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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

The activation of CD4+ T cells during malaria infection potentially resulted in the apoptosis of CD4+ TCMand TEMcells, leading to a reduction of the SIV reservoir. (A) Pc infection induced the co-expression of HLA-DR and CD38 in CD4+ T cells, which indicated the activation of these cells (1.97 ± 1.47% vs. 1.00 ± 0.61%). (B) A significant positive correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the percentage of apoptotic CD4+ TCM cells during the malaria phase in the two groups of monkeys. (C) A positive correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the percentage of apoptotic CD4+ TEM cells during the malaria phase in the two groups of monkeys. (D) A significant negative correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the SIV iDNA load in PBMCs. The percentages of HLA-DR + CD38 + CD4+ T cells at different time points in the same phase and group were combined to examine the difference between the two groups; the Mann–Whitney U test was utilized, and the data are shown as the mean ± SD. Spearman’s correlation analysis was used to analyze the relationship between the parameters tested in C and D.
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Fig4: The activation of CD4+ T cells during malaria infection potentially resulted in the apoptosis of CD4+ TCMand TEMcells, leading to a reduction of the SIV reservoir. (A) Pc infection induced the co-expression of HLA-DR and CD38 in CD4+ T cells, which indicated the activation of these cells (1.97 ± 1.47% vs. 1.00 ± 0.61%). (B) A significant positive correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the percentage of apoptotic CD4+ TCM cells during the malaria phase in the two groups of monkeys. (C) A positive correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the percentage of apoptotic CD4+ TEM cells during the malaria phase in the two groups of monkeys. (D) A significant negative correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the SIV iDNA load in PBMCs. The percentages of HLA-DR + CD38 + CD4+ T cells at different time points in the same phase and group were combined to examine the difference between the two groups; the Mann–Whitney U test was utilized, and the data are shown as the mean ± SD. Spearman’s correlation analysis was used to analyze the relationship between the parameters tested in C and D.

Mentions: Our previous study using the rhesus monkey model indicated that Pc infection activated CD4+ T cells in SIV-negative animals [7]. In the present study, we examined activation markers of CD4+ T cells in SIV-positive animals under ART, including HLA-DR and CD38 co-expression on CD4+ T cells and plasma cytokine concentrations. Malaria did not increase the concentrations of plasma cytokines such as TNF-α, interleukin-7 (IL-7), interleukin-2 (IL-2, represented by its activity marker, the IL-2 receptor, or IL-2R) and IL-6, which have been shown to promote provirus reactivation [18-21] and to represent activation of the immune system (Additional file 2: Figure S2A). However, CD4+ T cell activation was found in the ART + Pc group because a greater percentage of HLA-DR + CD38 + CD4+ T cells, which is a robust measure of CD4+ T cell activation, was observed (Figure 4A). Higher concentrations of plasma neopterin (an activity marker of interferon-gamma, or IFN-γ) were also observed in the ART + Pc group during malaria infection (Additional file 2: Figure S2B). There was a significant positive correlation between plasma neopterin levels and the percentage of HLA-DR + CD38 + CD4+ T cells during the malaria phase (P = 0.002; r = 0.493; Additional file 2: Figure S2C), suggesting that the activation of CD4+ T cells was associated with higher concentrations of neopterin induced by malaria. Moreover, the CD4+ T cell activation level, as indicated by the percentage of HLA-DR + CD38 + CD4+ T cells, was shown to be positively correlated with the percentage of annexin V + CD4+ TCM and TEM cells during the malaria phase (P = 0.031, r = 0.44 and P = 0.050, r = 0.404; respectively; Figure 4B and C). The CD4+ T cell activation level during the malaria phase was also negatively correlated with the iDNA levels in PBMCs (P = 0.005, r = −0.458; Figure 4D). Additionally, a greater percentage of CCR5 + CD4+ T cells, which have also been linked to the activation of CD4+ T cells and the immune system [22,23], was observed in the ART + Pc group during malaria infection (Additional file 2: Figure S2D). These results suggested that malaria activated CD4+ T cells, which might have led to the apoptosis of certain CD4+ TCM and TEM cells and contributed to the reduction of the SIV reservoir.Figure 4


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)

