Alteration of select gene expression patterns in individuals infected with HIV‐1

Serrao, Erik; Wang, Chia Hao; Frederick, Toinette; Lee, Chi Lin; Anthony, Patricia; Arribas-Layton, David; Baker, Kerry; Millstein, Joshua; Kovács, Andrea; Neamati, Nouri

doi:10.1002/jmv.23872

Cited by 6 publications

(3 citation statements)

References 55 publications

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“…6). While we have not experimentally targeted the HSP90 node in our system, HSP90 has recently been reported to be of major importance for HIV-1 latency control (87,88), further supporting the idea that kinome array analysis and PINs derived from these data are predictive beyond the limitations of our HIV-1 latency models.…”

Section: Discussionsupporting

confidence: 54%

Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection

Seu

Sabbaj

Duverger

et al. 2015

J Virol

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The extreme stability of the latent HIV-1 reservoir in the CD4 ؉ memory T cell population prevents viral eradication with current antiretroviral therapy. It has been demonstrated that homeostatic T cell proliferation and clonal expansion of latently infected T cells due to viral integration into specific genes contribute to this extraordinary reservoir stability. Nevertheless, given the constant exposure of the memory T cell population to specific antigen or bystander activation, this reservoir stability seems remarkable, unless it is assumed that latent HIV-1 resides exclusively in memory T cells that recognize rare antigens. Another explanation for the stability of the reservoir could be that the latent HIV-1 reservoir is associated with an unresponsive T cell phenotype. We demonstrate here that host cells of latent HIV-1 infection events were functionally altered in ways that are consistent with the idea of an anergic, unresponsive T cell phenotype. Manipulations that induced or mimicked an anergic T cell state promoted latent HIV-1 infection. Kinome analysis data reflected this altered host cell phenotype at a system-wide level and revealed how the stable kinase activity changes networked to stabilize latent HIV-1 infection. Protein-protein interaction networks generated from kinome data could further be used to guide targeted genetic or pharmacological manipulations that alter the stability of latent HIV-1 infection. In summary, our data demonstrate that stable changes to the signal transduction and transcription factor network of latently HIV-1 infected host cells are essential to the ability of HIV-1 to establish and maintain latent HIV-1 infection status. IMPORTANCEThe extreme stability of the latent HIV-1 reservoir allows the infection to persist for the lifetime of a patient, despite completely suppressive antiretroviral therapy. This extreme reservoir stability is somewhat surprising, since the latently HIV-1 infected CD4؉ memory T cells that form the structural basis of the viral reservoir should be exposed to cognate antigen over time. Antigen exposure would trigger a recall response and should deplete the reservoir, likely over a relatively short period. Our data demonstrate that stable and system-wide phenotypic changes to host cells are a prerequisite for the establishment and maintenance of latent HIV-1 infection events. The changes observed are consistent with an unresponsive, anergy-like T cell phenotype of latently HIV-1 infected host cells. An anergy-like, unresponsive state of the host cells of latent HIV-1 infection events would explain the stability of the HIV-1 reservoir in the face of continuous antigen exposure.

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Section: Discussionsupporting

confidence: 54%

Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection

Seu

Sabbaj

Duverger

et al. 2015

J Virol

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“…More than 39 million people have already died because of AIDS-related opportunistic infections and at present 35 million people are living with AIDS ( 57 ). HIV manipulates host cellular gene-expression for its benefit ( 8 , 58 ) and simultaneously its life cycle is also influenced by different host factors ( 6 , 7 , 10 ). Multiple cellular proteins have been identified which either facilitate or inhibit various steps of viral replication ( 59 , 60 ).…”

Section: Discussionmentioning

confidence: 99%

“…It will be interesting to study the mechanism of HspBP1 down regulation during HIV infection. Altered expression of cellular proteins has been demonstrated to have an impact on viral replication and gene expression ( 58 ). Knockdown and over-expression of HspBP1 in T-cells confirmed the inverse co-relation between HspBP1 and virus production.…”

Section: Discussionmentioning

confidence: 99%

HSP70 binding protein 1 (HspBP1) suppresses HIV-1 replication by inhibiting NF-κB mediated activation of viral gene expression

et al. 2015

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HIV-1 efficiently hijacks host cellular machinery and exploits a plethora of host–viral interactions for its successful survival. Identifying host factors that affect susceptibility or resistance to HIV-1 may offer a promising therapeutic strategy against HIV-1. Previously, we have reported that heat shock proteins, HSP40 and HSP70 reciprocally regulate HIV-1 gene-expression and replication. In the present study, we have identified HSP70 binding protein 1 (HspBP1) as a host-intrinsic inhibitor of HIV-1. HspBP1 level was found to be significantly down modulated during HIV-1 infection and virus production inversely co-related with HspBP1 expression. Our results further demonstrate that HspBP1 inhibits HIV-1 long terminal repeat (LTR) promoter activity. Gel shift and chromatin immunoprecipitation assays revealed that HspBP1 was recruited on HIV-1 LTR at NF-κB enhancer region (κB sites). The binding of HspBP1 to κB sites obliterates the binding of NF-κB hetero-dimer (p50/p65) to the same region, leading to repression in NF-κB mediated activation of LTR-driven gene-expression. HspBP1 also plays an inhibitory role in the reactivation of latently infected cells, corroborating its repressive effect on NF-κB pathway. Thus, our results clearly show that HspBP1 acts as an endogenous negative regulator of HIV-1 gene-expression and replication by suppressing NF-κB-mediated activation of viral transcription.

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Role of Heat Shock Factor 1 in HIV

Pan

Liu

2020

Heat Shock Proteins

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Alteration of select gene expression patterns in individuals infected with HIV‐1

Cited by 6 publications

References 55 publications

Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection

Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection

HSP70 binding protein 1 (HspBP1) suppresses HIV-1 replication by inhibiting NF-κB mediated activation of viral gene expression

Role of Heat Shock Factor 1 in HIV

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