Although women constitute more than half of the estimated 34-40 million people living with HIV/AIDS worldwide, little is known about the early events of HIV-1 infection in the female genital tract (FGT). Genital epithelial cells (GECs) line the FGT and act as intrinsic barriers providing mechanical protection against foreign microbes. GECs are also sentient and are capable of sensing and immunologically responding to various types of pathogens including sexually transmitted infections (STIs). These responses play a central role in preventing disease and also help mobilize both innate and adaptive immune cells against invading threats. While it is well understood that GECs exert important physical and immunological protective roles in the FGT, little is known regarding the role of GECs and GEC inflammatory responses in HIV infection.
It is estimated that 40% of all new HIV infections are established each year in the FGT. Our understanding of the early events following HIV transmission in the FGT remains particularly elusive in the context of endogenous or exogenous factors found in the genital microenvironment that may influence susceptibility to HIV-1. Inflammation is known to play a critical role in increasing HIV susceptibility, replication as well as initiating and maintaining chronic immune activation, a hallmark of disease progression. Among the key factors in the FGT that are known to or that could influence inflammation are sexually transmitted co-infections and female sex hormones.
The work summarized in this thesis examines how GEC innate immune responses to co-infecting microbes or female sex hormones impact HIV infection and replication in the FGT. Our results show that GEC innate immune response against herpes simplex virus type 2 (HSV-2), a common HIV co-infecting agent, consists of elevated proinflammatory cytokines and chemokines in addition to biologically active interferon-β. Furthermore, our results show that these responses require potent viral HSV-2 replication and that proinflammatory cytokine and chemokine responses are enhanced in the absence of the HSV-2 virus host shutoff protein. Based on this work, we decided to investigate whether GEC inflammatory responses to common STIs played a role in regulating HIV replication in T-cells. We found that HIV co-infecting microbes, specifically HSV-1, HSV-2 and Neisseria gonorrhoeae, directly induced HIV replication in T-cells, and caused primary GECs to upregulate inflammatory responses that indirectly increased HIV replication in T-cells.
Next we examined a translational aspect of the aforementioned studies by examining whether blocking inflammatory pathways, using the broad anti-inflammatory compound curcumin, could provide prophylactic or therapeutic protection against HIV. We found that curcumin pre-treatment a) protected the genital epithelial barrier against HIV-1-mediated disruption and inflammation, b) prevented the gp120-mediated upregulation of chemokines by GECs that recruit HIV target cells to the FGT, c) blocked GEC innate inflammatory responses to co-infecting microbes and indirect activation of the HIV promoter in T-cells, d) decreased HIV amplification in chronically infected T-cells and e) blocked HSV-2 viral replication in GECs by a mechanism that likely involves NFκB.
Lastly, it has long been speculated that female sex hormones can regulate inflammatory responses, and numerous lines of evidence suggest that they may also regulate susceptibility to HIV-1. Thus, we investigated how female sex hormones and the hormonal contraceptive medroxyprogesterone acetate (MPA), used by more than 100 million women worldwide, regulated HIV infection and replication in GECs and whether inflammation played an important role in this regulation. Our results showed that progesterone and in particular MPA increased uptake of HIV-1 and transcytosis, but not replication, across GECs – in the absence of a proinflammatory milieu - and that this enhanced transcytosis resulted in increased infection of HIV target cells.
These results demonstrate that sex hormones and co-infection both play an important role in regulating HIV-1 infection and replication in the FGT. Furthermore, our results suggest that anti-inflammatory compounds such as curcumin may offer paradigm shifting prophylactic or therapeutic strategies against HIV-1 infection and future research should investigate its potential benefit in vivo. / Thesis / Doctor of Philosophy (Medical Science)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/16638 |
| Date | 16 January 2015 |
| Creators | Ferreira, Victor H. |
| Contributors | Kaushic, Charu, Medical Sciences (Molecular Virology and Immunology Program) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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