The activation of CD4+ T cells during malaria infection potentially resulted in the apoptosis of CD4+ TCMand TEMcells, leading to a reduction of the SIV reservoir. (A) Pc infection induced the co-expression of HLA-DR and CD38 in CD4+ T cells, which indicated the activation of these cells (1.97 ± 1.47% vs. 1.00 ± 0.61%). (B) A significant positive correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the percentage of apoptotic CD4+ TCM cells during the malaria phase in the two groups of monkeys. (C) A positive correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the percentage of apoptotic CD4+ TEM cells during the malaria phase in the two groups of monkeys. (D) A significant negative correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the SIV iDNA load in PBMCs. The percentages of HLA-DR + CD38 + CD4+ T cells at different time points in the same phase and group were combined to examine the difference between the two groups; the Mann–Whitney U test was utilized, and the data are shown as the mean ± SD. Spearman’s correlation analysis was used to analyze the relationship between the parameters tested in C and D.
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Related In: Results  -  Collection

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Fig4: The activation of CD4+ T cells during malaria infection potentially resulted in the apoptosis of CD4+ TCMand TEMcells, leading to a reduction of the SIV reservoir. (A) Pc infection induced the co-expression of HLA-DR and CD38 in CD4+ T cells, which indicated the activation of these cells (1.97 ± 1.47% vs. 1.00 ± 0.61%). (B) A significant positive correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the percentage of apoptotic CD4+ TCM cells during the malaria phase in the two groups of monkeys. (C) A positive correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the percentage of apoptotic CD4+ TEM cells during the malaria phase in the two groups of monkeys. (D) A significant negative correlation was noted between the percentage of HLA-DR + CD38 + CD4+ T cells and the SIV iDNA load in PBMCs. The percentages of HLA-DR + CD38 + CD4+ T cells at different time points in the same phase and group were combined to examine the difference between the two groups; the Mann–Whitney U test was utilized, and the data are shown as the mean ± SD. Spearman’s correlation analysis was used to analyze the relationship between the parameters tested in C and D.
Mentions: Our previous study using the rhesus monkey model indicated that Pc infection activated CD4+ T cells in SIV-negative animals [7]. In the present study, we examined activation markers of CD4+ T cells in SIV-positive animals under ART, including HLA-DR and CD38 co-expression on CD4+ T cells and plasma cytokine concentrations. Malaria did not increase the concentrations of plasma cytokines such as TNF-α, interleukin-7 (IL-7), interleukin-2 (IL-2, represented by its activity marker, the IL-2 receptor, or IL-2R) and IL-6, which have been shown to promote provirus reactivation [18-21] and to represent activation of the immune system (Additional file 2: Figure S2A). However, CD4+ T cell activation was found in the ART + Pc group because a greater percentage of HLA-DR + CD38 + CD4+ T cells, which is a robust measure of CD4+ T cell activation, was observed (Figure 4A). Higher concentrations of plasma neopterin (an activity marker of interferon-gamma, or IFN-γ) were also observed in the ART + Pc group during malaria infection (Additional file 2: Figure S2B). There was a significant positive correlation between plasma neopterin levels and the percentage of HLA-DR + CD38 + CD4+ T cells during the malaria phase (P = 0.002; r = 0.493; Additional file 2: Figure S2C), suggesting that the activation of CD4+ T cells was associated with higher concentrations of neopterin induced by malaria. Moreover, the CD4+ T cell activation level, as indicated by the percentage of HLA-DR + CD38 + CD4+ T cells, was shown to be positively correlated with the percentage of annexin V + CD4+ TCM and TEM cells during the malaria phase (P = 0.031, r = 0.44 and P = 0.050, r = 0.404; respectively; Figure 4B and C). The CD4+ T cell activation level during the malaria phase was also negatively correlated with the iDNA levels in PBMCs (P = 0.005, r = −0.458; Figure 4D). Additionally, a greater percentage of CCR5 + CD4+ T cells, which have also been linked to the activation of CD4+ T cells and the immune system [22,23], was observed in the ART + Pc group during malaria infection (Additional file 2: Figure S2D). These results suggested that malaria activated CD4+ T cells, which might have led to the apoptosis of certain CD4+ TCM and TEM cells and contributed to the reduction of the SIV reservoir.Figure 4

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