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Review
. 2015 Sep 29;2(4):293-348.
doi: 10.3390/vetsci2040293.

Comparative Analysis of Tat-Dependent and Tat-Deficient Natural Lentiviruses

Deepanwita Bose  1 , Jean Gagnon  2 , Yahia Chebloune  3
Affiliations
Review

Comparative Analysis of Tat-Dependent and Tat-Deficient Natural Lentiviruses

Deepanwita Bose et al. Vet Sci. .

Abstract

The emergence of human immunodeficiency virus (HIV) causing acquired immunodeficiency syndrome (AIDS) in infected humans has resulted in a global pandemic that has killed millions. HIV-1 and HIV-2 belong to the lentivirus genus of the Retroviridae family. This genus also includes viruses that infect other vertebrate animals, among them caprine arthritis-encephalitis virus (CAEV) and Maedi-Visna virus (MVV), the prototypes of a heterogeneous group of viruses known as small ruminant lentiviruses (SRLVs), affecting both goat and sheep worldwide. Despite their long host-SRLV natural history, SRLVs were never found to be responsible for immunodeficiency in contrast to primate lentiviruses. SRLVs only replicate productively in monocytes/macrophages in infected animals but not in CD4+ T cells. The focus of this review is to examine and compare the biological and pathological properties of SRLVs as prototypic Tat-independent lentiviruses with HIV-1 as prototypic Tat-dependent lentiviruses. Results from this analysis will help to improve the understanding of why and how these two prototypic lentiviruses evolved in opposite directions in term of virulence and pathogenicity. Results may also help develop new strategies based on the attenuation of SRLVs to control the highly pathogenic HIV-1 in humans.

