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Chapter 5 : Intracellular Control of HIV Replication

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Intracellular Control of HIV Replication, Page 1 of 2

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Abstract:

This chapter talks about the virus:cell interactions that take place within the intracellular compartment. In cells not fully permissive to HIV replication, the relative expression of the regulatory proteins can differ, leading to abortive infection, low persistence, or a latent state. Further evidence of intracellular control is provided by biologic studies showing variations in replication of HIV isolates in different cell lines and peripheral blood mononuclear cells (PBMC) from various donors. Identification of all the cellular factors involved in the replicative cycle is an ongoing endeavor. Certain cytokines and hormones, as well as transactivating proteins from other viruses, can also increase HIV production via these intracellular events. The lower-molecular-weight mass (LMM) of APOBEC3G predominates in un-stimulated CD4 cells and monocytes and appears to block HIV replication. With monkey cells, the cyclosporine prevents the CA:CypA interaction and can increase HIV replication in these primate cells more than 100-fold. The intracellular factors that might influence the extent of virus production in resting CD4 cells are being defined. Most CD4 cells in vivo are in a relatively quiescent state but are still susceptible to productive virus infection. It seems more important, therefore, to focus on activation events that establish the infection in these cells. The HIV regulatory proteins, Tat, Rev, and Nef, and certain intracellular factors certainly could be involved either positively or negatively in inducing this biologic process.

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05

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Figures

Image of Figure 5.1
Figure 5.1

The HIV infection cycle. The steps are as follows: 1, attachment; 2, uncoating; 3, reverse transcription; 4, circularization; 5, integration; 6, transcription; 7, translation; 8, core particle assembly; and 9, final assembly and budding. In steps 3 to 5, some viral core proteins are associated with the viral genome (——, RNA, ----, DNA). Double-stranded circular forms can be found both covalently and noncovalently bound. The latter are the forms that integrate into the cell chromosome. Antiviral therapies can be directed against each step and can potentially interrupt virus replication and spread. Figure provided by H. Kessler.

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
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Image of Figure 5.2
Figure 5.2

Schematic diagram of intracellular signaling events that occur during T-cell activation. The activation process begins with the generation of a signal at the plasma membrane (top of figure) mediated by receptor-ligand interactions, e.g., interleukin-2 receptor (IL-2R) + IL-2, a receptor-linking T-cell receptor (TCR) + CD4 interaction, or passage of membrane-permeating molecules (e.g., phorbol myristate acetate [PMA]) across the membrane. In the case of the TCR, stimulation results in the activation of tyrosine kinases (top left of figure), such as Fyn (p59), ZAP-70, and Lck (p56). This action is probably regulated by tyrosine phosphatases such as CD45. The activated tyrosine kinases phosphorylate a number of different cytoplasmic substrates that initiate a chain of signaling events. These steps usually involve the association of intermediate signaling molecules. As an example, Ras (top middle of figure) can be activated upon binding to Grb2 and SOS. This action results in the activation of cytoplasmic serine kinases such as Raf, which initates a cascade of serine-threonine kinases (e.g., MAP kinase kinase, MAP kinase, Rsk, and S6 kinase), thereby propagating the activation signal. The serine-threonine kinase cascade results in the activation of DNA-binding proteins and transcription factors which regulate gene expression. Phosphorylation and/or proteolysis of IκB in the cytoplasm (bottom left of figure) dissociates it from NF-κB and permits the translocation of NF-κB across the nuclear membrane so that it can bind to DNA and activate transcription and protein synthesis. This signal transduction process can also be initiated by the stimulation of protein kinase C (PKC) by phorbol esters (e.g., PMA) (top right of figure). Activated PKC stimulates phospholipase Cγ (PLCγ) to generate the secondary messengers diacylglycerol (DAG) and phosphoinositol trisphosphate (PIP3), a process which results in the mobilization of intracellular calcium (Ca) and liberation of phosphoinositol (PI). Figure and legend provided by E. Sawai.

