Reversal of Human Immunodeficiency Virus Type 1 IIIB to a Neutralization-Resistant Phenotype in an Accidentally Infected Laboratory Worker with a Progressive Clinical Course

Beaumont, Tim; Nuenen, A. van; Broersen, S.; Blattner, William A.; Lukashov, Vladimir V.; Schuitemaker, Hanneke

doi:10.1128/jvi.75.5.2246-2252.2001

Cited by 72 publications

(45 citation statements)

References 65 publications

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“…SIV MAC Δvpr viruses rapidly revert to a WT version when injected in rhesus macaques (14). A similar reversion has been observed in a laboratory worker accidentally contaminated with a vpr-deficient strain of HIV-1 (15,16). Several studies also reported mutations in the vpr gene in long-term nonprogressor (LTNP) patients (17)(18)(19)(20).…”

mentioning

confidence: 57%

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks. Vpr subverts the DDB1-cullin4-associatedfactor 1 (DCAF1) adaptor of the Cul4A ubiquitin ligase to trigger proteasomal degradation of HLTF. This event takes place rapidly after Vpr delivery to cells, before and independently of Vpr-mediated G2 arrest. HLTF is degraded in lymphocytic cells and macrophages infected with Vpr-expressing HIV-1. Our results reveal a previously unidentified strategy for HIV-1 to antagonize DNA repair in host cells.HIV | restriction factor | DNA repair | Vpr target | SILAC

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mentioning

confidence: 57%

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Experiments on immune selection and changes in neutralization phenotypes in HIV-1-infected patients are generally complicated by the lack of knowledge of the infecting viral strain and time of infection and by the low levels of in vitro serum antibody neutralization characteristic of primary HIV-1 neutralization. However, a recent study did characterize the neutralization phenotypes of two HIV-1 IIIB variants that were isolated from a laboratory worker accidentally infected with the neutralization-sensitive HIV-1 IIIB strain (2). Compared to the original virus in the viral inoculum, the viral isolates displayed an increased resistance to neutralization over time.…”

Section: Discussionmentioning

confidence: 99%

Equine Infectious Anemia Virus Envelope Evolution In Vivo during Persistent Infection Progressively Increases Resistance to In Vitro Serum Antibody Neutralization as a Dominant Phenotype

Howe¹,

Leroux

Issel

et al. 2002

J Virol

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Equine infectious anemia virus (EIAV) infection of horses is characterized by well-defined waves of viremiaassociated with the sequential evolution of distinct viral populations displaying extensive envelope gp90 variation; however, a correlation of in vivo envelope evolution with in vitro serum neutralization phenotype remains undefined. Therefore, the goal of the present study was to utilize a previously defined panel of natural variant EIAV envelope isolates from sequential febrile episodes to characterize the effects of envelope variation during persistent infection on viral neutralization phenotypes and to define the determinants of EIAV envelope neutralization specificity. To assess the neutralization phenotypes of the sequential EIAV envelope variants, we determined the sensitivity of five variant envelopes to neutralization by a longitudinal panel of immune serum from the source infected pony. The results indicated that the evolution of the EIAV envelope sequences observed during sequential febrile episodes produced an increasingly neutralization-resistant phenotype. To further define the envelope determinants of EIAV neutralization specificity, we examined the neutralization properties of a panel of chimeric envelope constructs derived from reciprocal envelope domain exchanges between selected neutralization-sensitive and neutralization-resistant envelope variants. These results indicated that the EIAV gp90 V3 and V4 domains individually conferred serum neutralization resistance while other envelope segments in addition to V3 and V4 were evidently required for conferring total serum neutralization sensitivity. These data clearly demonstrate for the first time the influence of sequential gp90 variation during persistent infection in increasing envelope neutralization resistance, identify the gp90 V3 and V4 domains as the principal determinants of antibody neutralization resistance, and indicate distinct complex cooperative envelope domain interactions in defining sensitivity to serum antibody neutralization.

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“…With viruses isolated 4 years after the isolation of LW/C from the infected laboratory worker, a recent report suggests that env mutations in the in vivo revertants are involved in increased resistance to neutralizing antibodies and in AIDS development (4). Interestingly, the A-to-T mutation in the env V3 loop common to LW/C, HXB2/LW (40), and other isolates from the infected laboratory worker (27,44) is also associated with escape from antibody neutralization (10).…”

Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 IIIB Selected for Replication In Vivo Exhibits Increased Envelope Glycoproteins in Virions without Alteration in Coreceptor Usage: Separation of In Vivo Replication from Macrophage Tropism

Miller

Duus

Townsend

et al. 2001

J Virol

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Analysis of viral replication and pathogenicity after in vivo selection of human immunodeficiency virus type 1 (HIV-1) attenuated in vitro will help to define the functions involved in replication and pathogenesis in vivo. Using the SCID-hu Thy/Liv mouse and human fetal thymus organ culture as in vivo models, we previously defined HIV-1 env determinants (HXB2/LW) which were reverted for replication in vivo (L. Su et al., Virology 227:46-52, 1997). In this study, we examined the replication of four highly related HIV-1 clones directly derived from Lai/IIIB or after selection in vivo to investigate the envelope gp120 determinants associated with replication in macrophages and in the thymus models in vivo. The LW/C clone derived from the IIIB-infected laboratory worker and HXB2/LW both efficiently infected monocyte-derived macrophages (MDM) and the human thymus. Although the laboratory worker (LW) isolates showed altered tropism from IIIB, they still predominantly used CXCR4 as coreceptors for infecting peripheral blood mononuclear cells, macrophages, and the thymus. Interestingly, a single amino acid mutation in the V3 loop associated with resistance to neutralizing antibodies was also essential for the replication activity of the LW virus in the thymus models but not for its activity in infecting MDM. The LW virions were equally sensitive to a CXCR4 antagonist. We further demonstrated that the LW HIV-1 isolate selected in vivo produced more infectious viral particles that contained higher levels of the Env protein gp120. Thus, selection of the laboratory-attenuated Lai/IIIB isolate in vivo leads to altered tropism but not coreceptor usage of the virus. The acquired replication activity in vivo is correlated with an early A-to-T mutation in the V3 loop and increased virion association of HIV-1 Env gp120, but it is genetically separable from the acquired replication activity in macrophages.

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Reversal of Human Immunodeficiency Virus Type 1 IIIB to a Neutralization-Resistant Phenotype in an Accidentally Infected Laboratory Worker with a Progressive Clinical Course

Cited by 72 publications

References 65 publications

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Equine Infectious Anemia Virus Envelope Evolution In Vivo during Persistent Infection Progressively Increases Resistance to In Vitro Serum Antibody Neutralization as a Dominant Phenotype

Human Immunodeficiency Virus Type 1 IIIB Selected for Replication In Vivo Exhibits Increased Envelope Glycoproteins in Virions without Alteration in Coreceptor Usage: Separation of In Vivo Replication from Macrophage Tropism

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