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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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Inhibition by cervicovaginal lavage of T/F virus RPHA.c derived from a woman who reported heterosexual intercourse as her risk for contracting HIV.(A) There was no statistically significant difference between median values of inhibition of RPHA.c comparing women with and without HIV infection. (B) Among HIV-infected women, HIV disease progression stage modulated the inhibitory effect of cervicovaginal lavage fluid on RPHA.c. Negative anti-HIV activity values indicate enhancement of infection. Bars depict median, interquartile range and 95% confidence intervals; P values via (A) Mann-Whitney U test and (B) Kruskal-Wallis test.
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pone-0038100-g003: Inhibition by cervicovaginal lavage of T/F virus RPHA.c derived from a woman who reported heterosexual intercourse as her risk for contracting HIV.(A) There was no statistically significant difference between median values of inhibition of RPHA.c comparing women with and without HIV infection. (B) Among HIV-infected women, HIV disease progression stage modulated the inhibitory effect of cervicovaginal lavage fluid on RPHA.c. Negative anti-HIV activity values indicate enhancement of infection. Bars depict median, interquartile range and 95% confidence intervals; P values via (A) Mann-Whitney U test and (B) Kruskal-Wallis test.

Mentions: We recently reported the derivation of the T/F virus nucleotide sequence from subject RHPA4259, and the generation of an infectious molecular clone (IMC) RHPA.c [20]. RHPA.c represents the variant that established clinical infection in this female subject who reported heterosexual transmission as her only risk factor. In current study, we measured anti-HIV activity of CVL from HIV-uninfected as well as HIV-infected women. Of the 15 HIV-uninfected samples, 12 could be tested for activity against RHPA.c. As seen in Figure 3A, the majority inhibited this virus with the exception of three samples, which showed a stimulatory effect. Median percent inhibition in HIV-uninfected women was 36% (range −84% to 83%) whereas in 57 HIV-infected women, the median percent inhibition was 8% (range −368% to 93%; Figure 3A). There was no significant difference in CVL anti-HIV activity against RHPA.c between HIV-infected and HIV(−) women as determined by a Mann-Whitney U test. Among HIV-infected women, there was a trend toward lower CVL anti-RPHA.c activity among women with CD4 counts <200 cells/µl compared to women with higher CD4 counts (Figure 3B). In fact, of the 57 HIV-infected women, CVL from 19 (33%) enhanced RHPA.c infectivity of TZM-bl target cells.


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)

Inhibition by cervicovaginal lavage of T/F virus RPHA.c derived from a woman who reported heterosexual intercourse as her risk for contracting HIV.(A) There was no statistically significant difference between median values of inhibition of RPHA.c comparing women with and without HIV infection. (B) Among HIV-infected women, HIV disease progression stage modulated the inhibitory effect of cervicovaginal lavage fluid on RPHA.c. Negative anti-HIV activity values indicate enhancement of infection. Bars depict median, interquartile range and 95% confidence intervals; P values via (A) Mann-Whitney U test and (B) Kruskal-Wallis test.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3366961&req=5

pone-0038100-g003: Inhibition by cervicovaginal lavage of T/F virus RPHA.c derived from a woman who reported heterosexual intercourse as her risk for contracting HIV.(A) There was no statistically significant difference between median values of inhibition of RPHA.c comparing women with and without HIV infection. (B) Among HIV-infected women, HIV disease progression stage modulated the inhibitory effect of cervicovaginal lavage fluid on RPHA.c. Negative anti-HIV activity values indicate enhancement of infection. Bars depict median, interquartile range and 95% confidence intervals; P values via (A) Mann-Whitney U test and (B) Kruskal-Wallis test.
Mentions: We recently reported the derivation of the T/F virus nucleotide sequence from subject RHPA4259, and the generation of an infectious molecular clone (IMC) RHPA.c [20]. RHPA.c represents the variant that established clinical infection in this female subject who reported heterosexual transmission as her only risk factor. In current study, we measured anti-HIV activity of CVL from HIV-uninfected as well as HIV-infected women. Of the 15 HIV-uninfected samples, 12 could be tested for activity against RHPA.c. As seen in Figure 3A, the majority inhibited this virus with the exception of three samples, which showed a stimulatory effect. Median percent inhibition in HIV-uninfected women was 36% (range −84% to 83%) whereas in 57 HIV-infected women, the median percent inhibition was 8% (range −368% to 93%; Figure 3A). There was no significant difference in CVL anti-HIV activity against RHPA.c between HIV-infected and HIV(−) women as determined by a Mann-Whitney U test. Among HIV-infected women, there was a trend toward lower CVL anti-RPHA.c activity among women with CD4 counts <200 cells/µl compared to women with higher CD4 counts (Figure 3B). In fact, of the 57 HIV-infected women, CVL from 19 (33%) enhanced RHPA.c infectivity of TZM-bl target cells.

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