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Plasmodium infection reduces the volume of the viral reservoir in SIV-infected rhesus macaques receiving antiretroviral therapy.

Zhan XY, Wang N, Liu G, Qin L, Xu W, Zhao S, Qin L, Chen X - Retrovirology (2014)

Bottom Line: This reduction might be attributable to malaria-mediated activation and apoptotic induction of memory CD4+ T cells.Further studies indicated that histone acetylation and NF-kappaB (NF-κB) activation in resting CD4+ T cells may also play an important role in this reduction.As more HIV-1-infected individuals in malaria-endemic areas receive ART, we should explore whether any of the patients co-infected with Plasmodium experience virologic benefits.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pathogen Biology, State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Luogang District, Guangzhou Science Park, Guangzhou, 510530, Guangdong Province, China. zhan_xiaoyong@gibh.ac.cn.

ABSTRACT

Background: Previous studies indicated that Plasmodium infection activates the immune system, including memory CD4+ T cells, which constitute the reservoir of human immunodeficiency virus type-1 (HIV-1). Therefore, we postulated that co-infection with malaria might activate the reservoir of HIV-1. To test this hypothesis, we used a rhesus macaque model of co-infection with malaria and simian immunodeficiency virus (SIV), along with antiretroviral therapy (ART).

Results: Our results showed that Plasmodium infection reduced both the replication-competent virus pool in resting CD4+ T cells and the integrated virus DNA (iDNA) load in peripheral blood mononuclear cells in the monkeys. This reduction might be attributable to malaria-mediated activation and apoptotic induction of memory CD4+ T cells. Further studies indicated that histone acetylation and NF-kappaB (NF-κB) activation in resting CD4+ T cells may also play an important role in this reduction.

Conclusions: The findings of this work expand our knowledge of the interaction between these two diseases. As more HIV-1-infected individuals in malaria-endemic areas receive ART, we should explore whether any of the patients co-infected with Plasmodium experience virologic benefits.

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Related in: MedlinePlus

In vivoandin vitroassays for NF-κB activation. (A–B) An in vivo assay as performed to measure NF-κB activation levels during malaria infection. In particular, PBMCs were isolated from monkeys in the two groups at different time points for each phase. We counted the cells with NF-κB nuclear staining and classified them as cells with NF-κB activation. (A) NF-κB nuclear transport was measured by immunofluorescence to determine the activation of NF-κB in PBMCs. DAPI staining was used to identify the nuclear region to assess gross cell morphology. The white arrows show the NF-κB-positive nuclei in PBMCs. These cells were considered to contain activated NF-κB. (B) The ART + Pc group maintained higher levels of NF-κB activation in PBMCs during malaria infection, as indicated by the percentages of NF-κB-positive nuclei in the PBMCs (16.23 ± 3.12% vs. 9.69 ± 1.74%). The data in this figure are presented as the means, and the error bars show the SD. (C-D)In vitro assays were performed to detect specific factors associated with malaria that activate NF-κB. PBMCs isolated from monkeys were stimulated with Pf extract or 25 ng/ml PHA plus 1 μg/ml LPS. NF-κB activation in the cells was then measured by ELISA. (C) Pf soluble extract induced an increase in activated NF-κB in J-Lat cells at 5 μg/ml after a 2- or 4-hour incubation. (D) Pf soluble extract induced an increase in activated NF-κB in RM PBMCs at 50 μg/ml after a 2- or 4-hour incubation. The percentages of NF-κB+ PBMCs at different time points of the same phase in the same group were combined for statistical analyses. The Mann–Whitney U test was utilized to examine the difference in this parameter between the two groups. One-way ANOVA was used to compare the variables in C and D. The data in this figure are presented as the means, and the error bars indicate the SD.
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Fig7: In vivoandin vitroassays for NF-κB activation. (A–B) An in vivo assay as performed to measure NF-κB activation levels during malaria infection. In particular, PBMCs were isolated from monkeys in the two groups at different time points for each phase. We counted the cells with NF-κB nuclear staining and classified them as cells with NF-κB activation. (A) NF-κB nuclear transport was measured by immunofluorescence to determine the activation of NF-κB in PBMCs. DAPI staining was used to identify the nuclear region to assess gross cell morphology. The white arrows show the NF-κB-positive nuclei in PBMCs. These cells were considered to contain activated NF-κB. (B) The ART + Pc group maintained higher levels of NF-κB activation in PBMCs during malaria infection, as indicated by the percentages of NF-κB-positive nuclei in the PBMCs (16.23 ± 3.12% vs. 9.69 ± 1.74%). The data in this figure are presented as the means, and the error bars show the SD. (C-D)In vitro assays were performed to detect specific factors associated with malaria that activate NF-κB. PBMCs isolated from monkeys were stimulated with Pf extract or 25 ng/ml PHA plus 1 μg/ml LPS. NF-κB activation in the cells was then measured by ELISA. (C) Pf soluble extract induced an increase in activated NF-κB in J-Lat cells at 5 μg/ml after a 2- or 4-hour incubation. (D) Pf soluble extract induced an increase in activated NF-κB in RM PBMCs at 50 μg/ml after a 2- or 4-hour incubation. The percentages of NF-κB+ PBMCs at different time points of the same phase in the same group were combined for statistical analyses. The Mann–Whitney U test was utilized to examine the difference in this parameter between the two groups. One-way ANOVA was used to compare the variables in C and D. The data in this figure are presented as the means, and the error bars indicate the SD.

