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P. falciparum enhances HIV replication in an experimental malaria challenge system.

Orlov M, Vaida F, Finney OC, Smith DM, Talley AK, Wang R, Kappe SH, Deng Q, Schooley RT, Duffy PE - PLoS ONE (2012)

Bottom Line: HIV p24Ag production by PBMCs in the presence of iRBCs (but not uRBCs) further increased during convalescence (days 35, 56, and 90 post-challenge).In parallel, iRBCs induced higher secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, and MIP-1α) than uRBCs, and production increased further during convalescence.Because the increase in p24Ag production occurred after parasitemia and generalized immune activation had resolved, our results suggest that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines.

View Article: PubMed Central - PubMed

Affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.

ABSTRACT
Co-infection with HIV and P. falciparum worsens the prognosis of both infections; however, the mechanisms driving this adverse interaction are not fully delineated. To evaluate this, we studied HIV-1 and P. falciparum interactions in vitro using peripheral blood mononuclear cells (PBMCs) from human malaria naïve volunteers experimentally infected with P. falciparum in a malaria challenge trial. PBMCs collected before the malaria challenge and at several time points post-infection were infected with HIV-1 and co-cultured with either P. falciparum infected (iRBCs) or uninfected (uRBCs) red blood cells. HIV p24Ag and TNF-α, IFN-γ, IL-4, IL-6, IL-10, IL-17, and MIP-1α were quantified in the co-culture supernatants. In general, iRBCs stimulated more HIV p24Ag production by PBMCs than did uRBCs. HIV p24Ag production by PBMCs in the presence of iRBCs (but not uRBCs) further increased during convalescence (days 35, 56, and 90 post-challenge). In parallel, iRBCs induced higher secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, and MIP-1α) than uRBCs, and production increased further during convalescence. Because the increase in p24Ag production occurred after parasitemia and generalized immune activation had resolved, our results suggest that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines.

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Plasmodium falciparum stimulates enhanced secretion of TNF-α, IFN-γ, and MIP-1α, but not IL-6.PBMCs from the malaria challenge trial participants were infected with HIV and co-cultured with iRBC and uRBC at the 6 visits as described earlier. Cytokine secretion in the iRBC (red lines) and uRBC (black lines) co-culture supernatants was measured using the BioPlex platform. Cytokine production was measured at days 1, 4, 6, and 8 post initiation of co-culture and the area under the curve was calculated for each participant at each visit and plotted in A – D as the average for the 5 participants, error bars represent the 95% CI. Repeated measures ANOVA was used to determine significance in the difference in amount of cytokines secreted (iRBC-uRBC) at the post-exposure time points compared to the difference in amount of cytokine secreted (iRBC-uRBC) at baseline. p-values have been corrected for multiple comparisons: TNF-α day 35 p = 0.013, day 56 p = 0.29, day 90 p = 0.19; IFN-γ day 35 p<0.001, day 56 p = 0.019, day 90 p<0.001; MIP-1α day 35 p<0.001, day 56 p = 0.002, day 90 p<0.001. There was an increase in TNF-α, IFN-γ, and MIP-1α (A–C) secretion in the iRBC co-cultures compared to the uRBC co-cultures at all time points and an enhanced secretion at the convalescent time points. There was no difference in IL-6 secretion (D).
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pone-0039000-g002: Plasmodium falciparum stimulates enhanced secretion of TNF-α, IFN-γ, and MIP-1α, but not IL-6.PBMCs from the malaria challenge trial participants were infected with HIV and co-cultured with iRBC and uRBC at the 6 visits as described earlier. Cytokine secretion in the iRBC (red lines) and uRBC (black lines) co-culture supernatants was measured using the BioPlex platform. Cytokine production was measured at days 1, 4, 6, and 8 post initiation of co-culture and the area under the curve was calculated for each participant at each visit and plotted in A – D as the average for the 5 participants, error bars represent the 95% CI. Repeated measures ANOVA was used to determine significance in the difference in amount of cytokines secreted (iRBC-uRBC) at the post-exposure time points compared to the difference in amount of cytokine secreted (iRBC-uRBC) at baseline. p-values have been corrected for multiple comparisons: TNF-α day 35 p = 0.013, day 56 p = 0.29, day 90 p = 0.19; IFN-γ day 35 p<0.001, day 56 p = 0.019, day 90 p<0.001; MIP-1α day 35 p<0.001, day 56 p = 0.002, day 90 p<0.001. There was an increase in TNF-α, IFN-γ, and MIP-1α (A–C) secretion in the iRBC co-cultures compared to the uRBC co-cultures at all time points and an enhanced secretion at the convalescent time points. There was no difference in IL-6 secretion (D).

Mentions: We then measured cytokine production in culture supernatants to examine relationships between HIV production and cytokine secretion. We measured the secretion of 7 different cytokines: IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ, and MIP-1α. The levels of IL-4, IL-10, and IL-17 secretion were below the limit of detection of the BioPlex assay (data not shown). Increases in the secretion of TNF-α, IFN-γ, and MIP-1α were observed in the co-cultures that had been established with iRBCs compared to uRBCs. Production of these cytokines was further increased in PBMCs obtained 35, 56, and 90 days post malaria challenge compared to those obtained at baseline or at early stages of P. falciparum infection (Figure 2A–C, TNF-α: day 35 p = 0.013, day 56 p = 0.29, day 90 p = 0.19; IFN-γ: day 35 p<0.001, day 56 p = 0.019, day 90 p<0.001; MIP-1α: day 35 p<0.001, day 56 p = 0.002, day 90 p<0.001). These cytokine profiles closely mirror the HIV production profiles in Figure1D. IL-6 secretion was similar in iRBC and uRBC co-cultures (Figure 2D).


