Altered lymphocyte heat shock protein 70 expression in patients with HIV disease

Agnew, Linda L.; Kelly, Mark; Howard, Jonathan; Jeganathan, Sarangapany; Batterham, Marijka; Ffrench, Rosemary A.; Gold, Julian; Watson, Kenneth

doi:10.1097/00002030-200309050-00019

Cited by 19 publications

(17 citation statements)

References 8 publications

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“…First, genes encoding cellular chaperones such as the various heat shock proteins. The induction of heat shock proteins has been associated with stress responses including viral infection, and it was shown that recognition of HSP70 by TLR1 activates the innate immune response (41)(42)(43). Of interest was also the induction of X-linked retinitis pigmentosa 2 gene; although the function of this protein has not yet been completely established, it was shown that it may function as a chaperone (44).…”

Section: Discussionmentioning

confidence: 99%

Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection

Barnes

Richards²,

Mancl

et al. 2004

Journal of Biological Chemistry

206

193

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Section: Discussionmentioning

confidence: 99%

Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection

Barnes

Richards²,

Mancl

et al. 2004

Journal of Biological Chemistry

206

193

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“…Although the role of cellular heat shock proteins in HIV infection has been investigated by several groups, little information has been generated about the different Hsp family members except Hsp70. The up-regulation of Hsp70 has been reported in HIV infection along with its presence in the virion (23,24), however, its role in HIV-1 infection remains to be established. Hsp70 has been shown to interact with the Vpr protein and inhibit Vpr-induced apoptosis (48).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies reported increased expression of Hsp70 in HIV-1 infection and showed its presence in the virion (23,24,45). Therefore, we assessed the Hsp40 expression level in HIV-1-infected CEM-GFP cells by immunoblotting for Hsp40.…”

Section: Nl4-3 Nef Also Interacts With Hsp40 Both In Vitro and In Vivo-mentioning

confidence: 99%

“…Among all the heat shock proteins studied to date, Hsp70 has been shown to play an important role in the HIV-1 life cycle. Hsp70 is overexpressed in lymphocytes of HIV-positive individuals and is also found abundantly in HIV virions (23,24). Hsp70 and Hsp90 have been shown to stabilize the assembly of the active cdk9-cyclin T1 complex responsible for positive transcription elongation factor b (P-TEFb) or Tat-associated kinase complex-mediated Tat transactivation (25).…”

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confidence: 99%

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Heat Shock Protein 40 Is Necessary for Human Immunodeficiency Virus-1 Nef-mediated Enhancement of Viral Gene Expression and Replication

Kumar¹,

Mitra

2005

Journal of Biological Chemistry

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The human immunodeficiency virus-1 (HIV-1) Nef protein, originally identified as a negative factor, has now emerged as one of the most important viral proteins necessary for viral pathogenesis and disease progression. Nef has been also implicated in viral infectivity and replication, however, the molecular mechanism of Nef-induced viral gene expression and replication is not clearly understood. Although involvement of heat shock proteins in viral pathogenesis has been reported earlier, a clear understanding of their role remains to be elucidated. Here we report for the first time that Nef not only interacts with heat shock protein 40 (Hsp40) but it also induces the expression of Hsp40 in HIV-1-infected cells. The interaction between Nef and Hsp40 is important for increased Hsp40 translocation into the nucleus of infected cells, which seems to facilitate viral gene expression by becoming part of the cyclin-dependent kinase 9-associated transcription complex regulating long terminal repeat-mediated gene expression. The finding is consistent with the failure of the nef-deleted virus to induce Hsp40, resulting in reduced virus production. Our data further shows that, whereas, Hsp40 overexpression induces viral gene expression, silencing of Hsp40 reduces the gene expression in a Nef-dependent manner. Thus our results clearly indicate that Hsp40 is crucial for Nef-mediated enhancement of viral gene expression and replication.Viruses are known to modulate cellular proteins for successful replication within the host cells. The sequence of events in the establishment of a productive infection by human immunodeficiency virus type 1 (HIV-1) 3 not only involves interaction between a number of viral and cellular factors but is also accompanied by complex and dynamic changes in the patterns of cellular gene expression. Nef, a 27-30-kDa myristoylated phosphoprotein, encoded by HIV-1 has been shown to play a crucial role in viral pathogenesis by modulating cellular gene expression and signaling pathways (1, 2). nef-deleted viruses fail to replicate efficiently in vivo, and do not develop symptoms of acquired immunodeficiency syndrome (AIDS) (3, 4). Nef is also thought to contribute to viral pathogenesis by down-regulation of CD4 and major histocompatibility complex class I surface molecules preventing viral superinfection and by helping the virus to evade host immune system. Nef has also been implicated in the activation of T cells, making the cells permissible to the virus (5, 6). All these functions of Nef are manifested by a number of important events such as activation of upstream signaling molecules, inhibition of apoptosis in the infected cell, activation and up-regulation of transcription factors, alleviation of repressors of transcription, as well as increase of the infectivity of newly produced virions (1, 7). Even though these functions of Nef have been well studied, controversy exists on its role in viral infectivity and replication as both negative (8, 9) and positive (10, 11) effects are available in the literature...