Mentions: Given that previous studies demonstrated that NF-κB activation was associated with provirus reactivation [26,27], we investigated NF-κB translocation in monkey PBMCs in selected phases. This experiment used immunofluorescence confocal microscopy to assess the activation level of NF-κB. The percentage of NF-κB+ cells was significantly higher in the PBMCs of monkeys in the ART + Pc group during Plasmodium infection compared with the percentage in the ART group (means of 16.23% and 9.69%, respectively; P < 0.001; Figure 7A and B). This result suggested that the NF-κB signaling pathway might participate in the latent virus reactivation induced by malaria. An in vitro culture assay also indicated that 5 μg/ml or 50 μg/ml Plasmodium extract could induce NF-κB activation in J-Lat cells and monkey PBMCs (Figure 7C and D).Figure 7


Plasmodium infection reduces the volume of the viral reservoir in SIV-infected rhesus macaques receiving antiretroviral therapy.

Zhan XY, Wang N, Liu G, Qin L, Xu W, Zhao S, Qin L, Chen X - Retrovirology (2014)

In vivoandin vitroassays for NF-κB activation. (A–B) An in vivo assay as performed to measure NF-κB activation levels during malaria infection. In particular, PBMCs were isolated from monkeys in the two groups at different time points for each phase. We counted the cells with NF-κB nuclear staining and classified them as cells with NF-κB activation. (A) NF-κB nuclear transport was measured by immunofluorescence to determine the activation of NF-κB in PBMCs. DAPI staining was used to identify the nuclear region to assess gross cell morphology. The white arrows show the NF-κB-positive nuclei in PBMCs. These cells were considered to contain activated NF-κB. (B) The ART + Pc group maintained higher levels of NF-κB activation in PBMCs during malaria infection, as indicated by the percentages of NF-κB-positive nuclei in the PBMCs (16.23 ± 3.12% vs. 9.69 ± 1.74%). The data in this figure are presented as the means, and the error bars show the SD. (C-D)In vitro assays were performed to detect specific factors associated with malaria that activate NF-κB. PBMCs isolated from monkeys were stimulated with Pf extract or 25 ng/ml PHA plus 1 μg/ml LPS. NF-κB activation in the cells was then measured by ELISA. (C) Pf soluble extract induced an increase in activated NF-κB in J-Lat cells at 5 μg/ml after a 2- or 4-hour incubation. (D) Pf soluble extract induced an increase in activated NF-κB in RM PBMCs at 50 μg/ml after a 2- or 4-hour incubation. The percentages of NF-κB+ PBMCs at different time points of the same phase in the same group were combined for statistical analyses. The Mann–Whitney U test was utilized to examine the difference in this parameter between the two groups. One-way ANOVA was used to compare the variables in C and D. The data in this figure are presented as the means, and the error bars indicate the SD.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4269176&req=5

