HIV Envelope Induces Virus Expression from Resting CD4+ T Cells Isolated from HIV-Infected Individuals in the Absence of Markers of Cellular Activation or Apoptosis

Kinter, Audrey; Umscheid, Craig A.; Arthos, James; Cicala, Claudia; Yin, Lu; Jackson, Robert W.; Donoghue, Eileen T.; Ehler, Linda; Adelsberger, Joseph W.; Rabin, Ronald L.; Fauci, Anthony S.

doi:10.4049/jimmunol.170.5.2449

Cited by 49 publications

(41 citation statements)

References 46 publications

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“…Both types of envelopes significantly impacted genes associated with cell proliferation and protein tyrosine kinases, consistent with our previous demonstration that envelopes can induce viral replication in resting cells (19). However, R5 envelopes were more pronounced in their capacity to modulate the p38 MAPK cascade.…”

Section: Discussionsupporting

confidence: 77%

“…However, we find that 9.0% of the genes in cluster 1 overlap with the genes specifically up-regulated in the CD4 ϩ T cell reservoir of viremic individuals, yielding a Fisher's exact P value of 4.3 ϫ 10 Ϫ8 . Consistent with our hypothesis that envelope signaling facilitates the replication of virus from the resting CD4 ϩ T cell reservoir (13,14,19), cell cycle and transcription are among the descriptive terms significantly associated with those 47 genes (Fig. 6).…”

Section: T Cell Pool Latently Infected Resting Cd4supporting

confidence: 73%

“…If this latter scenario is correct, it raises the possibility that envelope engagement of resting CD4 ϩ T cells promotes low level viral replication from this reservoir. As previously noted, we have demonstrated that envelope possesses this capacity to induce virus replication in vitro in PBMCs from HIVinfected individuals (19).…”

Section: Discussionmentioning

confidence: 57%

“…These cells constitute one of the latent reservoirs of HIV that prevents eradication of virus from infected individuals, even after prolonged treatment with potent antiretroviral drugs (17,18). In vitro exposure of resting CD4 ϩ T cells derived from HIV-infected individuals to envelope results in a burst of viral replication (19). Insight into the mechanisms that produce this burst was obtained from a study of the gene expression profiles in peripheral blood mononuclear cells (PBMCs) treated with gp120 derived from an R5 strain of HIV (14).…”

Section: Iv-1 Infection Of Cd4mentioning

confidence: 99%

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R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells

Cicala

Arthos²,

Martinelli³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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HIV envelope binds to and signals through its primary cellular receptor, CD4, and through a coreceptor, either CC chemokine receptor 5 (CCR5) or CXC chemokine receptor 4 (CXCR4). Here, we evaluate the response of peripheral blood mononuclear cells to a panel of genetically diverse R5 and X4 envelope proteins. Modulation of gene expression was evaluated by using oligonucleotide microarrays. Activation of transcription factors was evaluated by using an array of oligonucleotides encoding transcription factor binding sites. Responses were strongly influenced by coreceptor specificity. Treatment of cells from CCR5⌬32 homozygous donors with glycoprotein (gp)120 derived from an R5 virus demonstrated that the majority of responses elicited by R5 envelopes required engagement of CCR5. R5 envelopes, to a greater extent than X4 envelopes, induced the expression of genes belonging to mitogenactivated protein kinase signal transduction pathways and genes regulating the cell cycle. A number of genes induced by R5, but not X4, envelopes were also up-regulated in the resting CD4 ؉ T cell population of HIV-infected individuals. These results suggest that R5 envelope facilitates replication of HIV in the pool of resting CD4 ؉ T cells. Additionally, signaling by R5 gp120 may facilitate the transmission of R5 viruses by inducing a permissive environment for HIV replication.ϩ T cells begins with the fusion of the viral envelope with the outer membrane of a target cell. Fusion is initiated when the viral envelope glycoprotein (gp)120 binds first to CD4 and then to a coreceptor, primarily CC chemokine receptor 5 (CCR5) or CXC chemokine receptor 4 (CXCR4) (1-4). These interactions between gp120 and cell-surface receptors transduce signals in the target cell. Ligation of CD4 by gp120 increases the tyrosine kinase activity of p56lck, a src-related protein kinase associated with the cytoplasmic domain of CD4 on CD4 ϩ T cell membranes (5). Engagement of CCR5 and CXCR4 by gp120 also mediates signaling events (6-9), as evidenced by the rapid mobilization of Ca ϩϩ , and the phosphorylation of intracellular substrates including PYK2 and FAK (10,11). In this respect, the HIV envelope protein delivers a unique near simultaneous dual signal to CD4 ϩ T cells. No protein in the human proteome has been shown to deliver an analogous signal. The response to this stimulus depends on the state of differentiation and activation of the targeted cell. A number of reports demonstrate that envelope induces activated CD4 ϩ T cells to apoptose in vitro (12-15). Envelope proteins have also been shown to disrupt antigen-specific CD4 ϩ T cell responses (16). We have focused on the impact of envelope-mediated signaling on resting CD4 ϩ T cells. These cells constitute one of the latent reservoirs of HIV that prevents eradication of virus from infected individuals, even after prolonged treatment with potent antiretroviral drugs (17,18). In vitro exposure of resting CD4 ϩ T cells derived from HIV-infected individuals to envelope results in a burst of viral replicatio...

