HIV Infection in the Female Genital Tract: Discrete Influence of the Local Mucosal Microenvironment

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DOI: 10.1111/j.1600-0897.2010.00843.x · Source: PubMed
Abstract
Citation Kaushic C, Ferreira VH, Kafka JK, Nazli A. HIV infection in the female genital tract: discrete influence of the local mucosal microenvironment. Am J Reprod Immunol 2010 Women acquire HIV infections predominantly at the genital mucosa through heterosexual transmission. Therefore, the immune milieu at female genital surfaces is a critical determinant of HIV susceptibility. In this review, we recapitulate the evidence suggesting that several distinctive innate immune mechanisms in the female genital tract (FGT) serve to significantly deter or facilitate HIV-1 infection. Epithelial cells lining the FGT play a key role in forming a primary barrier to HIV entry. These cells express Toll-like receptors and other receptors that recognize and respond directly to pathogens, including HIV-1. In addition, innate biological factors produced by epithelial and other cells in the FGT have anti-HIV activity. Female sex hormones, co-infection with other pathogens and components in semen may also exacerbate or down-modulate HIV transmission. A combination of innate and adaptive immune factors and their interactions with the local microenvironment determine the outcome of HIV transmission. Improving our understanding of the female genital microenvironment will be useful in developing treatments that augment and sustain protective immune responses in the genital mucosa, such as microbicides and vaccines, and will provide greater insight into viral pathogenesis in the FGT.
HIV Infection in the Female Genital Tract: Discrete Influence of
the Local Mucosal Microenvironment
Charu Kaushic, Vitor H. Ferreira, Jessica K. Kafka, Aisha Nazli
Center For Gene Therapeutics, Michael G. DeGroote Institute of Infectious Diseases Research, Department of Pathology and Molecular Medicine,
McMaster University, Hamilton, Ontario, Canada
Introduction
According to recent estimates, women constitute
>50% of the 40 million people currently living with
HIV worldwide.
1
In fact, the fastest growing phase of
the pandemic is heterosexual transmission in
women. Although vaginal intercourse carries a lower
HIV transmission probability per exposure event, it
contributes more new HIV cases than anal inter-
course or parenteral inoculation.
2
Recent estimates
suggest that 30–40% of annual worldwide HIV infec-
tions occur through heterosexual transmission via
the female genital tract (FGT).
1,2
Given these statis-
tics, it is becoming increasingly clear that a better
understanding of HIV interactions in the FGT is criti-
cal to developing strategies for prevention of hetero-
sexual HIV transmission. This review will focus on
selected aspects that could influence the outcome of
heterosexual exposure to HIV-1 and are unique to
the local mucosal microenvironment of the FGT.
Innate Barriers in the Female Genital Tract to
HIV-1 Infection
For HIV-1 to establish a productive infection in the
FGT, it must first evade a number of intrinsic
Keywords
Antimicrobial peptides, epithelial barrier
function, HIV susceptibility, hormonal
contraceptive, seminal plasma, sexually
transmitted infections
Correspondence
Charu Kaushic, Center for Gene Therapeutics,
Department of Pathology and Molecular
Medicine, McMaster University, 1200 Main
Street West, Hamilton, Ontario, Canada
L7P4M9.
E-mail: kaushic@mcmaster.ca
Submitted February 23, 2010;
accepted February 24, 2010.
