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Selective impact of HIV disease progression on the innate immune system in the human female reproductive tract.

Lahey T, Ghosh M, Fahey JV, Shen Z, Mukura LR, Song Y, Cu-Uvin S, Mayer KH, Wright PF, Kappes JC, Ochsenbauer C, Wira CR - PLoS ONE (2012)

Bottom Line: CVL exhibited broad anti-HIV activity against multiple laboratory-adapted and transmitted/founder (T/F) viruses, with anti-HIV activity ranging from 0 to 100% showing wide variation between viral strains.HIV disease progression, measured by declining CD4 T cell counts, resulted in a selective reduction in intrinsic anti-HIV activity in CVL that paralleled CVL decreases in human beta-defensin 2 and increases in Elafin and secretory leukocyte protease inhibitor.Overall, these studies indicate that innate immune protection in the FRT is compromised as women progress to AIDS.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America. Timothy.Lahey@Dartmouth.edu

ABSTRACT

Background: We have previously demonstrated intrinsic anti-HIV activity in cervicovaginal lavage (CVL) from HIV-infected women with high CD4 counts and not on antiretroviral therapy. However, the impact of HIV disease progression on CVL innate immune responses has not been delineated.

Methods: CVL from 57 HIV-infected women not on antiretroviral therapy were collected by washing the cervicovaginal area with 10 ml of sterile normal saline. We characterized subject HIV disease progression by CD4 count strata: >500 cells/µl, 200-500 cells/µl, or <200 cells/µl of blood. To assess CVL anti-HIV activity, we incubated TZM-bl cells with HIV plus or minus CVL. Antimicrobials, cytokines, chemokines and anti-gp160 HIV IgG antibodies were measured by ELISA and Luminex.

Results: CVL exhibited broad anti-HIV activity against multiple laboratory-adapted and transmitted/founder (T/F) viruses, with anti-HIV activity ranging from 0 to 100% showing wide variation between viral strains. Although there was broad CVL inhibition of most both laboratory-adapted and T/F virus strains, there was practically no inhibition of T/F strain RHPA.c, which was isolated from a woman newly infected via heterosexual intercourse. HIV disease progression, measured by declining CD4 T cell counts, resulted in a selective reduction in intrinsic anti-HIV activity in CVL that paralleled CVL decreases in human beta-defensin 2 and increases in Elafin and secretory leukocyte protease inhibitor. HIV disease progress predicted decreased CVL anti-HIV activity against both laboratory-adapted and T/F strains of HIV. Anti-HIV activity exhibited close associations with CVL levels of fourteen cytokines and chemokines.

Conclusions: Amid a multifaceted immune defense against HIV-1 and other sexually transmitted pathogens, HIV disease progression is associated with selective disturbances in both CVL anti-HIV activity and specific innate immune defenses in the human female reproductive tract (FRT). Overall, these studies indicate that innate immune protection in the FRT is compromised as women progress to AIDS.

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HIV disease progression exerts a selective impact on anti-HIV activity of cervicovaginal lavage fluid.HIV disease progression to CD4 counts <200 was associated with significant reductions in anti-HIV activity against the R5-tropic virus BaL (A) but not Yu2.c (B), on one of two X4 tropic viruses IIIB and NL4.3 (C &D), and against both transmitted/founder (T/F) viruses CH058.c or CH077.c (E & F). Negative anti-HIV activity values indicate enhancement of infection. Bars depict median, interquartile range and 95% confidence intervals; P values derived via Kruskal-Wallis tests.
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pone-0038100-g002: HIV disease progression exerts a selective impact on anti-HIV activity of cervicovaginal lavage fluid.HIV disease progression to CD4 counts <200 was associated with significant reductions in anti-HIV activity against the R5-tropic virus BaL (A) but not Yu2.c (B), on one of two X4 tropic viruses IIIB and NL4.3 (C &D), and against both transmitted/founder (T/F) viruses CH058.c or CH077.c (E & F). Negative anti-HIV activity values indicate enhancement of infection. Bars depict median, interquartile range and 95% confidence intervals; P values derived via Kruskal-Wallis tests.

Mentions: We have shown previously that CVL from HIV-infected women with CD4 counts >350 cells/µl exhibit intrinsic anti-HIV activity [9]. In the current study we included HIV-infected women with a broader CD4 count spectrum in the absence of antiretroviral treatment: 30 had CD4>500 cells/µl, 21 had CD4 200–500 cells/µl and 6 had CD4<200 cells/µl. As seen in Figure 2, we found a progressive loss of median anti-HIV activity among women with lower CD4 counts against R5 tropic HIV-1 BaL, X4-tropic HIV-1 IIIB, and against the T/F strains CH058.c and CH077.c. There was no significant loss of median CVL anti-HIV activity for R5-tropic Yu2.c, and X4-tropic NL4-3. Overall our data indicate that HIV disease progression is associated with the loss of CVL anti-HIV activity against multiple HIV-1 strains.


