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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

Pc infection induced CD4+ TCM and TEM cell apoptosis during the malaria phase. (A) During the malaria phase, the apoptosis level of CD4+ TCM cells in the ART + Pc group was higher than that in the ART group, especially during acute malaria (weeks 49–53), although this difference was not significant (10.24 ± 7.34% vs. 6.98 ± 3.77%, P = 0.12; perhaps the limited significance was a result of the small number of monkeys). (B) Pc infection induced higher levels of apoptosis of CD4+ TEM cells throughout the malaria phase (12.09 ± 10.58% vs. 7.46 ± 6.81%). (C) A negative correlation was noted between the percentage of apoptotic CD4+ TCM cells and the SIV iDNA load in PBMCs during the malaria phase. (D) An approximate negative correlation was noted between the percentage of apoptotic CD4+ TEM cells and the SIV iDNA load in PBMCs during the malaria phase. Variables at different time points in the same phase and group were combined for statistical analyses. The Mann–Whitney U test was utilized. Pearson’s correlation analysis was used to analyze the relationship between the parameters tested in C and D.
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Fig3: Pc infection induced CD4+ TCM and TEM cell apoptosis during the malaria phase. (A) During the malaria phase, the apoptosis level of CD4+ TCM cells in the ART + Pc group was higher than that in the ART group, especially during acute malaria (weeks 49–53), although this difference was not significant (10.24 ± 7.34% vs. 6.98 ± 3.77%, P = 0.12; perhaps the limited significance was a result of the small number of monkeys). (B) Pc infection induced higher levels of apoptosis of CD4+ TEM cells throughout the malaria phase (12.09 ± 10.58% vs. 7.46 ± 6.81%). (C) A negative correlation was noted between the percentage of apoptotic CD4+ TCM cells and the SIV iDNA load in PBMCs during the malaria phase. (D) An approximate negative correlation was noted between the percentage of apoptotic CD4+ TEM cells and the SIV iDNA load in PBMCs during the malaria phase. Variables at different time points in the same phase and group were combined for statistical analyses. The Mann–Whitney U test was utilized. Pearson’s correlation analysis was used to analyze the relationship between the parameters tested in C and D.

Mentions: Induction of memory-cell apoptosis potentially leads to reduction of SIV reservoirs in rhesus macaques [16]. To determine whether Pc infection affects CD4+ TCM and TEM cell viability, we measured the percentages of CD4+ TCM and TEM cells with annexin V expressed on the cell membrane. The marker Ki67 was also used to evaluate the proliferation of these cells. CD28 + CD95 + CD4+ T cells were defined as CD4+ TCM cells, CD28 + CD95-CD4+ T cells were defined as CD4+ TEM cells in rhesus macaques according to previously report [17]. Our results suggested that Pc infection did not increase the proliferation levels of CD4+ TCM and TEM cells (data not shown). However, the apoptosis levels of CD4+ TCM cells in the ART + Pc group were higher than those in the ART group during the malaria phase (especially during the acute phase, from weeks 49–53; means of 8.25% and 6.56%, respectively; P = 0.12; Figure 3A). There were also significantly more apoptotic CD4+ TEM cells in the ART + Pc group than in the ART group (means of 12.09% and 7.46%, respectively; P = 0.046; Figure 3B). We also observed that the number of iDNA copies in PBMCs during the malaria phase was negatively correlated with the apoptosis levels of CD4+ TCM cells in the two groups (P = 0.025, r = −0.372; Figure 3C). Additionally, the number of iDNA copies was negatively correlated with the apoptosis levels of CD4+ TEM cells (P = 0.11, r = −0.270, respectively; Figure 3D). These results suggested that the reduction of the viral reservoir in the ART + Pc group might have been associated with the increased levels of CD4+ TCM and TEM cell apoptosis during the course of malaria.Figure 3


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)

Pc infection induced CD4+ TCM and TEM cell apoptosis during the malaria phase. (A) During the malaria phase, the apoptosis level of CD4+ TCM cells in the ART + Pc group was higher than that in the ART group, especially during acute malaria (weeks 49–53), although this difference was not significant (10.24 ± 7.34% vs. 6.98 ± 3.77%, P = 0.12; perhaps the limited significance was a result of the small number of monkeys). (B) Pc infection induced higher levels of apoptosis of CD4+ TEM cells throughout the malaria phase (12.09 ± 10.58% vs. 7.46 ± 6.81%). (C) A negative correlation was noted between the percentage of apoptotic CD4+ TCM cells and the SIV iDNA load in PBMCs during the malaria phase. (D) An approximate negative correlation was noted between the percentage of apoptotic CD4+ TEM cells and the SIV iDNA load in PBMCs during the malaria phase. Variables at different time points in the same phase and group were combined for statistical analyses. The Mann–Whitney U test was utilized. Pearson’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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Fig3: Pc infection induced CD4+ TCM and TEM cell apoptosis during the malaria phase. (A) During the malaria phase, the apoptosis level of CD4+ TCM cells in the ART + Pc group was higher than that in the ART group, especially during acute malaria (weeks 49–53), although this difference was not significant (10.24 ± 7.34% vs. 6.98 ± 3.77%, P = 0.12; perhaps the limited significance was a result of the small number of monkeys). (B) Pc infection induced higher levels of apoptosis of CD4+ TEM cells throughout the malaria phase (12.09 ± 10.58% vs. 7.46 ± 6.81%). (C) A negative correlation was noted between the percentage of apoptotic CD4+ TCM cells and the SIV iDNA load in PBMCs during the malaria phase. (D) An approximate negative correlation was noted between the percentage of apoptotic CD4+ TEM cells and the SIV iDNA load in PBMCs during the malaria phase. Variables at different time points in the same phase and group were combined for statistical analyses. The Mann–Whitney U test was utilized. Pearson’s correlation analysis was used to analyze the relationship between the parameters tested in C and D.
Mentions: Induction of memory-cell apoptosis potentially leads to reduction of SIV reservoirs in rhesus macaques [16]. To determine whether Pc infection affects CD4+ TCM and TEM cell viability, we measured the percentages of CD4+ TCM and TEM cells with annexin V expressed on the cell membrane. The marker Ki67 was also used to evaluate the proliferation of these cells. CD28 + CD95 + CD4+ T cells were defined as CD4+ TCM cells, CD28 + CD95-CD4+ T cells were defined as CD4+ TEM cells in rhesus macaques according to previously report [17]. Our results suggested that Pc infection did not increase the proliferation levels of CD4+ TCM and TEM cells (data not shown). However, the apoptosis levels of CD4+ TCM cells in the ART + Pc group were higher than those in the ART group during the malaria phase (especially during the acute phase, from weeks 49–53; means of 8.25% and 6.56%, respectively; P = 0.12; Figure 3A). There were also significantly more apoptotic CD4+ TEM cells in the ART + Pc group than in the ART group (means of 12.09% and 7.46%, respectively; P = 0.046; Figure 3B). We also observed that the number of iDNA copies in PBMCs during the malaria phase was negatively correlated with the apoptosis levels of CD4+ TCM cells in the two groups (P = 0.025, r = −0.372; Figure 3C). Additionally, the number of iDNA copies was negatively correlated with the apoptosis levels of CD4+ TEM cells (P = 0.11, r = −0.270, respectively; Figure 3D). These results suggested that the reduction of the viral reservoir in the ART + Pc group might have been associated with the increased levels of CD4+ TCM and TEM cell apoptosis during the course of malaria.Figure 3

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