Citation
Kaushic C, Ferreira VH, Kafka JK, Nazli A. HIV
infection in the female genital tract: discrete
influence of the local mucosal
microenvironment. Am J Reprod Immunol
2010; 63: 566–575
doi:10.1111/j.1600-0897.2010.00843.x
Women acquire HIV infections predominantly at the genital mucosa
through heterosexual transmission. Therefore, the immune milieu at
female genital surfaces is a critical determinant of HIV susceptibility. In
this review, we recapitulate the evidence suggesting that several distinc-
tive innate immune mechanisms in the female genital tract (FGT) serve
to significantly deter or facilitate HIV-1 infection. Epithelial cells lining
the FGT play a key role in forming a primary barrier to HIV entry. These
cells express Toll-like receptors and other receptors that recognize and
respond directly to pathogens, including HIV-1. In addition, innate bio-
logical factors produced by epithelial and other cells in the FGT have
anti-HIV activity. Female sex hormones, co-infection with other patho-
gens and components in semen may also exacerbate or down-modulate
HIV transmission. A combination of innate and adaptive immune factors
and their interactions with the local microenvironment determine the
outcome of HIV transmission. Improving our understanding of the
female genital microenvironment will be useful in developing treat-
ments that augment and sustain protective immune responses in the
genital mucosa, such as microbicides and vaccines, and will provide
greater insight into viral pathogenesis in the FGT.
REVIEW ARTICLE
American Journal of Reproductive Immunology 63 (2010) 566–575
566 ª 2010 John Wiley & Sons A/S
mechanical, chemical and biological barriers. The
structure of the FGT forms the first line of defense
against HIV. The FGT can be divided into two major
compartments: the lower reproductive tract, consisting
of the vagina and ectocervix, lined by stratified
squamous epithelium; and the upper reproductive
tract consisting of the endocervix, endometrium and
fallopian tubes, lined by a single layer of columnar
epithelium.
3
The tight junctions between the colum-
nar cells of the endocervix and endometrium form a
mechanical barrier, preventing pathogens from
breaching the epithelium. In the vagina and ectocer-
vix, the continuous sloughing of the superficial layers
of the stratified epithelium prevents many pathogens
from colonizing and establishing infections, providing
a better mechanical protection against HIV invasion
than the single layer columnar epithelium that lines
the upper reproductive tract. However, the greater sur-
face area of the vaginal wall and ectocervix arguably
allows greater access for HIV entry, particularly when
breaches occur in the epithelium, such as during sex-
ual intercourse.
2,4,5
Epithelial cells (ECs) of the FGT produce several
biological factors that create an inhospitable environ-
ment for HIV including a hydrophilic surface layer of
glycoproteins and glycolipids called the glycocalyx,
and thick hydrophobic glycoprotein mucus.
6
Both
the glycocalyx and the mucus act as mucosal barriers
and may play a variety of important physiological
functions. For example, human cervicovaginal
mucus obtained from donors with normal lactobacil-
lus-dominated vaginal flora, efficiently traps HIV,
causing it to diffuse more than 1000-fold more
slowly than it would in water.
7
Several innate
immune proteins secreted from ECs with anti-HIV
activity are also present within the secretions of the
FGT. Those with established anti-HIV properties
include secretory leukocyte protease inhibitor (SLPI),
lactoferrin, beta (b)-defensins and trappin-2 elafin.
The antileukoprotease SLPI is secreted by resident
ECs and infiltrating leukocytes in the FGT.
8,9
It has
been suggested to play an important role in genital
mucosal defenses against HIV because of its potent
ability to inhibit HIV infection in vitro.
10–12
Similarly,
lactoferrin, a protein found in breast milk and the
genital tract, has also been shown to inhibit HIV at
the early stages of viral infection in vitro, by blocking
viral adsorption and uptake.
13,14
Defensins, a family
of small cationic proteins produced in the genital
tract, have demonstrated significant antimicrobial
effects in studies.
15,16
Alpha (a)-defensins are pro-
duced by neutrophils, macrophages and cd T cells,
whereas b-defensins are mainly produced by ECs,
such as those of the genital mucosa.
17
Human
b-defensin-1 (HBD-1) is expressed constitutively
while HBD-2 and HBD-3 are inducible and have
been shown to inhibit HIV-1, particularly X4 tropic
strains.
18–20
More recently, the serine protease inhib-
itor, trappin-2 elafin has also been implicated in
anti-HIV activity at mucosal surfaces.