Selective impact of HIV disease progression on the innate immune system in the human female reproductive tract.

Lahey T, Ghosh M, Fahey JV, Shen Z, Mukura LR, Song Y, Cu-Uvin S, Mayer KH, Wright PF, Kappes JC, Ochsenbauer C, Wira CR - PLoS ONE (2012)

HIV disease progression exerts a selective impact on anti-HIV activity of cervicovaginal lavage fluid.HIV disease progression to CD4 counts <200 was associated with significant reductions in anti-HIV activity against the R5-tropic virus BaL (A) but not Yu2.c (B), on one of two X4 tropic viruses IIIB and NL4.3 (C &D), and against both transmitted/founder (T/F) viruses CH058.c or CH077.c (E & F). Negative anti-HIV activity values indicate enhancement of infection. Bars depict median, interquartile range and 95% confidence intervals; P values derived via Kruskal-Wallis tests.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366961&req=5

pone-0038100-g002: HIV disease progression exerts a selective impact on anti-HIV activity of cervicovaginal lavage fluid.HIV disease progression to CD4 counts <200 was associated with significant reductions in anti-HIV activity against the R5-tropic virus BaL (A) but not Yu2.c (B), on one of two X4 tropic viruses IIIB and NL4.3 (C &D), and against both transmitted/founder (T/F) viruses CH058.c or CH077.c (E & F). Negative anti-HIV activity values indicate enhancement of infection. Bars depict median, interquartile range and 95% confidence intervals; P values derived via Kruskal-Wallis tests.
Mentions: We have shown previously that CVL from HIV-infected women with CD4 counts >350 cells/µl exhibit intrinsic anti-HIV activity [9]. In the current study we included HIV-infected women with a broader CD4 count spectrum in the absence of antiretroviral treatment: 30 had CD4>500 cells/µl, 21 had CD4 200–500 cells/µl and 6 had CD4<200 cells/µl. As seen in Figure 2, we found a progressive loss of median anti-HIV activity among women with lower CD4 counts against R5 tropic HIV-1 BaL, X4-tropic HIV-1 IIIB, and against the T/F strains CH058.c and CH077.c. There was no significant loss of median CVL anti-HIV activity for R5-tropic Yu2.c, and X4-tropic NL4-3. Overall our data indicate that HIV disease progression is associated with the loss of CVL anti-HIV activity against multiple HIV-1 strains.

Bottom Line: CVL exhibited broad anti-HIV activity against multiple laboratory-adapted and transmitted/founder (T/F) viruses, with anti-HIV activity ranging from 0 to 100% showing wide variation between viral strains.HIV disease progression, measured by declining CD4 T cell counts, resulted in a selective reduction in intrinsic anti-HIV activity in CVL that paralleled CVL decreases in human beta-defensin 2 and increases in Elafin and secretory leukocyte protease inhibitor.Overall, these studies indicate that innate immune protection in the FRT is compromised as women progress to AIDS.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America. Timothy.Lahey@Dartmouth.edu

ABSTRACT

Background: We have previously demonstrated intrinsic anti-HIV activity in cervicovaginal lavage (CVL) from HIV-infected women with high CD4 counts and not on antiretroviral therapy. However, the impact of HIV disease progression on CVL innate immune responses has not been delineated.

Methods: CVL from 57 HIV-infected women not on antiretroviral therapy were collected by washing the cervicovaginal area with 10 ml of sterile normal saline. We characterized subject HIV disease progression by CD4 count strata: >500 cells/µl, 200-500 cells/µl, or <200 cells/µl of blood. To assess CVL anti-HIV activity, we incubated TZM-bl cells with HIV plus or minus CVL. Antimicrobials, cytokines, chemokines and anti-gp160 HIV IgG antibodies were measured by ELISA and Luminex.

Results: CVL exhibited broad anti-HIV activity against multiple laboratory-adapted and transmitted/founder (T/F) viruses, with anti-HIV activity ranging from 0 to 100% showing wide variation between viral strains. Although there was broad CVL inhibition of most both laboratory-adapted and T/F virus strains, there was practically no inhibition of T/F strain RHPA.c, which was isolated from a woman newly infected via heterosexual intercourse. HIV disease progression, measured by declining CD4 T cell counts, resulted in a selective reduction in intrinsic anti-HIV activity in CVL that paralleled CVL decreases in human beta-defensin 2 and increases in Elafin and secretory leukocyte protease inhibitor. HIV disease progress predicted decreased CVL anti-HIV activity against both laboratory-adapted and T/F strains of HIV. Anti-HIV activity exhibited close associations with CVL levels of fourteen cytokines and chemokines.

Conclusions: Amid a multifaceted immune defense against HIV-1 and other sexually transmitted pathogens, HIV disease progression is associated with selective disturbances in both CVL anti-HIV activity and specific innate immune defenses in the human female reproductive tract (FRT). Overall, these studies indicate that innate immune protection in the FRT is compromised as women progress to AIDS.

Show MeSH
Related in: MedlinePlus