Keywords: CAEV; HIV; Lentiviruses; Tat; latency; pathogenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Comparison of SRLV and HIV-1 properties. SRLV replication is restricted to monocyte/macrophage cell lineage. HIV-1 can target both monocytes/macrophages and CD4+ T cells using CD4 as the main receptor and either CCR5 or CXCR4 as the co-receptor. The replication of HIV/SIV is highly dependent on Tat transactivation, while replication of SRLVs is fully independent and constitutive. The pathogenesis of SRLVs is characterized by local inflammatory diseases in target organs while HIV-1 induces chronic systemic inflammation and immunodeficiency leading to AIDS and multi-organ degenerative diseases.
Figure 2
Figure 2
Genomic organization of HIV-1 and SRLV proviruses. Both genomes have the structural and enzyme gag, pol, and env genes (solid red bars), with LTRs at the 5’ and 3’ends (solid brown and green rectangles in HIV-1 and SRLVs, respectively) common to all retroviruses. The six additional open reading frames (vif, vpr, vpu, tat, rev, and nef) that encode regulatory and accessory proteins are indicated (solid blue bars), while the SRLV genomes have only three additional open reading frames (vif, vpr-like, and rev) [13].
Figure 3
Figure 3
Signaling model of Nef-mediated (A) apoptosis/anti-apoptosis, (B) down-regulation of expression of MHC class I molecules, and (C) down-regulation of the expression of CD4 molecules. A. Internalization of MHC-I: Nef accelerates the endocytosis of MHC class I molecules through PI3K-dependent activation of ADP ribosylation factor 6 (ARF6)-mediated endocytosis. First, the Nef binds PACS-2 and targets to the late Golgi/TGN; at the TGN, Nef binds and activates a TGN-localized SFK. The activated Nef–SFK complex, which leads to the signal transduction pathway recruiting and activating ZAP-70/Syk, then binds to a class I PI3K. The activated PI3K causes the accumulation of phosphatidylinositol-3,4,5-triphosphate (PtdInsP3) (PIP3) on the inner leaflet of the plasma membrane. PIP3 recruits the ARF6 guanosine exchange factor (ARF6-GEF) to the plasma membrane. Nef mediates the internalization of MHC-I from the plasma membrane to an ARF-6 endosomal compartment. The endocytosed MHC-I forms a complex with Nef and AP-1 via phosphofurin acidic cluster sorting protein 1 (PACS1). B. Internalization of CD4: Lck disassociates from the cytoplasmic tail of CD4 and Nef is attached to the cytoplasmic tail of CD4 within clathrin-coated pits through the interaction of adaptor protein 2 (AP-2) and vacuolar ATPase (v-ATPase). This leads to the internalization of CD4 into the early endosome. During the formation of the late endosome, Nef intacts with βCOP1 and through ARF-1, which targets CD4 to the lysosomal degradation. C. Apoptotic role of Nef: Intrinsic Nef signals localized on plasma membrane activate MAP kinase kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK) to induce caspase-dependent apoptosis, while the anti-apoptotic pathway is mediated by Fas cell surface death receptor (FAS) and tumor-necrosis factor receptor (TNFR) by inhibiting the apoptosis signal-regulating kinase (ASK1) and P53. Nef-mediated p21-activated kinase (PAK) activation involves PI3K, which acts upstream of PAK. Nef-associated PI3K and PAK phosphorylate the pro-apoptotic Bad protein to inactivate Bad, thus blocking the apoptosis mediated by BCL-2.
Figure 4
Figure 4
Structural organization of Tat and TAR: (A) The boxes in different colors indicate the position of the six different domains in the amino acid sequence of HIV-1 Tat. The Basic region from 49–57 is required for RNA binding. (B) Schematic representation of the trans-activation response (TAR) stem-loop structure with its different regions and the bulge structure which is essential for the high-affinity binding of Tat. The minimal sequence element required for Tat-responsiveness is from residues 19–42.
Figure 5
Figure 5
Genomic organization of HIV-1 and mechanisms of LTR transactivation. (A) The modulatory region consists of transcription factors such as COUP, AP1, NFAT-1, IL2RE, C/EBP, USF, TCF-1α, ETS and LEF1. The enhancer region has the NF-κB and C/EBP, and the core region consists of three tandem SP1 sites and the TATA box and E-box to which RBE1 and RBE2 (USF1, USF2, TFII-I) binds. Downstream to the TATA box is the initiator element from the TAR region. A weak transcription starts at -430 at U3 with TAGAA and is enhanced at the downstream TAR region at the +1 AAUAA polyadenylation site. (Not all the transcription binding sites are shown here). (B) Initiation stage: the cellular transcription factors TAFs and TBP (TAFs + TBP + TFIID) are recruited which, along with the other components of the basal transcription, help in recruiting the RNA polymerase holoenzymes. The CDK7 kinase presents the CTD of the RNA polymerase in the TFIIH phosphorylates. (C) The hypo-phosphorylated state of the CTD correlates with the low processivity of the RNA polymerase enzyme complex. Due to hypo-phosphorylation, and in absence of Tat, there is mainly production of short RNA. Furthermore, DSIF and NELF that bind to the RNA pol II inhibit the transcriptional elongation. (D) CDK9 phosphorylates the CTD and, along with cyclin T1, they produce the complex P-TEFb (positive transcription elongation factor b). TAT is recruited and binds to the bulge sequence of the TAR RNA. The hyper-phosphorylation of CTD is induced by the binding of the P-TEFb to the TAR, resulting in dissociation of DSIF and NELF. HATS and SWI/SNF, which induces acetylation of the nucleosomes, are recruited and remove any blocks due to epigenetic modification and support elongation. The acetylation of Tat creates a binding site for P300/CREB binding protein-associated factors (PCAF) which enhances the transcription elongation.
Figure 5
Figure 5
Genomic organization of HIV-1 and mechanisms of LTR transactivation. (A) The modulatory region consists of transcription factors such as COUP, AP1, NFAT-1, IL2RE, C/EBP, USF, TCF-1α, ETS and LEF1. The enhancer region has the NF-κB and C/EBP, and the core region consists of three tandem SP1 sites and the TATA box and E-box to which RBE1 and RBE2 (USF1, USF2, TFII-I) binds. Downstream to the TATA box is the initiator element from the TAR region. A weak transcription starts at -430 at U3 with TAGAA and is enhanced at the downstream TAR region at the +1 AAUAA polyadenylation site. (Not all the transcription binding sites are shown here). (B) Initiation stage: the cellular transcription factors TAFs and TBP (TAFs + TBP + TFIID) are recruited which, along with the other components of the basal transcription, help in recruiting the RNA polymerase holoenzymes. The CDK7 kinase presents the CTD of the RNA polymerase in the TFIIH phosphorylates. (C) The hypo-phosphorylated state of the CTD correlates with the low processivity of the RNA polymerase enzyme complex. Due to hypo-phosphorylation, and in absence of Tat, there is mainly production of short RNA. Furthermore, DSIF and NELF that bind to the RNA pol II inhibit the transcriptional elongation. (D) CDK9 phosphorylates the CTD and, along with cyclin T1, they produce the complex P-TEFb (positive transcription elongation factor b). TAT is recruited and binds to the bulge sequence of the TAR RNA. The hyper-phosphorylation of CTD is induced by the binding of the P-TEFb to the TAR, resulting in dissociation of DSIF and NELF. HATS and SWI/SNF, which induces acetylation of the nucleosomes, are recruited and remove any blocks due to epigenetic modification and support elongation. The acetylation of Tat creates a binding site for P300/CREB binding protein-associated factors (PCAF) which enhances the transcription elongation.
Figure 6
Figure 6
Genomic organization of SRLVs and mechanism of LTR transactivation independent of Tat. (A) Various regions of the SRLV LTR are distinguished. (B) The transcriptional elements in U3 consist of TATA box, Ets-1, Stat-1, AP4, GAS, AML, NFAT-2, IRF-1, and AP-1 sites. The proposed transactivation pathway suggests that IFN-γ activates STAT-1 phosphorylation. Phosphorylated homodimer binds to the gamma activation site (GAS) while tumor necrosis factor alpha (TNF-α) activates the transcription by binding to the 17-nucleotide TNF-activated site (TAS) within the 70-nucleotide repeats. Vpr interacts with the Jun protein of the Fos-Jun complex bound to the AP-1 site and also interacts with the TATA box-binding proteins TBP, which interact with the TATA box.
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