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“…Among a large, nonrandom selection of host proteins, HSP70 was found in the virion membrane of HIV-1; the amount was similar to that of Pol protein, and HSP70 functions as a chaperone during intracellular transport (17). HSP70 mRNA is upregulated in CD4 ϩ T cells infected with HIV-1 (35), and the expression of HSP70 is significantly increased in lymphocytes from HIV-1-infected subjects (1). HSP70 elicits innate immune responses by generating chemokines and cytokines (23,27,38), which exert robust adjuvanticity in nonhuman primates (5).…”

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confidence: 99%

Inhibition of Human Immunodeficiency Virus Type 1 Infection of Human CD4 ⁺ T Cells by Microbial HSP70 and the Peptide Epitope 407-426

Babaahmady

Oehlmann

Singh

et al. 2007

J Virol

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Targeting the cognate human immunodeficiency virus type 1 (HIV-1) antigen is the classical way of preventing HIV-1 infection, but this approach has encountered serious problems in eliciting effective cytotoxic T lymphocytes (CTL) and neutralizing antibodies. Both CTL and neutralizing antibodies are subject to viral escape, and HIV-1 mutation may occur in the acute (30), as well as the chronic, phase of infection (4,12,15). Indeed, HIV-1 sequences found in a population may represent largely CTL escape variants restricted by the most prevalent HLA alleles in that population (29). Alternative preventive strategies such as the use of host antigens may have to be considered. Among a large, nonrandom selection of host proteins, HSP70 was found in the virion membrane of HIV-1; the amount was similar to that of Pol protein, and HSP70 functions as a chaperone during intracellular transport (17). HSP70 mRNA is upregulated in CD4 ϩ T cells infected with HIV-1 (35), and the expression of HSP70 is significantly increased in lymphocytes from HIV-1-infected subjects (1). HSP70 elicits innate immune responses by generating chemokines and cytokines (23, 27, 38), which exert robust adjuvanticity in nonhuman primates (5). Furthermore, alloimmune responses can be enhanced by stimulating the CD40-CD40L costimulatory pathway (13) and the alternative CD40-HSP70 pathway may function in a similar way by upregulating CD40, CD80/86, HLA-II, and tumor necrosis factor alpha (TNF-␣) (38, 39). Recently, we and others have demonstrated that HSP70 binds directly to CCR5 expressed on the surfaces of human CD4 ϩ T cells and dendritic cells (11,41).The aims of the present investigations were to explore and characterize any inhibitory effect of microbial HSP70 on HIV-1. An examination of the effect of HSP70 on HIV infectivity revealed a dose-dependent inhibition of HIV-1 infection of activated CD4 ϩ T cells. The inhibitory function of HSP70 was progressively localized, first to the C-terminal fragment (the peptide comprising amino acids [aa] 359 to 609 [p359-609]), then to the peptide binding domain (p359-494), and finally to the 20-mer peptide epitope (aa 407 to 426). The kinetics of the HIV-1-inhibitory effects of the HSP70 peptides over 24 h were comparable for HSP70, p359-609, and p359-494, though the duration of inhibition varied among the HSP70 fragments. We then explored any complementary inhibitory effect on HIV-1 by adding anti-CCR5 monoclonal or polyclonal antibodies to HSP70. Whereas HSP70 alone inhibited the R5 strains of HIV-1 in a dose-dependent way by up to a mean (Ϯ the standard error of the mean [SEM]) of 72.8% (Ϯ14.8%) and monoclonal antibody (mAb) to CCR5 inhibited HIV-1 up to 93.5% (Ϯ3.9%), combining HSP70 with mAb to CCR5 enhanced the level of inhibition to 99.7% (Ϯ0.9%). MATERIALS AND METHODSPreparation of HSP70, its C-terminal (aa 359 to 609) and N-terminal (aa 1 to 358) fragments, and the peptide binding domain (aa 359 to 494). The recombinant Mycobacterium tuberculosis HSP70, p359-609, p1-358, and p359-494 were prepared fr...

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Altered lymphocyte heat shock protein 70 expression in patients with HIV disease

Cited by 19 publications

References 8 publications

Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection

Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection

Heat Shock Protein 40 Is Necessary for Human Immunodeficiency Virus-1 Nef-mediated Enhancement of Viral Gene Expression and Replication

Inhibition of Human Immunodeficiency Virus Type 1 Infection of Human CD4 ⁺ T Cells by Microbial HSP70 and the Peptide Epitope 407-426

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Altered lymphocyte heat shock protein 70 expression in patients with HIV disease

Cited by 19 publications

References 8 publications

Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection

Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection

Heat Shock Protein 40 Is Necessary for Human Immunodeficiency Virus-1 Nef-mediated Enhancement of Viral Gene Expression and Replication

Inhibition of Human Immunodeficiency Virus Type 1 Infection of Human CD4 + T Cells by Microbial HSP70 and the Peptide Epitope 407-426

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Inhibition of Human Immunodeficiency Virus Type 1 Infection of Human CD4 ⁺ T Cells by Microbial HSP70 and the Peptide Epitope 407-426