Inhibiting lentiviral replication by HEXIM1, a cellular negative regulator of the CDK9/cyclin T complex

Shimizu, Saki; Urano, Emiko; Futahashi, Yuko; Miyauchi, Katsumi; Isogai, Maya; Matsuda, Zene; Nohtomi, Kyoko; Onogi, Toshinari; Takebe, Yutaka; Yamamoto, Naoki; Komano, Jun

doi:10.1097/qad.0b013e32801424a5

Cited by 21 publications

(22 citation statements)

References 24 publications

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“…AIDS illness and death also often reduce household income, through the loss of a prime aged worker or through changes in work patterns for prime aged caregivers. In addition, in many parts of Africa, even poor households are expected to host elaborate funerals, adding to the financial burden the household shoulders (Collins and Leibbrandt 2007, Case and Menendez 2011, Case et al 2013). …”

Section: Introductionmentioning

confidence: 99%

The economic consequences of AIDS mortality in South Africa

Ardington

Bärnighausen

Case

et al. 2014

Journal of Development Economics

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We quantify the impact of adult deaths on household economic wellbeing, using a large longitudinal dataset spanning more than a decade. Verbal autopsies allow us to distinguish AIDS mortality from that due to other causes. The timing of the lower socioeconomic status observed for households with AIDS deaths suggests that the socioeconomic gradient in AIDS mortality is being driven primarily by poor households being at higher risk for AIDS, rather than AIDS impoverishing the households. Following a death, households that experienced an AIDS death are observed being poorer still. However, the additional socioeconomic loss following an AIDS death is very similar to the loss observed from sudden death. Funeral expenses can explain some of the impoverishing effects of death in the household. In contrast, the loss of an employed member cannot. To date, antiretroviral therapy has not changed the socioeconomic status gradient observed in AIDS deaths.

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Section: Introductionmentioning

confidence: 99%

The economic consequences of AIDS mortality in South Africa

Ardington

Bärnighausen

Case

et al. 2014

Journal of Development Economics

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“…In another study, Hsp40 was shown to interact and co-localize with Nef in the nucleus and thereby augment LTRdriven gene expression (23). In contrast, HEXIM1 and Hsp70 negatively regulate HIV-1 gene expression and replication (24,25). HEXIM1 along with 7SK RNA was shown to be essential for inactivation of the P-TEFb complex (26,27).…”

mentioning

confidence: 99%

Cyclin K Inhibits HIV-1 Gene Expression and Replication by Interfering with Cyclin-dependent Kinase 9 (CDK9)-Cyclin T1 Interaction in Nef-dependent Manner

Khan

Mitra

2011

Journal of Biological Chemistry

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Human immunodeficiency virus type-1 (HIV-1) perpetuates its survival in the host by utilizing multiple strategies such as irreversible integration of its DNA into the host cell genome to establish the provirus (1), diversification of its genome to escape or tolerate adaptive immune responses (2), and use of the accessory genes (nef, vif, vpu, and vpr) to modulate host cell immune responses further (3-5). These viral accessory genes are frequently seen as dispensable in many in vitro cell culture systems but seem to be indispensable, in the context of natural infections in vivo. Among these accessory genes, pleiotropic functions of Nef have been studied extensively. It is a 27-30-kDa, N-terminally myristoylated protein having a well characterized CD4 down-regulatory activity (6). Nef does not possess any enzymatic activity, but it modulates diverse signaling pathways and the gene expression of host cell proteins (7,8). Furthermore, Nef influences the activation state of the host cell by bringing together different host cell proteins, protein kinases, and components of the endocytic machinery and making the cells permissible to the virus (9, 10). All these functions of Nef are manifested by a number of events such as activation of signaling molecules, modulation of apoptosis, activation of transcription factors, mitigation of transcriptional repressors, and an increase in the infectivity of virions (11). Although these functions of Nef have been well studied, controversy exists on its role in viral infectivity and replication as both negative (12, 13) and positive (14, 15) roles have been attributed in the literature. Although a number of reports show that Nef increases viral replication by activating T-cells, the molecular basis of Nef-induced viral gene expression and replication remains to be clearly elucidated. Nef was also shown to physically interact with Tat and augment viral gene expression (16), although availability of Tat is critical for the elongation step of long terminal repeat (LTR) 2 -driven transcription by RNA polymerase II. Several cellular factors have been identified for their roles in this process, including positive transcription elongation factor b (P-TEFb) complex. Different P-TEFb complexes isolated from mammalian cells contain a common catalytic subunit, cyclin-dependent kinase 9 (CDK9), and one of the regulatory cyclins, CycT1, CycT2a, CycT2b,. However, CycT1-containing P-TEFb complex is the key complex responsible for HIV-1 transcription elongation (19). Tat is expressed early in the replicative cycle of HIV and is essential for viral gene expression from the LTR promoter. It recognizes the 5Ј-bulge in the transactivation response stem loop RNA, which is located at the 5Ј-end of all viral transcripts. Tat binds to CycT1, and together they form the combinatorial surface that interacts with the transactivation response RNA with high affinity and specificity. The obligate partner of CycT1, CDK9, then hyperphosphorylates the C-terminal domain (CTD) of RNA polymerase II, resulting in incre...

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“…22 Western Blotting and Immunoprecipitation Western blotting and immunoprecipitation were performed according to previously described techniques. 26,27 The following reagents were used: anti-FLAG (F7425; Sigma), anti-HA polyclonal antibody (Sigma), anti-p24 CA (CA, 183-H12-5C, NIH AIDS Research and Reference Reagent Program), anti-actin (clone MAB1501R; Millipore, Tokyo, Japan), antiBiP/GRP78 (clone 40; Clontech), biotinylated antigoat antibodies (GE Healthcare, Tokyo, Japan), streptavidin-HRP (GE Healthcare), and Envision + Dual Link System-HRP (Dako, Glostrup, Denmark).…”

Section: Measuring Viral Production and Replicationmentioning

confidence: 97%