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- Title
- THE EFFECT OF BACTERIAL VAGINOSIS-ASSOCIATED BACTERIA ON EPITHELIAL FACTORS MEDIATING HIV TRANSMISSION.
- Creator
-
Nguyen, April, Cole, Alexander, University of Central Florida
- Abstract / Description
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Bacterial vaginosis (BV), a common female reproductive tract (FRT) condition characterized by an overgrowth of anaerobic species concurrent with the disappearance of commensal Lactobacilli species, is associated with a 60% increased risk of HIV-1 transmission. However, the role of the FRT epithelia in bacterial vaginosis-associated bacteria (BVAB)-augmented HIV-1 transmission is unclear. To evaluate the increased risk of HIV-1 acquisition, we treated FRT epithelia with Atopobium vaginae, a...
Show moreBacterial vaginosis (BV), a common female reproductive tract (FRT) condition characterized by an overgrowth of anaerobic species concurrent with the disappearance of commensal Lactobacilli species, is associated with a 60% increased risk of HIV-1 transmission. However, the role of the FRT epithelia in bacterial vaginosis-associated bacteria (BVAB)-augmented HIV-1 transmission is unclear. To evaluate the increased risk of HIV-1 acquisition, we treated FRT epithelia with Atopobium vaginae, a prevalent BVAB, to determine the nature of the host response to BVAB exposure. Treatment of endocervical cells with A. vaginae resulted in a 1500-fold increase in the expression of the antimicrobial peptide hBD-2, an inflammatory cytokine response, and delocalization of the tight junction protein ZO-1 from cell borders. Conditioned media (CM) from the coculture of FRT epithelia and A. vaginae also generated an inflammatory immune response and lowered the transepithelial electrical resistance in polarized endocervical monolayers. Changes in HIV-1 infection were measured in TZM-bl reporter cells, which contain a luciferase gene under the control of an HIV-1 long terminal repeat (LTR) region that is activated by the binding of Tat, an HIV-1 protein that drives viral replication. NF[kappa]B is a major host-derived transcription factor that regulates the expression of many genes involved in inflammation and the innate immune response. Interestingly, NF[kappa]B has been reported to bind Tat-activated response elements within the LTR of HIV-1, driving viral transcription. TZM-bl cells were treated with CM in the absence of HIV-1, which resulted in increased luciferase production that could be suppressed by the NF[kappa]B inhibitor TPCA-1. These data suggest that epithelially derived products from the coculture of FRT cells and A. vaginae enhance HIV-1 infection by causing cervical barrier dysfunction and increasing HIV replication efficiency through NF[kappa]B.
Show less - Date Issued
- 2015
- Identifier
- CFH0004752, ucf:45365
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH0004752
- Title
- Characterization of Innate Immunity in the Female Reproductive Tract for the Prevention of HIV Acquisition.
- Creator
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Eade, Colleen, Cole, Alexander, Jewett, Travis, Naser, Saleh, Khaled, Annette, University of Central Florida
- Abstract / Description
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Human immunodeficiency virus (HIV) infects 30 million people worldwide. In sub-Saharan Africa, the region most affected by HIV, women comprise 60% of the infected population. Heterosexual transmission is a major mode of viral acquisition, mandating further research of the process and prevention of HIV acquisition via the female reproductive tract (FRT). The FRT is a dynamic environment, protected by host immune mechanisms and commensal microbes. The disruption of either of these elements can...