21,22
In addition to antimicrobial peptides, cells of the
FGT can produce interferons (IFNs), which have a
wide variety of antiproliferative, immunomodulatory
and antiviral effects. Type I interferons (IFN-a, IFN-
b) impede the HIV replication cycle through numer-
ous mechanisms, including induction of the antiviral
molecule apolipoprotein B mRNA-editing enzyme-
catalytic polypeptide-like 3G (APOBEC3G).
23,24
Type
I IFNs also induce the production of inactive 2¢,5¢-
oligoadenylate synthetase (2¢,5¢-OAS), which acti-
vates a latent endoribonuclease, RNase L, that
degrades viral and cellular RNAs resulting in inhibi-
tion of protein synthesis.
25,26
The 2¢,5¢-OAS RNase L
pathway has been shown to inhibit the replication
of HIV-1.
27,28
Protein kinase R, inducible nitric oxide
(NO) synthase, myxovirus (Mx)-family proteins and
9–27 proteins are other interferon-inducible proteins
shown to have anti-HIV properties.
29
A number of
studies have shown the inhibitory effect of type II IFN
(IFN-c) on HIV-1 replication in monocytes, mono-
cyte-derived macrophage and lymphocytes.
30–32
However, some studies have found a stimulatory
effect of IFN-c on HIV-1 infection.
33,34
The recently
described type III IFN (IFN-k, or IL-28 29), which has
similar antiviral properties to type I IFN, has been
shown to block HIV-1 infection of macrophages by
the upregulation of CCR5 ligands (MIP-1a, MIP-1b),
as well as anti-HIV proteins like APOBEC3G 3F and
type I IFNs.
35
The expression of Toll-like receptors (TLRs) by
cells of the FGT bestows on them the ability to
innately sense their environment for pathogenic
motifs and rapidly relay messages to other innate
and adaptive cells should a pathogenic breach occur.
Vaginal and cervical EC lines express TLRs 1–3, 5
and 6, while primary endocervical ECs express TLRs
1–3 and 6.
3
Primary human uterine ECs express
TLRs 1–9, indicating the potential of upper reproduc-
tive tract to respond to a wide range of pathogens.
TLR-mediated activation leads to production of
chemokines and cytokines, including IL-6, IL-8,
SDF-1 by ECs, as well as resident immune cells in
HIV INFECTION IN THE FEMALE GENITAL TRACT
American Journal of Reproductive Immunology 63 (2010) 566–575
ª 2010 John Wiley & Sons A/S
567
the FGT, allowing for immediate responsiveness to
pathogens.
36–39
Similarly, the b-chemokines MIP-1a,
MIP-1b and RANTES are all secreted by ECs of the
upper and lower genital tract constitutively and fol-
lowing infection.
40–42
As natural ligands for the
CCR5 receptor, these may play a role in blocking
R5-tropic HIV-1.
The induction of antiviral responses by activation
of TLR pathways in genital ECs also provides a
unique potential for utilizing TLR ligands as innate
microbicides. To test this possibility, we recently
examined the antiviral responses induced in genital
ECs following treatment with TLR ligands. The abil-
ity of eight different TLR ligands to induce antiviral
responses in genital ECs against herpes simplex virus
type 2 (HSV-2) infection was determined.
43
TLR3
[poly (I:C)], TLR9 (CpG A) and TLR5 ligands (flagel-
lin) showed the greatest ability to reduce HSV-2 rep-
lication. Poly (I:C) treatment not only induced
maximum interferon-b and NO, but also enhanced
production of inflammatory cytokines IL-1a, IL-6
and TNF-a. Similar effects on the inhibition of
human cytomegalovirus (CMV) replication in human
genital tissues were also recently reported.
44
These
studies clearly demonstrate that the FGT is equipped
with a number of innate defenses against reproduc-
tive tract pathogens, including HIV.