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Section: Discussionsupporting

confidence: 77%

Section: T Cell Pool Latently Infected Resting Cd4supporting

confidence: 73%

Section: Discussionmentioning

confidence: 57%

Section: Iv-1 Infection Of Cd4mentioning

confidence: 99%

See 2 more Smart Citations

R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells

Cicala

Arthos²,

Martinelli³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…35 These include the observation that stimulation with R5 gp120 Env trimers triggered calcium fluxes in CD4 ϩ T cells infected in vitro 36 and virus replication in cultures of resting CD4 ϩ T cells of infected persons. 37 Of note, a signaling-deficient R5 HIV-1 was shown to successfully infect monocyte-derived macrophages but failed to replicate thereafter because of a block occurring at a postentry level. 36 Thus, CCR5 engagement by HIV-1 triggers a signaling cascade that leads to productive viral replication, whereas gp120 Env/CXCR4 interaction seems to be devoid of such a function.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 envelope-dependent restriction of CXCR4-using viruses in child but not adult untransformed CD4+ T-lymphocyte lines

Mariani¹,

Brigida

Kajaste‐Rudnitski

et al. 2012

Blood

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Phytohemagglutin-stimulated child and adult leukocytes equally supported CCR5-dependent (R5) and CXCR4-dependent (X4) HIV-1 replication. In contrast, when phytohemagglutin-stimulated leukocytes from either healthy or congenitally immunodeficient children were cultured on feeder cells, they well supported R5, but not X4 HIV-1 replication, whereas both viruses equally spread in adult cells maintained in similar conditions. Both child and adult cells showed similar levels of IntroductionHIV type-1 (HIV-1) infects human beings of all ages and ethnicities. HIV-1 infects T lymphocytes and mononuclear phagocytes by engaging the primary receptor CD4 with its trimeric gp120 envelope (Env). Such an interaction leads to exposure of a second cryptic site of gp120 Env that becomes competent to bind to a chemokine coreceptor (CoR) molecule. Among other chemokine R, only CCR5 and CXCR4 are frequently used in vivo by HIV-1. Viruses using these CoRs are termed R5 and X4, respectively, 1 and CoR use varies with different clinical phases with R5 viruses dominating the early stages and with CXCR4 use being mostly confined to subtype B viruses, although described also in subtype A and E. 2 Furthermore, both in adults and children, infection starts as a monophyletic infection carried on by an R5 virus regardless of the viral phenotype predominant in the transmitter. 3,4 In the case of subtype B infection (dominant in the North America, Europe, and Australia), an extension of CoR use to CXCR4, or the presence of so-called "dual mix" viral phenotypes, occurs in approximately 50% of persons resulting in dual-tropic R5ϫ4 viruses; quite rarely, a true "switch" from R5 to X4 is observed. 5 CXCR4 usage, however, is frequently associated with an accelerated disease progression. 4 HIV-1 infection in children differs from that of adults by several parameters. First, although an acute mononucleosis-like illness is experienced in 50% to 70% of adults, 6 the clinical outcomes of primary HIV infection are not as evident in infants. 7 Second, quantification of plasma viremia during the first months of life frequently shows levels higher than those of acutely infected adults. 8 The following decline in plasma virus in perinatally infected infants usually takes place over years rather than months in the absence of combination antiretroviral therapy (cART), therefore resulting in a higher systemic viral exposure during the first months of life. 9 Third, although a clinically asymptomatic period follows primary HIV infection for many years in most adults (in the absence of cART), approximately 25% of infected children show a rapidly downhill course developing features characteristic of AIDS within the first year of life. 10,11 In addition, the mortality rate of children who develop features of AIDS early in life is substantially higher than for those who become symptomatic later during childhood. 12 However, as in adults, a minority of children do not show any signs or symptoms of AIDS by the age of 8 to 10 years. 10,13 A link between HIV disease prog...

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HIV-1, AIDS, and Related Malignancies

Goodenow

Kohler

Principles of Molecular Medicine

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HIV Envelope Induces Virus Expression from Resting CD4+ T Cells Isolated from HIV-Infected Individuals in the Absence of Markers of Cellular Activation or Apoptosis

Cited by 49 publications

References 46 publications

R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells

R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells

HIV-1 envelope-dependent restriction of CXCR4-using viruses in child but not adult untransformed CD4+ T-lymphocyte lines

HIV-1, AIDS, and Related Malignancies

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