Inhibition of pathogenic SHIV replication in macaques treated with antisense DNA of interleukin-4

Dhillon, Navneet K.; Sui, Yongjun; Potula, Raghava; Dhillon, Sukhbir; Adany, Istvan; Li, Zhuang; Villinger, François; Pinson, David M.; Narayan, Opendra; Buch, Shilpa

doi:10.1182/blood-2004-09-3515

Cited by 10 publications

(11 citation statements)

References 32 publications

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“…IL-4 and IL-13 expression has been found to be present in the normal brain (Szczepanik et al 2001), and IL-4 has been found to have a role in the CNS and other pathologies induced by SHIV infection in macaques (Buch et al 2004;Dhillon et al 2005). The cellular sources of IL-4 and IL-13 in the brain, however, are uncertain.…”

Section: Discussionmentioning

confidence: 99%

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Yadav

Burudi

Alirezaei

et al. 2007

Glia

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Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-γ and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-γ in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-γ induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-γ, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-γ induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.

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Section: Discussionmentioning

confidence: 99%

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Yadav

Burudi

Alirezaei

et al. 2007

Glia

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“…Previous studies (10,28) have suggested that Th2-inducing parasite infestations enhance lentiviral production at local sites. Work in our labo- ratory had indicated that the IL-4 and the chemokine, MCP-1, selectively enhanced replication of CXCR4-utilizing viruses (11,13,33). Other studies have confirmed the importance of these cytokines in supporting SIV (7) and HIV replication (18,19,32,37).…”

Section: Discussionmentioning

confidence: 67%

“…The dramatic effect of host factors on replication of the virus was identified in our subsequent studies. In previous reports, we (26,33) have shown that monocyte chemotactic protein-1 (MCP-1), CXC chemokine ligand 10 (CXCL10), interleukin-4 (IL-4), and platelet-derived growth factor (PDGF) caused enhancement of viral replication in macrophages, and these cytokines were found in abundance in inflamed virus-infected lungs of macaques (8,11,33).…”

Section: Pneumonia Is a Major Complication Of Human Immunodeficiency mentioning

confidence: 99%

“…Simian immunodeficiency virus (SIV) and simian HIV (SHIV) infections in macaques have reproduced the pathogenesis of HIV infection in macaques and have been used as models to explore mechanisms of pathogenesis, treatment strategies, and vaccine development against HIV (4,11,17,20). Pneumonia is a rare complication of the disease in macaques, even in animals that have been rendered severely immunodeficient by the virus.…”

Section: Pneumonia Is a Major Complication Of Human Immunodeficiency mentioning

confidence: 99%

“…Total RNA from the three regions of the lungs was extracted with TRIzol (Invitrogen) (11). Viral gag mRNA was quantified using real-time RT-PCR from total RNA isolated from lung tissues.…”

Section: Animalsmentioning

confidence: 99%

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Bleomycin treatment causes enhancement of virus replication in the lungs of SHIV-infected macaques

Dhillon¹,

Pinson²,

Dhillon³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pneumonia is a major complication of human immunodeficiency virus (HIV) pathogenesis but it develops only after prolonged infection. We used the macaque model to explore a hypothesis that the disease is a two-stage process, the first stage being establishment of the viral infection in the lung and the second being amplification of virus replication by host factors induced by chemical agents or opportunistic pathogens in the lung. Bleomycin, a chemical known to induce diffuse alveolar damage and pulmonary fibrosis with accumulation of macrophages and a rich T helper type 2 (Th2) cytokine environment, was inoculated intratracheally into five of eight SHIV 89.6P-infected macaques and into one uninfected macaque. Three additional simian HIV (SHIV)-infected macaques without bleomycin treatment served as untreated virus controls. Although none of the animals became clinically ill, bleomycin induced classical host responses in the lungs of all the treated, virus-infected macaques. There was enhanced production of the chemokine, monocyte chemotactic protein-1 (MCP-1), that had previously been shown to cause enhanced replication of the virus. Four of the five treated animals developed more productive SHIV infection in the lungs compared with the infected untreated animals. Enhanced virus replication was found primarily in infiltrating macrophages. Enhanced replication of the virus in the lungs was associated with host factors induced by the drug and supported the hypothesis for a two-stage process of pulmonary pathogenesis.

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Polymorphisms in the interleukin-4 receptor α chain gene influence susceptibility to HIV-1 infection and its progression to AIDS

et al. 2005

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Interleukin (IL) 4 is a key T helper-2 cytokine that downregulates and upregulates CCR5 and CXCR4, respectively, the main coreceptors for HIV. Our objective is to investigate whether single-nucleotide polymorphisms (SNPs) in the IL-4 receptor alpha chain gene (IL4RA) affect HIV infection and its progression to AIDS. The I50V SNP in exon 5 and the haplotypes of six SNPs in exon 12 (E375A, C406R, S411L, S478P, Q551R, and V554I) were studied by polymerase chain reaction and sequencing in 30 HIV+ long-term nonprogressors (LTNP), 36 HIV+ typical progressors (TP), 55 highly exposed but uninfected individuals (EU), 25 EU-sexuals (EU-Sex; mostly women) and 30 EU-hemophiliacs (EU-Hem; hepatitis C virus+), and 97 healthy controls (HC), all Caucasians and lacking CCR5Delta32 homozygosity. V50 homozygosity was increased in LTNP (44%) compared with the other groups [p = 0.005; relative risk ratio = 3.4, 95% confidence interval (CI) = 1.12-10.6, p = 0.03]. The most common (C) exon 12 haplotype, ECSSQV, predominated in all groups, but uncommon (U) haplotypes were increased in HIV+ individuals (n = 64), especially in those (51 of 64) infected via parenteral exposure (35.3%) compared with HC (20.4%) and EU-Hem (18.4%) [p = 0.01; odds ratio (OR) = 2.14, 95% CI = 1.25-3.67, p = 0.01]. EU-Sex also had an increased frequency of U-haplotypes (34.8%) (OR = 2.10, 95% CI = 1.03-4.21, p = 0.01) as well as an increased frequency of CU + UU genotypes (60.9%) compared with HC (38.2%) and EU-Hem (26.6%) (p = 0.043). Distributions of genotypes fitted Hardy-Weinberg equilibrium. Data suggest that V50 homozygosity associates with slow progression and that exon 12 U-haplotypes might be associated with both susceptibility to infection via parenteral route and resistance to infection via sexual exposure. Further studies are required to confirm these findings.

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Inhibition of pathogenic SHIV replication in macaques treated with antisense DNA of interleukin-4

Cited by 10 publications

References 32 publications

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Bleomycin treatment causes enhancement of virus replication in the lungs of SHIV-infected macaques

Polymorphisms in the interleukin-4 receptor α chain gene influence susceptibility to HIV-1 infection and its progression to AIDS

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