HIV interactions with epithelial barrier and target
cells in the genital tract
If the intrinsic barriers of the FGT, described earlier,
are overcome, HIV-1 is capable of traversing the
genital epithelium and establishing an infection. HIV
virions have been suggested to cross the epithelium
through several pathways, including direct infection
of ECs,
45
transcytosis of viral particles across the epi-
thelium
46–48
and penetration of the virus through
epithelial breaches.
4,5
HIV-1 can infect both ECs
from the lower
49,50
and upper FGT.
45,48
The nature
of viral entry into ECs are likely distinct from the
canonical HIV-1 entry pathways as genital ECs dem-
onstrate inconsistent or no expression of CD4 and
the chemokine co-receptors CCR5 and
CXCR4.
49,51,52
In lieu of these molecules, ECs may
facilitate HIV transmission using cell surface glycos-
phingolipids, sulphated lactosylceramide expressed
by vaginal ECs
53
and galactosylceramide expressed
by ectocervical ECs,
52
which have been found to
bind HIV-1 gp120 and foster transcytosis. Interac-
tions of HIV-1 gp120 with transmembrane heparin
sulfate molecules, such as syndecans, expressed by
genital ECs may also contribute to HIV-1 attachment
and entry.
47,50
A variant of salivary agglutinin
named gp340, which is expressed on cervical and
vaginal ECs, has also been implicated in the passage
of HIV through the epithelium.
54,55
The relative con-
tribution of these receptors to HIV entry and infec-
tion in genital ECs is unclear.
In addition to ECs, there are a number of resident
immune cells in the FGT that may also contribute to
HIV transmission, most notably dendritic cells (DCs)
and T cells. DCs appear to play a major role in HIV
transmission and dissemination, as well as driving
the early inflammatory response to infection.
56
How-
ever, the relative contribution of different types of
DCs is not completely understood. Langerhans cells
in the cervicovaginal epithelium express CD4 and
CCR5, but not CXCR4 or the surface adhesion mole-
cule DC-SIGN, which has been shown to assist in
HIV transmission at mucosal surfaces. In a study
using ex vivo human organ culture system, HIV-1
rapidly infected both intraepithelial vaginal Langer-
hans and CD4
+
T cells. HIV-1 entered CD4
+
T cells
almost exclusively by CD4 and CCR5 receptor-medi-
ated direct fusion, without requiring passage from
Langerhans cells, resulting in productive infection.
By contrast, HIV-1 entered CD1a
+
Langerhans cells
primarily by endocytosis, and virions persisted intact
within these cells for several days without active
replication.
57
In contrast, a recent study was unable
to detect translocation of HIV-1 in reconstructed
human vaginal mucosa, and presence of Langerhans
cells did not alter HIV-1 transmission.
58
These stud-
ies suggest that the main target cells for HIV-1 are
CD4
+
DCs and T cells in the lamina propria of genital
mucosa. Consequently, the enriched population of
CD4
+
T cells and APCs present in the transformation
zone, where the ectocervix transitions into the endo-
cervix, may be a particularly susceptible site for HIV
entry.
59
In addition to the interactions described earlier,
we recently reported a novel mechanism that may
allow HIV to breach the epithelial barrier of the
intestinal and genital mucosae, resulting in translo-
cation of both HIV-1 and other luminal microbes.
60
In this study, we demonstrated that HIV-1 surface
glycoprotein could directly reduce transepithelial
resistance, a measure of epithelial monolayer integ-
rity, by 30–60% in primary genital epithelial and
intestinal cell lines cultures. The disruption in barrier
functions was associated with viral and bacterial
KAUSHIC ET AL.
