HIV-1 Nef Disrupts Maturation of CD4+ T Cells through CD4/Lck Modulation

Chrobák, Pavel; Simard, Marie-Chantal; Bouchard, Nathalie; Ndolo, Thomas; Guertin, Joël; Hanna, Zaher; Davé, Vibhuti P.; Jolicoeur, Paul

doi:10.4049/jimmunol.1001064

Cited by 15 publications

(18 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because we have recently found that the Tg thymic SP CD4 ϩ T-cell developmental block is largely the impairment of CD4/Lck function, 54 the reversion of the Nefmediated CD4 down-regulation by sdAb19 probably explains the reversal of thymic developmental block of CD4 ϩ T cells. In peripheral LN cells, sdAb19 was found to efficiently reverse not only CD4 down-regulation but also the up-regulation of CD44 and CD25.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of the Nef regulatory protein of HIV-1 by a single-domain antibody

Bouchet

Basmaciogullari

Chrobák

et al. 2011

Blood

Self Cite

View full text Add to dashboard Cite

IntroductionThe advent of monoclonal antibodies was a major breakthrough for the development of antibody-based therapies against various diseases, including virus infection. 1 However, expression in the cytoplasm or nucleus of eukaryotic cells of full-length immunoglobulin G or single-chain antibody variable domain fragments aiming at blocking an intracellular target is poorly efficient because of the reducing nature of these compartments. The engineering of single-chain antibody variable domain fragments (scFvs) that consist in a tandem fusion of the VH and VL domains of a specific antibody partially overcame this limitation. Numerous scFvs have shown their potency for inhibition of the function of their target proteins in cells. In particular, a HIV-1 Tat-specific scFv was shown to neutralize the trans-activating function of this viral protein and to prevent full expression of the viral genome in infected cells. 2 ScFvs specific for HIV-1 matrix, integrase, or regulatory proteins such as Tat, Rev, and Vif are also able to interfere with HIV-1 replication. [3][4][5][6][7][8][9] However, disulfide bonds between VH and VL chains of scFvs are unlikely to form when scFvs are targeted to reducing compartments such as the cytoplasm or the nucleus, resulting in scFvs with lower or no affinity for their antigen. 10 Recently, a major improvement was brought by the use of single-domain antibodies (sdAbs) derived from camelids. In addition to conventional antibodies, camelids express antibodies composed of heavy chains only, with a single variable domain (VHH) capable of recognizing their cognate antigens. 11 These variable domains, called sdAbs, are endowed with many attractive features. 12 The absence of requirement for disulfide bond formation in sdAbs is particularly interesting when targeting of proteins found in reducing cell compartments is considered. 13 In contrast to conventional antibodies, these 13-kDa sdAb fragments can penetrate in cavities located on the surface of antigens (for review, see Nguyen et al 14 ). These cryptic sites are often more conserved than exposed epitopes on viral proteins and are a target of choice for blocking antibodies. Interestingly, sdAb fragments targeting the HIV-1 Rev or Vif proteins have been already characterized and have displayed antiviral activity in cell-culture assays. 15,16 In the present study, we characterized an sdAb from a llama immunized with a recombinant form of Nef, an HIV-1 nonstructural protein found both in the cytoplasm of infected cells and in association with cellular membranes. Considering Nef as a potential target for antiviral therapy arose from the findings that this HIV-1 protein is important for AIDS pathogenesis in vivo (for review, see Foster and Garcia 17 ). Nef is abundantly expressed early after virus infection and perturbs the trafficking of several membrane proteins through action on the endocytic pathway. This leads to the modulation of cell surface expression of some receptors, including CD4 and major histocompatibility complex class I (MHC-I...