Fig7: In vivoandin vitroassays for NF-κB activation. (A–B) An in vivo assay as performed to measure NF-κB activation levels during malaria infection. In particular, PBMCs were isolated from monkeys in the two groups at different time points for each phase. We counted the cells with NF-κB nuclear staining and classified them as cells with NF-κB activation. (A) NF-κB nuclear transport was measured by immunofluorescence to determine the activation of NF-κB in PBMCs. DAPI staining was used to identify the nuclear region to assess gross cell morphology. The white arrows show the NF-κB-positive nuclei in PBMCs. These cells were considered to contain activated NF-κB. (B) The ART + Pc group maintained higher levels of NF-κB activation in PBMCs during malaria infection, as indicated by the percentages of NF-κB-positive nuclei in the PBMCs (16.23 ± 3.12% vs. 9.69 ± 1.74%). The data in this figure are presented as the means, and the error bars show the SD. (C-D)In vitro assays were performed to detect specific factors associated with malaria that activate NF-κB. PBMCs isolated from monkeys were stimulated with Pf extract or 25 ng/ml PHA plus 1 μg/ml LPS. NF-κB activation in the cells was then measured by ELISA. (C) Pf soluble extract induced an increase in activated NF-κB in J-Lat cells at 5 μg/ml after a 2- or 4-hour incubation. (D) Pf soluble extract induced an increase in activated NF-κB in RM PBMCs at 50 μg/ml after a 2- or 4-hour incubation. The percentages of NF-κB+ PBMCs at different time points of the same phase in the same group were combined for statistical analyses. The Mann–Whitney U test was utilized to examine the difference in this parameter between the two groups. One-way ANOVA was used to compare the variables in C and D. The data in this figure are presented as the means, and the error bars indicate the SD.
Mentions: Given that previous studies demonstrated that NF-κB activation was associated with provirus reactivation [26,27], we investigated NF-κB translocation in monkey PBMCs in selected phases. This experiment used immunofluorescence confocal microscopy to assess the activation level of NF-κB. The percentage of NF-κB+ cells was significantly higher in the PBMCs of monkeys in the ART + Pc group during Plasmodium infection compared with the percentage in the ART group (means of 16.23% and 9.69%, respectively; P < 0.001; Figure 7A and B). This result suggested that the NF-κB signaling pathway might participate in the latent virus reactivation induced by malaria. An in vitro culture assay also indicated that 5 μg/ml or 50 μg/ml Plasmodium extract could induce NF-κB activation in J-Lat cells and monkey PBMCs (Figure 7C and D).Figure 7

Bottom Line: This reduction might be attributable to malaria-mediated activation and apoptotic induction of memory CD4+ T cells.Further studies indicated that histone acetylation and NF-kappaB (NF-κB) activation in resting CD4+ T cells may also play an important role in this reduction.As more HIV-1-infected individuals in malaria-endemic areas receive ART, we should explore whether any of the patients co-infected with Plasmodium experience virologic benefits.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pathogen Biology, State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Luogang District, Guangzhou Science Park, Guangzhou, 510530, Guangdong Province, China. zhan_xiaoyong@gibh.ac.cn.

ABSTRACT

Background: Previous studies indicated that Plasmodium infection activates the immune system, including memory CD4+ T cells, which constitute the reservoir of human immunodeficiency virus type-1 (HIV-1). Therefore, we postulated that co-infection with malaria might activate the reservoir of HIV-1. To test this hypothesis, we used a rhesus macaque model of co-infection with malaria and simian immunodeficiency virus (SIV), along with antiretroviral therapy (ART).

Results: Our results showed that Plasmodium infection reduced both the replication-competent virus pool in resting CD4+ T cells and the integrated virus DNA (iDNA) load in peripheral blood mononuclear cells in the monkeys. This reduction might be attributable to malaria-mediated activation and apoptotic induction of memory CD4+ T cells. Further studies indicated that histone acetylation and NF-kappaB (NF-κB) activation in resting CD4+ T cells may also play an important role in this reduction.

Conclusions: The findings of this work expand our knowledge of the interaction between these two diseases. As more HIV-1-infected individuals in malaria-endemic areas receive ART, we should explore whether any of the patients co-infected with Plasmodium experience virologic benefits.

Show MeSH
Related in: MedlinePlus