Evolution of subtype C HIV-1 Env in a slowly progressing Zambian infant

Zhou, Hong; Hoffmann, Federico G.; He, Jun; He, Xiang; Kankasa, Chipepo; Ruprecht, Ruth M.; West, John T.; Ortı́, Guillermo; Wood, Charles

doi:10.1186/1742-4690-2-67

Cited by 26 publications

(21 citation statements)

References 64 publications

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“…Clade B primary viruses (D02-2562 BG and G0048 CPx) were isolated from the basal ganglia (BG) or choroid plexus (CPx) in the trigone of the lateral ventricle of infected patients with HIV encephalitis (Burkala et al, 2005). Clade C primary isolate (2669I) was isolated from peripheral blood mononuclear cells of HIV-1 infected infant pairs in Africa (Zhang et al, 2005; Zhang et al, 2006). The 50% tissue culture infective dose (TCID 50 ) of each viral stock was determined by monitoring infection of TZM-bl cells obtained through NIH AIDS Research & Reference Reagent Program, and all primary viruses were infected with 800 TCID 50 /ml.…”

Section: Methodsmentioning

confidence: 99%

Glutaminase Dysregulation in HIV-1-Infected Human Microglia Mediates Neurotoxicity: Relevant to HIV-1-Associated Neurocognitive Disorders

Huang¹,

Zhao²,

Jia³

et al. 2011

J. Neurosci.

127

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Microglia represent the main cellular targets of HIV-1 in the brain. Infected and/or activated microglia play a pathogenic role in HIV-associated neurocognitive disorders (HAND) by instigating primary dysfunction and subsequent death of neurons. Although microglia are known to secrete neurotoxins when infected with HIV-1, the detailed mechanism of neurotoxicity remains unclear. Using a human microglia primary culture system and macrophage-tropic HIV-1 strains, we have now demonstrated that HIV-1 infection of microglia resulted in a significant increase in extracellular glutamate concentrations and elevated levels of neurotoxicity. RNA and protein analysis revealed upregulation of the glutamate-generating enzyme glutaminase isoform glutaminase C in HIV-1-infected microglia. The clinical relevance of these findings was further corroborated with investigation of post mortem brain tissues. The glutaminase C levels in the brain tissues of HIV dementia individuals were significantly higher than HIV serum negative control and correlated with elevated concentrations of glutamate. When glutaminase was subsequently inhibited by siRNA or by a small molecular inhibitor, the HIV-induced glutamate production and the neuronal loss was diminished. In conclusion, these findings support glutaminase as a potential component of the HAND pathogenic process as well as a novel therapeutic target in their treatment.

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Section: Methodsmentioning

confidence: 99%

Glutaminase Dysregulation in HIV-1-Infected Human Microglia Mediates Neurotoxicity: Relevant to HIV-1-Associated Neurocognitive Disorders

Huang¹,

Zhao²,

Jia³

et al. 2011

J. Neurosci.

127

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“…Notably, further investigations into interclade differences in the Env V1V2 loops and the CD4 binding site may aid in explaining the distinct association between antibodies against these regions and MTCT risk in the WITS and BAN cohorts. As over half of current infant HIV-1 infections occur in sub-Saharan populations infected with clade C HIV (25), it is critical to study additional clade C virus-infected cohorts to confirm the association we observed in the BAN cohort. A study of clade C HIV-1-infected cohorts with a higher proportion of intrapartum transmission cases would be useful to further shed light on humoral immune correlates of distinct modes of MTCT.…”

Section: Discussionmentioning

confidence: 99%

Maternal Humoral Immune Correlates of Peripartum Transmission of Clade C HIV-1 in the Setting of Peripartum Antiretrovirals