show abstract

Section: Discussionmentioning

confidence: 98%

Inhibition of the Nef regulatory protein of HIV-1 by a single-domain antibody

Bouchet

Basmaciogullari

Chrobák

et al. 2011

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…These Tg mice express Nef under the regulation of the upstream elements of the human CD4 gene and develop a very severe AIDSlike disease. In particular, they exhibit abnormal development of thymic CD4 + T cells, loss, and enhanced apoptosis of CD4 + T cells and activation of CD4 + and CD8 + T cells (16)(17)(18). We show in this work that HIV or SIV Nef has the capacity to induce a cell-autonomous, lymphopenia-independent relative preservation of the CD4 + Treg, while maintaining their suppressive potential.…”

mentioning

confidence: 75%

“…1D), but no depletion of total thymocytes (Supplemental Fig. 1A) (18). In these young Tg mice, the frequency of thymic CD4 + CD25 + T cells was not enhanced (Supplemental Fig.…”

Section: Cd8mentioning

confidence: 99%

“…Lck adopts three main molecular forms in T cells, as follows: an inactive closed form in which tyrosine (Y) 394 and Y505 are dephosphorylated, an active open form in which Y394 is phosphorylated with Y505 remaining nonphosphorylated, and an active form in which both Y394 and Y505 are phosphorylated (54 transgene is likely to significantly modify the ratio of the different molecular forms of pLck, this successful rescue experiment also suggests that modification of pLck pool ratios by Nef may be responsible for its effect. We previously reported that Nef-expressing thymic T cells exhibit higher levels of Lck and activated p-Lck Y394 but paradoxically apparently decreased Lck output (18). However, despite their rescue by Lck…”

Section: Y505fmentioning

confidence: 99%

“…Because Lck Y505F also totally rescues the loss of peripheral CD4 + T cells in Nef Tg mice (18), CD4 + T cell depletion and relative Treg expansion appear to be caused by Lck dysregulation. Altered ratio of its phosphorylated forms and its subcellular mislocalization may represent elements of this dysregulation.…”

Section: Y505fmentioning

confidence: 99%

See 2 more Smart Citations

HIV Nef Expression Favors the Relative Preservation of CD4+ T Regulatory Cells That Retain Some Important Suppressive Functions

Chrobák

Afkhami

Priceputu

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

HIV-1 infection causes depletion and/or dysfunction of distinct CD4+ T cell subsets and may affect these differently. Using the CD4C/HIV-1Nef transgenic (Tg) mice as a model, we report that HIV-1 Nef causes depletion of total CD4+ T cells, but preserves and relatively enriches CD4+ regulatory T cells (Treg). We found that Nef-mediated CD4+ Treg enrichment is the direct result of Nef expression in CD4+ T cells, occurs independently of Nef-induced lymphopenia, and most likely results from multiple mechanisms: lower apoptosis, enhanced cell division, and increased generation from precursors. Interestingly, Tg Treg relative enrichment could be reversed by enhancing Lck activity. Most importantly, we show that, in contrast to Tg helper CD4+ T cells that have lost their function, Nef-expressing CD4+ Treg retain their regulatory function in vitro and also in vivo, under some settings. In particular, we found that Treg prevent expansion of Tg B and non-Treg T cells in vivo. Our study reveals that Nef affects distinct CD4+ T cell subsets differently and uncovers the high proliferative potential of B and non-Treg T cells in this mouse model.

show abstract

Prospects of Modulating Protein–Protein Interactions

Zhong

Oashi

et al. 2012

Protein‐Ligand Interactions

View full text Add to dashboard Cite

HIV-1 Nef Disrupts Maturation of CD4+ T Cells through CD4/Lck Modulation

Cited by 15 publications

References 61 publications

Inhibition of the Nef regulatory protein of HIV-1 by a single-domain antibody

Inhibition of the Nef regulatory protein of HIV-1 by a single-domain antibody

HIV Nef Expression Favors the Relative Preservation of CD4+ T Regulatory Cells That Retain Some Important Suppressive Functions

Prospects of Modulating Protein–Protein Interactions

Contact Info

Product

Resources

About