binding site, CCR5, or fusion or to MAb 2G12 were apparent, rendering treatment with entry inhibitors feasible across disease stages. The notable exceptions were antibodies 2F5 and 4E10, which were more potent in inhibiting viruses from acute infection (P = 0.0088 and 0.0005, respectively), although epitopes of these MAbs were equally well preserved in both groups. Activities of these MAbs correlated significantly with each other, suggesting that common features of the viral envelope modulate their potencies.

SUBMITTER: Rusert P

PROVIDER: S-EPMC1143729 | biostudies-literature | 2005 Jul

REPOSITORIES: biostudies-literature

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Virus isolates during acute and chronic human immunodeficiency virus type 1 infection show distinct patterns of sensitivity to entry inhibitors.

Rusert Peter P Kuster Herbert H Joos Beda B Misselwitz Benjamin B Gujer Cornelia C Leemann Christine C Fischer Marek M Stiegler Gabriela G Katinger Hermann H Olson William C WC Weber Rainer R Aceto Leonardo L Günthard Huldrych F HF Trkola Alexandra A

Journal of virology 20050701 13

We studied the effect of entry inhibitors on 58 virus isolates derived during acute and chronic infection to validate these inhibitors in vitro and to probe whether viruses at early and chronic disease stages exhibit general differences in the interaction with entry receptors. We included members of all types of inhibitors currently identified: (i) agents that block gp120 binding to CD4 (CD4-IgG2 and monoclonal antibody [MAb] IgG1b12), (ii) compounds that block the interaction with CCR5 (the che ...[more]

PMID: 15956589

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Project description:Replication of human immunodeficiency virus type 1 (HIV-1) in diverse conditions limiting for viral entry into cells frequently leads to adaptive mutations in the V3 loop of the gp120 envelope glycoprotein. This has suggested that the V3 loop limits the efficiencies of HIV-1 infections, possibly by directly affecting gp120-coreceptor affinities. In contrast, V3 loop mutations that enable HIV-1(JR-CSF) to use the low-affinity mutant coreceptor CCR5(Y14N) are shown here to have negligible effects on the virus-coreceptor affinity but to dramatically accelerate the irreversible conformational conversion of the envelope gp41 subunits from a three-stranded coil into a six-helix bundle. This slow step is blocked irreversibly by the inhibitor T-20. To further evaluate the role of entry rates in controlling infection efficiencies and viral adaptations, we developed methods to quantitatively measure viral entry kinetics. The virions were adsorbed by spinoculation at 4 degrees C onto HeLa-CD4/CCR5 cell clones that either had limiting or saturating concentrations of CCR5. After warming to 37 degrees C, the completion of entry was monitored over time by the resistance of infections to the competitive CCR5 inhibitor TAK-779. Our results suggest that the efficiency of entry of cell-attached infectious HIV-1 is principally controlled by three kinetic processes. The first is a lag phase that is caused in part by the concentration-dependent reversible association of virus with CD4 and CCR5 to form an equilibrium assemblage of complexes. Second, this assembly step lowers but does not eliminate a large activation energy barrier for a rate-limiting, CCR5-dependent conformational change in gp41 that is sensitive to blockage by T-20. The rate of infection therefore depends on the fraction of infectious virions that are sufficiently saturated with CCR5 to undergo this conformational change and on the magnitude of the activation energy barrier. Although only a small fraction of fully assembled viral complexes overcome this barrier per hour, the ensuing steps of entry are rapidly completed within 5 to 10 min. Thus, this barrier limits the overall flow rate at which the attached virions enter cells, but it has no effect on the lag time that precedes this entry flow. Third, a relatively rapid and kinetically dominant process of viral inactivation, which may partly involve endocytosis, competes with infectious viral entry. Our results suggest that the V3 loop of gp120 has a major effect on the rate-limiting coreceptor-dependent conformational change in gp41 and that adaptive viral mutations, including V3 loop mutations, function kinetically by accelerating this inherently slow step in the entry pathway.

Project description:Respiratory syncytial virus (RSV) is a major respiratory pathogen of infants and young children. Multiple strains of both subgroup A and B viruses circulate during each seasonal epidemic. Genetic heterogeneity among RSV genomes, in large part due to the error prone RNA-dependent, RNA polymerase, could mediate variations in pathogenicity. We evaluated clinical strains of RSV for their ability to induce the innate immune response. Subgroup B viruses were used to infect human pulmonary epithelial cells (A549) and primary monocyte-derived human macrophages (MDM) from a variety of donors. Secretions of IL-6 and CCL5 (RANTES) from infected cells were measured following infection. Host and viral transcriptome expression were assessed using RNA-SEQ technology and the genomic sequences of several clinical isolates were determined. There were dramatic differences in the induction of IL-6 and CCL5 in both A549 cells and MDM infected with a variety of clinical isolates of RSV. Transcriptome analyses revealed that the pattern of innate immune activation in MDM was virus-specific and host-specific. Specifically, viruses that induced high levels of secreted IL-6 and CCL5 tended to induce cellular innate immune pathways whereas viruses that induced relatively low level of IL-6 or CCL5 did not induce or suppressed innate immune gene expression. Activation of the host innate immune response mapped to variations in the RSV G gene and the M2-1 gene. Viral transcriptome data indicated that there was a gradient of transcription across the RSV genome though in some strains, RSV G was the expressed in the highest amounts at late times post-infection. Clinical strains of RSV differ in cytokine/chemokine induction and in induction and suppression of host genes expression suggesting that these viruses may have inherent differences in virulence potential. Identification of the genetic elements responsible for these differences may lead to novel approaches to antiviral agents and vaccines.

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Virus isolates during acute and chronic human immunodeficiency virus type 1 infection show distinct patterns of sensitivity to entry inhibitors.

Publications

Virus isolates during acute and chronic human immunodeficiency virus type 1 infection show distinct patterns of sensitivity to entry inhibitors.

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