P. falciparum enhances HIV replication in an experimental malaria challenge system.

Orlov M, Vaida F, Finney OC, Smith DM, Talley AK, Wang R, Kappe SH, Deng Q, Schooley RT, Duffy PE - PLoS ONE (2012)

Plasmodium falciparum stimulates enhanced secretion of TNF-α, IFN-γ, and MIP-1α, but not IL-6.PBMCs from the malaria challenge trial participants were infected with HIV and co-cultured with iRBC and uRBC at the 6 visits as described earlier. Cytokine secretion in the iRBC (red lines) and uRBC (black lines) co-culture supernatants was measured using the BioPlex platform. Cytokine production was measured at days 1, 4, 6, and 8 post initiation of co-culture and the area under the curve was calculated for each participant at each visit and plotted in A – D as the average for the 5 participants, error bars represent the 95% CI. Repeated measures ANOVA was used to determine significance in the difference in amount of cytokines secreted (iRBC-uRBC) at the post-exposure time points compared to the difference in amount of cytokine secreted (iRBC-uRBC) at baseline. p-values have been corrected for multiple comparisons: TNF-α day 35 p = 0.013, day 56 p = 0.29, day 90 p = 0.19; IFN-γ day 35 p<0.001, day 56 p = 0.019, day 90 p<0.001; MIP-1α day 35 p<0.001, day 56 p = 0.002, day 90 p<0.001. There was an increase in TNF-α, IFN-γ, and MIP-1α (A–C) secretion in the iRBC co-cultures compared to the uRBC co-cultures at all time points and an enhanced secretion at the convalescent time points. There was no difference in IL-6 secretion (D).
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pone-0039000-g002: Plasmodium falciparum stimulates enhanced secretion of TNF-α, IFN-γ, and MIP-1α, but not IL-6.PBMCs from the malaria challenge trial participants were infected with HIV and co-cultured with iRBC and uRBC at the 6 visits as described earlier. Cytokine secretion in the iRBC (red lines) and uRBC (black lines) co-culture supernatants was measured using the BioPlex platform. Cytokine production was measured at days 1, 4, 6, and 8 post initiation of co-culture and the area under the curve was calculated for each participant at each visit and plotted in A – D as the average for the 5 participants, error bars represent the 95% CI. Repeated measures ANOVA was used to determine significance in the difference in amount of cytokines secreted (iRBC-uRBC) at the post-exposure time points compared to the difference in amount of cytokine secreted (iRBC-uRBC) at baseline. p-values have been corrected for multiple comparisons: TNF-α day 35 p = 0.013, day 56 p = 0.29, day 90 p = 0.19; IFN-γ day 35 p<0.001, day 56 p = 0.019, day 90 p<0.001; MIP-1α day 35 p<0.001, day 56 p = 0.002, day 90 p<0.001. There was an increase in TNF-α, IFN-γ, and MIP-1α (A–C) secretion in the iRBC co-cultures compared to the uRBC co-cultures at all time points and an enhanced secretion at the convalescent time points. There was no difference in IL-6 secretion (D).
Mentions: We then measured cytokine production in culture supernatants to examine relationships between HIV production and cytokine secretion. We measured the secretion of 7 different cytokines: IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ, and MIP-1α. The levels of IL-4, IL-10, and IL-17 secretion were below the limit of detection of the BioPlex assay (data not shown). Increases in the secretion of TNF-α, IFN-γ, and MIP-1α were observed in the co-cultures that had been established with iRBCs compared to uRBCs. Production of these cytokines was further increased in PBMCs obtained 35, 56, and 90 days post malaria challenge compared to those obtained at baseline or at early stages of P. falciparum infection (Figure 2A–C, TNF-α: day 35 p = 0.013, day 56 p = 0.29, day 90 p = 0.19; IFN-γ: day 35 p<0.001, day 56 p = 0.019, day 90 p<0.001; MIP-1α: day 35 p<0.001, day 56 p = 0.002, day 90 p<0.001). These cytokine profiles closely mirror the HIV production profiles in Figure1D. IL-6 secretion was similar in iRBC and uRBC co-cultures (Figure 2D).

Bottom Line: HIV p24Ag production by PBMCs in the presence of iRBCs (but not uRBCs) further increased during convalescence (days 35, 56, and 90 post-challenge).In parallel, iRBCs induced higher secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, and MIP-1α) than uRBCs, and production increased further during convalescence.Because the increase in p24Ag production occurred after parasitemia and generalized immune activation had resolved, our results suggest that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines.

View Article: PubMed Central - PubMed

Affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.

ABSTRACT
Co-infection with HIV and P. falciparum worsens the prognosis of both infections; however, the mechanisms driving this adverse interaction are not fully delineated. To evaluate this, we studied HIV-1 and P. falciparum interactions in vitro using peripheral blood mononuclear cells (PBMCs) from human malaria naïve volunteers experimentally infected with P. falciparum in a malaria challenge trial. PBMCs collected before the malaria challenge and at several time points post-infection were infected with HIV-1 and co-cultured with either P. falciparum infected (iRBCs) or uninfected (uRBCs) red blood cells. HIV p24Ag and TNF-α, IFN-γ, IL-4, IL-6, IL-10, IL-17, and MIP-1α were quantified in the co-culture supernatants. In general, iRBCs stimulated more HIV p24Ag production by PBMCs than did uRBCs. HIV p24Ag production by PBMCs in the presence of iRBCs (but not uRBCs) further increased during convalescence (days 35, 56, and 90 post-challenge). In parallel, iRBCs induced higher secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, and MIP-1α) than uRBCs, and production increased further during convalescence. Because the increase in p24Ag production occurred after parasitemia and generalized immune activation had resolved, our results suggest that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines.

Show MeSH
Related in: MedlinePlus