Show moreHuman immunodeficiency virus (HIV) infects 30 million people worldwide. In sub-Saharan Africa, the region most affected by HIV, women comprise 60% of the infected population. Heterosexual transmission is a major mode of viral acquisition, mandating further research of the process and prevention of HIV acquisition via the female reproductive tract (FRT). The FRT is a dynamic environment, protected by host immune mechanisms and commensal microbes. The disruption of either of these elements can increase susceptibility to HIV. Accordingly, one common risk factor for HIV acquisition is the microbial shift condition known as bacterial vaginosis (BV), which is characterized by the displacement of healthy lactobacilli by an overgrowth of pathogenic bacteria. As the bacteria responsible for BV pathogenicity and their interactions with host immunity are not understood, we sought to evaluate the effects of BV-associated bacteria on reproductive epithelia. Here we have characterized the interaction between BV-associated bacteria and the female reproductive tract by measuring cytokine and defensin induction in FRT epithelial cells following bacterial inoculation. Four BV-associated bacteria were evaluated alongside six lactobacilli for a comparative assessment. Our model showed good agreement with clinical BV trends; we observed a distinct cytokine and human ?-defensin-2 response to BV-associated bacteria, especially Atopobium vaginae, compared to most lactobacilli. One lactobacillus species, Lactobacillus vaginalis, induced an immune response similar to that elicited by BV-associated bacteria. These data provide an important prioritization of BV-associated bacteria and support further characterization of reproductive bacteria and their interactions with host epithelia. We next evaluated the effect of this interaction on HIV infection by investigating the soluble effectors secreted when FRT epithelial cells were cocultured with A. vaginae. We observed increased proviral activity mediated by secreted low molecular weight effectors, and determined that this activity was not likely mediated by cytokine responses. Instead, we identified a complex mixture containing several upregulated host proteins. Selected individual proteins from the mixture exhibited HIV-enhancing activity only when applied with the complex mixture of proviral factors, suggesting that HIV enhancement might be mediated by synergistic effects.In addition to characterizing the immune interactions that mediate the enhanced HIV acquisition associated with BV, we also evaluated the safety and efficacy of RC-101, a candidate vaginal microbicide being developed for the prevention of HIV transmission. RC-101 has been effective and well tolerated in preliminary cell culture and macaque models. However, the effect of RC-101 on primary vaginal tissues and resident vaginal microflora requires further evaluation. Here, we treated primary vaginal tissues and vaginal bacteria, both pathogenic and commensal, with RC-101 to investigate compatibility of this microbicide with FRT tissue and microflora. RC-101 was well tolerated by host tissues and commensal vaginal bacteria, while BV-associated bacteria were inhibited by RC-101. By establishing vaginal microflora, the specific antibacterial activity of RC-101 may provide a dual mechanism of HIV protection.
Show less - Date Issued
- 2013
- Identifier
- CFE0004677, ucf:49867
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0004677
- Title
- PROTECTION OF THE FEMALE REPRODUCTIVE TRACT IN THE PREVENTION OF HIV.
- Creator
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Diaz, Camila, Cole, Alexander, University of Central Florida
- Abstract / Description
-
Worldwide, more than half of all HIV-infected individuals are women. Since mucosal surfaces are the primary gateway for HIV entry, maintaining the integrity of the female reproductive tract (FRT) is essential for preventing infection. The FRT employs many immune mechanisms that serve as the first line of defense against HIV transmission. Among these are vaginal fluid secretions rich in antimicrobial peptides, and commensal bacteria that colonize the vagina and prevent infections. We sought to...
Show moreWorldwide, more than half of all HIV-infected individuals are women. Since mucosal surfaces are the primary gateway for HIV entry, maintaining the integrity of the female reproductive tract (FRT) is essential for preventing infection. The FRT employs many immune mechanisms that serve as the first line of defense against HIV transmission. Among these are vaginal fluid secretions rich in antimicrobial peptides, and commensal bacteria that colonize the vagina and prevent infections. We sought to study vaginal fluid as an innate immune component of the FRT in the prevention of HIV infection. Additionally, we investigated the anti-HIV microbicide candidate RC-101 as a possible treatment against pathogenic bacteria that disrupt the healthy microbiota of the FRT and create a suboptimal immune state that increases host susceptibility to viruses, such as HIV. Here we report that vaginal fluid collected from healthy females inhibits HIV infection. Moreover, our studies reveal that vaginal fluid collected from Black and White women exhibit disparate anti-HIV activity, possibly rendering Black women more susceptible to HIV infection. In addition, we show that RC-101, which is active against HIV, can also inhibit pathogenic bacteria that compromise FRT innate immunity, providing a dual mechanism of protection against HIV acquisition. Overall, these findings show that vaginal fluid is an important part of female innate immunity that protects the host from heterosexual HIV acquisition. Furthermore, the microbicide RC-101 may prevent HIV infection by both directly preventing viral entry, and by restricting the growth of pathogenic bacteria that disrupt the protective commensal vaginal flora. Together, innate mechanisms and bolstered protection present a multifaceted approach to maintaining effective host immunity.
Show less - Date Issued
- 2012
- Identifier
- CFH0004150, ucf:44842
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH0004150