Participation of Tyrosine Phosphorylation in the Cytopathic Effect of Human Immunodeficiency Virus-1

Cohen, David I.; Tani, Yoichi; Tian, Huan; Boone, Elizabeth J.; Samelson, Lawrence E.; Lane, H. Clifford

doi:10.1126/science.1570514

Cited by 97 publications

(43 citation statements)

References 40 publications

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“…This could allow the phosphorylation process to start at the proper time. For example, it has been shown that the interaction between gp120 and CD4 is able to activate cellular kinases implicated in signal transduction (55)(56)(57)(58)(59). One of these kinases could be the stimulus useful to trigger the phosphorylation of CAp24 and thus the disassembly of viral core.…”

Section: Discussionmentioning

confidence: 99%

Identification of Three Major Phosphorylation Sites within HIV-1 Capsid

Cartier

Sivard

Tranchat

et al. 1999

Journal of Biological Chemistry

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We previously reported the presence of two cellular serine/threonine protein kinases incorporated in human immunodeficiency virus type 1 (HIV-1) particles. One protein kinase is MAPK ERK2 (mitogen-activated protein kinase), whereas the other one, a 53-kDa protein, still needs to be identified. Furthermore, we demonstrated that the capsid protein CAp24 is phosphorylated by one of those two virion-associated protein kinases (Cartier, C., Deckert, M., Grangeasse, C., Trauger, R., Jensen, F., Bernard, A., Cozzone, A., Desgranges, C., and Boyer, V. (1997) J. Virol. 71, 4832-4837). In this study, we showed that CAp24 is not a direct substrate of MAPK ERK2. Moreover, using site-directed mutagenesis of each of the 9 serine residues of CAp24, we demonstrated the phosphorylation of 3 serine residues (Ser-109, Ser-149, and Ser-178) in the CAp24. Substitution of each serine residue did not affect viral budding, nor viral structure. By contrast, substitution of Ser-109, Ser-149, or Ser-178 affects viral infectivity by preventing the reverse transcription process to be completely achieved. Our results suggest that CAp24 serine phosphorylation is essential for viral uncoating process.

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Section: Discussionmentioning

confidence: 99%

Identification of Three Major Phosphorylation Sites within HIV-1 Capsid

Cartier

Sivard

Tranchat

et al. 1999

Journal of Biological Chemistry

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“…Our data, obtained in a normal Thl clone, are clearly in agreement with these last results. Although further work is needed to identify the specific PTKs involved in gpl20-apoptosis, the possibility of using PTK inhibitors for AIDS therapy is attractive, since they could reduce CD4+ cell apoptosis as well as interfere with virus replication [34] and its cytopathic effect [35].…”

Section: Time (H)mentioning

confidence: 99%

Apoptosis induced by HIV‐gp120 in a Th1 clone involves the generation of reactive oxygen intermediates downstream CD95 triggering

et al. 1997

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HIV-gpl20 sensitizes Thl clones from seronegative donors to apoptosis, which occurs through two distinct events: expression of CD95L followed by its interaction with CD95 to trigger cell death. gpl20-apoptosis of the Thl clone 103 was inhibited by Cyclosporin A, the PTK inhibitors Genistein and PNU152518, as well as the anti-oxidants Ascorbic Acid and Glutathione. Cyclosporin A interfered with CD95L expression, Ascorbic Acid and Glutathione inhibited cell death triggered by CD95/CD95L interaction; Genistein and PNU152518 acted on both steps. The occurrence of oxidative stress during CD95-dependent apoptosis was supported by the direct evidence of ROI production.

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“…Experimental observations in vitro describe several phenomena that might independently contribute to the cell death in vivo. Cytopathicity can be a direct consequence of viral replication inside infected lymphocytes (2)(3)(4)(5). Induction of apoptosis by HIV-1 has been suggested as a cause of the depletion of infected CD4+ cells (6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

CD4+ blood lymphocytes are rapidly killed in vitro by contact with autologous human immunodeficiency virus-infected cells.

Nardelli

Gonzalez

Schechter

et al. 1995

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

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We have investigated the ability of human immunodeficiency virus (HIV)-infected cells to kill uninfected CD4+ lymphocytes. Infected peripheral blood mononuclear cells were cocultured with autologous 51Cr-labeled uninfected cells. Rapid death of the normal CD4-expressing target population was observed following a brief incubation. Death of blood CD4+ lymphocytes occurred before syncytium formation could be detected or productive viral infection established in the normal target cells. Cytolysis could not be induced by free virus, was dependent on gpl2O-CD4 binding, and occurred in resting, as well as activated, lymphocytes. CD8+ cells were not involved in this phenomenon, since HIV-infected CEMT4 cells (CD4+, CD8-cells) mediated the cytolysis of uninfected targets. Reciprocal isotope-labeling experiments demonstrated that infected CEMT4 cells did not die in parallel with their targets. The uninfected target cells manifested DNA fragmentation, followed by the release of the 51Cr label. Thus, in HIV patients, infected lymphocytes may cause the depletion of the much larger population of uninfected CD4+ cells without actually infecting them, by triggering an apoptotic death.

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Participation of Tyrosine Phosphorylation in the Cytopathic Effect of Human Immunodeficiency Virus-1

Cited by 97 publications

References 40 publications

Identification of Three Major Phosphorylation Sites within HIV-1 Capsid

Identification of Three Major Phosphorylation Sites within HIV-1 Capsid

Apoptosis induced by HIV‐gp120 in a Th1 clone involves the generation of reactive oxygen intermediates downstream CD95 triggering

CD4+ blood lymphocytes are rapidly killed in vitro by contact with autologous human immunodeficiency virus-infected cells.

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