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
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Image of Figure 5.3
Figure 5.3

Capsid-specific restriction factors. After entry into the cytoplasm, retroviral capsids can be recognized and infection can be blocked by one of many factors. Fv-1, unique to the mouse, blocks infection by murine leukemia virus (MLV) only, in an Fv-1 allele- and MLVstrain-specificway.TRIM5α, which is present in most primates, can block infection by a range of retroviruses, including N-tropic N-MLV, equine infectious anemia virus (EIAV), simian immunodeficiency virus (SIV), and HIV-1. The precise spectrum of TRIM5α antiretroviral activity depends on its species of origin. A unique form of TRIM5 exists in owl monkeys, due to transposition of a CypA pseudogene, and the resulting fusion protein inhibits HIV-1 because of the latter’s CypA-core binding activity. Reprinted with permission from Macmillan Publishers: (361), © 2004. CypA, cyclophilin A.

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
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Image of Figure 5.4
Figure 5.4

Positive transcription elongation factor b (P-TEFb) and HIV transcription. The viral promoter contains many common promoter elements, as well as enhancer sequences and the transactivation response (TAR) element. They recruit and position RNA polymerase II (RNAPII) on the HIV long terminal repeat (LTR). RNAPII then clears the promoter but stalls at or near TAR. P-TEFb, which consists of cyclin T1 (CycT1) and cyclin-dependent kinase 9 (CDK9), is necessary for transcription complexes to elongate. It phosphorylates the C-terminal domain of RNAPII. This change removes initiation and negative transcription factors from RNAPII and replaces them with capping, splicing, and polyadenylation machineries. P-TEFb exists in two forms in cells. The larger, inactive complex contains CycT1, inactive CDK9 kinase, HEXIM1, and 7SK RNA. The smaller, active complex contains only CycT1 and CDK9 and is required for effects of NF-κB and Tat. Most cells contain sufficient amounts of active P-TEFb to support HIV replication. The binding between NF-κB and P-TEFb allows for initial rounds of viral transcription. However, when sufficient amounts of Tat are made, then Tat and P-TEFb bind TAR with high affinity and lead to greatly increased rates of viral replication. Importantly, both NF-κB and Tat ensure that viral genes are copied and processed correctly. Figure provided by M. Peterlin.

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
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Image of Figure 5.5
Figure 5.5

HIV can infect a resting CD4 cell that expresses the CD4 molecule (step 1). If that cell is not activated, virus replication cannot take place. Because the CD4 molecule is still expressed on a resting cell, super-infection by another virus can occur (step 2). With no activation of the resting cell after infection, an abortive infection takes place (step 3). With activation, active virus replication takes place (step 4). Similarly, activation of the superinfected cell can lead to virus production, and both type viruses and recombinants might be found. Following activation and virus production (step 5), the CD4 molecule is down-modulated so superinfection cannot occur.

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
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Image of Figure 5.6
Figure 5.6

Latent HIV infection of an established T-cell line. The HIV-1 strain, obtained from a patient of Dr. E. Koenig from the Dominican Republic, was used to infect the Jurkat T-cell line. After 6 days in culture, very little virus replication was detected by the reverse transcriptase assay. After the addition on day 6 of iododeoxyuridine (IUDR) (50μg/ml), HIV-1 was released to high levels, as measured by particle-associated reverse transcriptase activity. Within 2 weeks, virus replication decreased to almost a latent state. Reproduced from reference (2535) with permission.

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
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References

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Tables

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Table 5.1

Level of arrest of virus replication in different cell types

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
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Table 5.2

Host-specific interactions of the cellular protein APOBEC3G with viral Vif proteins

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
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Table 5.3

Intracellular retrovirus restriction factors

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
Generic image for table
Table 5.4

Natural intracellular resistance to HIV replication

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
Generic image for table
Table 5.5

Studies of quiescent cells

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
Generic image for table
Table 5.6

Induction of retroviruses from a latent state

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
Generic image for table
Table 5.7

Possible mechanisms of HIV latency

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05
Generic image for table
Table 5.8

Retrovirus latency and persistence

Citation: Levy J. 2007. Intracellular Control of HIV Replication, p 109-131. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch05

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