American Journal of Reproductive Immunology 63 (2010) 566–575
568 ª 2010 John Wiley & Sons A/S
translocation across the epithelial monolayers and
was mediated by direct response of ECs to the
envelope glycoprotein of HIV-1 seen by upregula-
tion of inflammatory cytokines that lead to impair-
ment of barrier functions. The increased
permeability could be responsible for small but sig-
nificant migration across the mucosal epithelium by
virus and bacteria present in the lumen. This mech-
anism could be particularly relevant to mucosal
transmission of HIV-1.
Hormonal contraception and altered susceptibility
to HIV infection
The regulatory effects exerted by the cyclic presence
of sex hormones confer the female reproductive tract
with a unique microenvironment. Estradiol and
progesterone play a key role in regulating physiology
and functions of the FGT, including immune
responses (reviewed in
3
). Therefore, the use of hor-
monal contraception needs to be carefully studied,
as long-term, or even short-term administration of
these hormones may have far-reaching effects on
host responses. Long-acting, progesterone-based con-
traceptives, such as depot medroxy-progesterone
acetate, are highly effective and currently used by
more than 100 million women worldwide.
61
Multi-
ple studies in humans and rhesus macaques suggest
that the use of progesterone-based formulations may
predispose one to increased risk of HIV-1 or SIV
infection, higher viral burden and increased viral
shedding.
62–64
A recent study further suggested that
women who use progesterone-based contraceptives
display accelerated HIV-1 disease progression and
mortality, compared to women who do not.
65
Although the pathways involved in these outcomes
are not clear, progesterone is known to regulate a
number of immunological pathways, including the
inhibition of CTLs and natural killer cells.
66–68
It also
decreases the production and alters glycosylation of
IgG and IgA antibodies, modulates cytokine produc-
tion and upregulates HIV-1 receptor expression on
CD4
+
T cells.
69,70
In contrast to progesterone, estro-
gen and its derivatives may exert a strong protective
effect against HIV-1 infection.
71
Systemic administra-
tion of estrogen in the form of subcutaneous
implants protected against intravaginal challenge of
ovariectomized female rhesus macaques with highly
pathogenic SIV
MAC251
.
72
While these studies suggest
that hormone-based contraceptives may perturb the
mucosal environment resulting in altered HIV-1 sus-
ceptibility, the mechanisms underlying these obser-
vations need to be clearly elucidated. This is because
several studies have failed to observe an overall
effect of hormonal contraception on the incidence of
HIV-1 infection,
73,74
while other studies report
increased risk of infection, but only in subgroups of
subjects differing in age and HSV-2 status.
75,76
Inter-
pretation of these studies is complicated by multiple
factors (type, dose and method of administration of
hormonal contraceptives) and design of studies
(cross sectional, longitudinal).
To gain a better understanding of mechanism by
which hormones regulate susceptibility in the FGT,
we have conducted studies in a model of genital her-
pes infection. Using this model, we demonstrated
that long-acting progestational formulation Depo-
Provera increased susceptibility to genital HSV-2
infection by 100-fold.
77
Further studies indicated
that longer progesterone treatment regimes resulted
in poor mucosal immune responses and increased
susceptibility.
78
In other studies, mice were ovariec-
tomized and treated with exogenous estradiol and
progesterone prior to primary infection with genital
herpes or immunization with attenuated strain of
herpes virus. The results from these studies indicate
that estradiol treatment regulates susceptibility while
progesterone treatment leads to increased chronic
inflammation and pathology.
79,80
Further support for
the role of estradiol in controlling pathology comes
from a more recent study where mice immunized
with attenuated HSV-2 via subcutaneous or intrana-
sal route under the influence of estradiol, developed
remarkably decreased pathology compared to proges-
terone-treated mice, following genital challenge.
81
These findings were recently confirmed using an
HSV-2 vaccine formulation.
82
Co-infections in the female genital tract
Sexually transmitted infections (STI) and other genital
infections have been associated with increased HIV
genital shedding, transmission and susceptibility.