Mutucumarana

Eudailey

McGuire

et al. 2017

Clin Vaccine Immunol

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Despite the widespread use of antiretrovirals (ARV), more than 150,000 pediatric HIV-1 infections continue to occur annually. Supplemental strategies are necessary to eliminate pediatric HIV infections. We previously reported that maternal HIV envelope-specific anti-V3 IgG and CD4 binding site-directed antibodies, as well as tier 1 virus neutralization, predicted a reduced risk of mother-to-child transmission (MTCT) of HIV-1 in the pre-ARV era U.S.-based Women and Infants Transmission Study (WITS) cohort. As the majority of ongoing pediatric HIV infections occur in subSaharan Africa, we sought to determine if the same maternal humoral immune correlates predicted MTCT in a subset of the Malawian Breastfeeding, Antiretrovirals, and Nutrition (BAN) cohort of HIV-infected mothers (n ϭ 88, with 45 transmitting and 43 nontransmitting). Women and infants received ARV at delivery; thus, the majority of MTCT was in utero (91%). In a multivariable logistic regression model, neither maternal anti-V3 IgG nor clade C tier 1 virus neutralization was associated with MTCT. Unexpectedly, maternal CD4 binding-site antibodies and anti-variable loop 1 and 2 (V1V2) IgG were associated with increased MTCT, independent of maternal viral load. Neither infant envelope (Env)-specific IgG levels nor maternal IgG transplacental transfer efficiency was associated with transmission. Distinct humoral immune correlates of MTCT in the BAN and WITS cohorts could be due to differences between transmission modes, virus clades, or maternal antiretroviral use. The association between specific maternal antibody responses and in utero transmission, which is distinct from potentially protective maternal antibodies in the WITS cohort, underlines the importance of investigating additional cohorts with well-defined transmission modes to understand the role of antibodies during HIV-1 MTCT.

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“…Clade B primary viruses (D02-2562 BG, A00-086 CPx, D02-2562 Sp, and G0048 CPx) were isolated from the spleen (Sp), basal ganglia (BG), or choroid plexus (CPx) in the trigone of the lateral ventricle of infected patients with HIV encephalitis (HIVE) (Burkala et al, 2005). Clade C primary isolates (2873M, 2669M, 1084M, and 1157I) were isolated from PBMCs from a HIV-1-infected mother and infant pair in Africa (Zhang et al, 2005; Zhang et al, 2006). After human MDMs were incubated with the virus overnight, the medium was replaced with MDM culture medium and half the media was replaced every other day.…”

Section: Methodsmentioning

confidence: 99%

RIG-I detects HIV-1 infection and mediates type I interferon response in human macrophages from patients with HIV-1-associated neurocognitive disorders

Wang¹,

Huang²,

Huang³

et al. 2015

Genet. Mol. Res.

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The aim of this study was to explore the precise role of retinoic acid-inducible gene-I (RIG-I) signaling in human immunodeficiency virus type 1 (HIV-1)-infected macrophages from patients with HIV-1-associated neurocognitive disorders (HAND). Postmortem brain tissues were collected from patients with HIV-1-associated dementia and were compared to samples collected from HIV serum-positive patients without dementia and HIV serum-negative patients. A human monocyte-derived macrophage (MDM) primary culture system was established to evaluate the expression of RIG-I in these samples. Knockdown of RIG-I pathways genes was employed and STAT1 expression and phosphorylation levels were examined to explore the molecular mechanisms of HAND. The expression of RIG-I in postmortem brain tissue from HAND patients was significantly higher than in patients who were HIV serum-positive without dementia or HIV serum-negative. Moreover, we demonstrated that HIV-1 infection could result in a significant increase in the level of RIG-I in human MDMs. Moreover, a correlation was found between the increase in RIG-I expression and STAT1 expression and phosphorylation. Accordingly, knockdown of RIG-I decreased the phosphorylation of STAT1 and downregulated interferon-related genes. These observations highlight the importance of RIG-I signaling in anti-HIV innate immunity in macrophages, which may be beneficial for the treatment of HIV and aid in the understanding of the neuropathogenesis of HAND.

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Evolution of subtype C HIV-1 Env in a slowly progressing Zambian infant

Cited by 26 publications

References 64 publications

Glutaminase Dysregulation in HIV-1-Infected Human Microglia Mediates Neurotoxicity: Relevant to HIV-1-Associated Neurocognitive Disorders

Glutaminase Dysregulation in HIV-1-Infected Human Microglia Mediates Neurotoxicity: Relevant to HIV-1-Associated Neurocognitive Disorders

Maternal Humoral Immune Correlates of Peripartum Transmission of Clade C HIV-1 in the Setting of Peripartum Antiretrovirals

RIG-I detects HIV-1 infection and mediates type I interferon response in human macrophages from patients with HIV-1-associated neurocognitive disorders

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