Upregulation of Interferon-?? and RANTES in the Cervix of HIV-1-Seronegative Women With High-Risk Behavior

Hirbod, Taha; Nilsson, Jakob; Andersson, Sonia; Uberti-Foppa, Caterina; Ferrari, Davide; Manghi, Mara; Andersson, Jan; Lopalco, Lucia; Broliden, Kristina

doi:10.1097/01.qai.0000229016.85192.60

Cited by 36 publications

(28 citation statements)

References 31 publications

(24 reference statements)

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“…This effect was by no means universal, however, with a third of the women experiencing an increase in RANTES after BV treatment. Other reports of exposed, uninfected women have demonstrated higher levels of RANTES compared to low-risk or HIV-infected women (12,14). The methods used differed somewhat from those of the present study.…”

Section: Discussioncontrasting

confidence: 51%

“…A recent study of commercial sex workers (CSW) who are exposed to HIV but remain uninfected has found elevated RANTES expression in cervical lymphocytes compared with low-risk controls (12) and in HIV-resistant CSW compared to non-HIV-infected CSW (14). There is a paucity of data regarding Lf and SLPI levels in the vaginal mucosal secretions in women with a low or increased risk of acquiring HIV infection that might support a role for these innate antimicrobial factors in vivo, and there has been no study to date which specifically investigated the effect of treatment of BV on genital tract RANTES levels.…”

mentioning

confidence: 99%

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Cervicovaginal Levels of Lactoferrin, Secretory Leukocyte Protease Inhibitor, and RANTES and the Effects of Coexisting Vaginoses in Human Immunodeficiency Virus (HIV)-Seronegative Women with a High Risk of Heterosexual Acquisition of HIV Infection

Novak

Donoval

Graham

et al. 2007

Clin Vaccine Immunol

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Innate immune factors in mucosal secretions may influence human immunodeficiency virus type 1 (HIV-1) transmission. This study examined the levels of three such factors, genital tract lactoferrin [Lf], secretory leukocyte protease inhibitor [SLPI], and RANTES, in women at risk for acquiring HIV infection, as well as cofactors that may be associated with their presence. Women at high risk for HIV infection meeting established criteria (n ‫؍‬ 62) and low-risk controls (n ‫؍‬ 33) underwent cervicovaginal lavage (CVL), and the CVL fluid samples were assayed for Lf and SLPI. Subsets of 26 and 10 samples, respectively, were assayed for RANTES. Coexisting sexually transmitted infections and vaginoses were also assessed, and detailed behavioral information was collected. Lf levels were higher in high-risk (mean, 204 ng/ml) versus low-risk (mean, 160 ng/ml, P ‫؍‬ 0.007) women, but SLPI levels did not differ, and RANTES levels were higher in only the highest-risk subset. Lf was positively associated only with the presence of leukocytes in the CVL fluid (P < 0.0001). SLPI levels were lower in women with bacterial vaginosis [BV] than in those without BV (P ‫؍‬ 0.04). Treatment of BV reduced RANTES levels (P ‫؍‬ 0.05). The influence, if any, of these three cofactors on HIV transmission in women cannot be determined from this study. The higher Lf concentrations observed in high-risk women were strongly associated with the presence of leukocytes, suggesting a leukocyte source and consistent with greater genital tract inflammation in the high-risk group. Reduced SLPI levels during BV infection are consistent with an increased risk of HIV infection, which has been associated with BV. However, the increased RANTES levels in a higher-risk subset of high-risk women were reduced after BV treatment.

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Section: Discussioncontrasting

confidence: 51%

mentioning

confidence: 99%

Cervicovaginal Levels of Lactoferrin, Secretory Leukocyte Protease Inhibitor, and RANTES and the Effects of Coexisting Vaginoses in Human Immunodeficiency Virus (HIV)-Seronegative Women with a High Risk of Heterosexual Acquisition of HIV Infection

Novak

Donoval

Graham

et al. 2007

Clin Vaccine Immunol

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“…Hence, it remains to be further explored which levels of APOBEC family proteins are required for effective block of HIV-1 acquisition in vivo and means to induce their expression without providing fuel for HIV-1 infection. It can be noted that highly exposed seronegative women were reported to have upregulated IFN-a expression in the cervix as quantified by immunohistochemistry (60). In addition, immunomodulatory or immunization strategies inducing A3G expression were reported to -correlate with reduced viral load or protection against infection in macaques (26,61,62).…”

Section: Discussionmentioning

confidence: 99%

IFN-α Induces APOBEC3G, F, and A in Immature Dendritic Cells and Limits HIV-1 Spread to CD4+ T Cells

Mohanram

Sköld

Bächle

et al. 2013

The Journal of Immunology

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Cytokines and IFNs, such as TNF-α and IFN-α, upregulate costimulatory molecules in monocyte-derived dendritic cells (MDDCs), enabling effective Ag presentation to T cells. This activation of MDDCs is often accompanied by upregulation of apolipoprotein B mRNA–editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) (A3) family proteins that are able to restrict HIV-1 replication in MDDCs by inducing hypermutations in the viral genome. In this study, we show that TNF-α upregulates costimulatory molecules and are able to restrict HIV-1BaL replication in MDDCs without significant induction of A3G, A3A, or A3F. Conversely, low quantities of IFN-α failed to upregulate costimulatory molecules, did not induce IL-12p40 or migration, but significantly induced A3G, A3A, and A3F mRNA expression and restricted viral replication in MDDCs. We also showed that transmission of HIV-1 from MDDCs to autologous T cells was significantly reduced in the presence of IFN-α. Sequence analyses detected the induction of high frequency of G-to-A hypermutations in the env genes from HIV-1BaL–infected MDDCs treated with low quantities of IFN-α2b. These findings show that low quantities of IFN-α can induce functional A3 family proteins and restrict HIV-1 replication in MDDCs while keeping an immature nonmigratory phenotype, supporting further investigations of modalities that enhance retroviral restriction factors. In addition, the findings highlight the role of IFN-α as a double-edged sword in HIV-1 infection, and we show that IFN-α can be powerful in reducing HIV-1 infection both in MDDCs and T cells.

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“…Ectocervical biopsy specimens (3 by 3 mm) from the superior portion of the ectocervix were collected according to standard procedures. The biopsy specimens were processed as previously described (19,29). Cryopreserved biopsy specimens were cut to 8 m thick, fixed in 2% formaldehyde, and blocked for endogenous biotin (biotin/avidin blocking kit; Vector Laboratories, Burlingame, CA).…”

Section: Methodsmentioning

confidence: 99%

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

Luo

Sainsbury

Tuff

et al. 2012

J Virol

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A subgroup of women enrolled in the Pumwani sex worker cohort remain seronegative and PCR negative for human immunodeficiency virus type 1 despite repeated exposure through high-risk sex work. Studies have shown that polymorphisms of genes involved in antigen presentation and viral restriction factors are associated with resistance to HIV infection. To discover other possible genetic factors underlying this HIV-resistant phenotype, we conducted an exploratory nonbiased, low-resolution, genome-wide single-nucleotide polymorphism (SNP) analysis comparing 60 HIV-resistant women to 48 HIV-infected controls. The SNP minor allele rs1552896, in an intron of FREM1, was significantly associated with the resistant phenotype (P ‫؍‬ 1.68 ؋ 10 ؊5 ; adjusted P ‫؍‬ 2.37 ؋ 10 ؊4 ; odds ratio [OR], 9.51; 95% confidence interval [CI], 2.82 to 32.05). We expanded the sample size by genotyping rs1552896 in the Pumwani cohort and comparing 114 HIV-resistant women to 609 HIV-infected controls and confirmed the association (P ‫؍‬ 1.7 ؋ 10 ؊4 ; OR, 2.67; 95% CI, 1.47 to 4.84). To validate the association in a second cohort, we genotyped 783 women enrolled in a mother-child health study and observed the minor allele of rs1552896 enriched in HIV-uninfected women (n ‫؍‬ 488) compared to HIV-infected enrollees (n ‫؍‬ 295) (P ‫؍‬ 0.036; OR, 1.69; 95% CI, 0.98 to 2.93). Quantitative reverse transcription-PCR showed that FREM1 mRNA was highly expressed in tissues relevant for HIV-1 infection, and immunohistochemical analysis revealed that FREM1 protein is expressed in the ectocervical mucosa of HIV-resistant women. The significant association of rs1552896 with an HIV-resistant phenotype, together with the expression profile of FREM1 in tissues relevant to HIV infection, suggests that FREM1 is a potentially novel candidate gene for resistance to HIV infection.

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Upregulation of Interferon-?? and RANTES in the Cervix of HIV-1-Seronegative Women With High-Risk Behavior

Abstract: Induction of IFNalpha and RANTES expression in cervical mucosa may contribute to protection of sexual HIV-1 transmission in subjects with a higher risk behavior.

Cited by 36 publications

References 31 publications

Cervicovaginal Levels of Lactoferrin, Secretory Leukocyte Protease Inhibitor, and RANTES and the Effects of Coexisting Vaginoses in Human Immunodeficiency Virus (HIV)-Seronegative Women with a High Risk of Heterosexual Acquisition of HIV Infection

Cervicovaginal Levels of Lactoferrin, Secretory Leukocyte Protease Inhibitor, and RANTES and the Effects of Coexisting Vaginoses in Human Immunodeficiency Virus (HIV)-Seronegative Women with a High Risk of Heterosexual Acquisition of HIV Infection

IFN-α Induces APOBEC3G, F, and A in Immature Dendritic Cells and Limits HIV-1 Spread to CD4+ T Cells

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

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