83,84
These may include CMV, gonorrhea, syphilis, bacte-
rial vaginosis, candidiasis and genital herpes. Bacterial
STIs, such as Chlamydia and gonorrhea have been
epidemiologically associated with increased subse-
quent HIV acquisition and, by extension, with
increased sexual transmission of HIV.
85,86
The
increased HIV susceptibility may relate to local
micro-ulcerations because of the pathologies
associated with the infection or to the local recruit-
HIV INFECTION IN THE FEMALE GENITAL TRACT
American Journal of Reproductive Immunology 63 (2010) 566–575
ª 2010 John Wiley & Sons A/S
569
ment of activated immune cells, which may act as
targets for HIV.
87
HSV-2 is one of the most prevalent
STIs, infecting 20–30% of sexually active adults in
North America and over 70% in sub-Saharan Africa.
88
A recent meta-analysis demonstrated HSV-2 infection
to be associated with a threefold increase in suscepti-
bility to HIV by both men and women from the gen-
eral population.
89
Part of this increased susceptibility
is more likely attributed to HSV-2-induced ulcer-
ations, which creates a breach in the physical barrier
of the genital epithelium.
90
Genital HIV-1 shedding is
also markedly increased during clinical HSV-2 reacti-
vations, accompanied by an increase in HIV-1 plasma
viral load.
91
Other studies have shown that, among
individuals shedding both viruses, the amounts of
viral shedding are closely related.
92
Herpetic lesions
and possibly asymptomatic HSV-2 mucosal shedding
generates an influx of activated CD4
+
T cells that per-
sist for months after healing, which may facilitate the
transmission of HIV.
93
HSV-2 replication is also associ-
ated with a 10-fold increase in the number of imma-
ture DCs expressing DC-SIGN and a threefold increase
in CCR5 expression on CD4
+
T cells.
94
Therefore, it is
possible that HSV-2 infection may increase the num-
ber of HIV-target cells in the FGT, facilitating the
transmission of HIV. Certain immediate early proteins
of HSV-1 such as infected cell protein (ICP)-0 and
ICP4 have been shown to interact with the HIV-1 LTR
to induce HIV replication,
95
suggesting that HSV can
directly upregulate HIV replication. Recent observa-
tions in our laboratory show that genital ECs infected
with HSV-2 or treated with an array of TLR ligands,
representative of various bacterial and viral patho-
gens, are capable of inducing HIV replication, directly
and indirectly (V.H. Ferreira and C. Kaushic, unpub-
lished). Altogether, these studies demonstrate that co-
infections may directly or indirectly enhance HIV
acquisition and transmission.
Influence of semen on HIV transmission
Semen represents the main vector of HIV dissemina-
tion, as transmission occurs more efficiently from
men to women, and men to men than from women
to men.
96
It is composed of cells and secretions from
the testes, epididymis, prostate, seminal vesicles and
bulbourethral gland, and it has been reported to
enhance HIV infection.
97
A number of components
of seminal fluid, whose physiological purpose is to
protect spermatozoa, also protect HIV virions. For
example, basic amines such as spermine, spermidine,
putrescine and cadaverine commonly protect both
spermatozoa and HIV virions from the threat of acid
inactivation in the vaginal tract.
97
In recent studies,
fractionation of semen from healthy donors has led
to the identification of a semen-derived enhancer of
viral infection (SEVI). SEVI consists of amyloid fibrils
composed of internal 34–40 amino acid proteolytic
fragments from prostatic acid phosphatase, a protein
present at a concentration of approximately
1–2 mg mL in semen that can enhance HIV infec-
tion up to 105-fold in cell culture.
97,98
Semen also plays an active role in transforming
the molecular and cellular environment of the FGT.
Studies suggest that vaginal epithelium secretes the
chemokine CCL20 in response to seminal plasma,
which enhances recruitment of Langerhans cells to
the vaginal mucosa. This may facilitate the transport
of virions across the vaginal epithelium barrier to
the lymph nodes.
99
It was also found that the HT-29
human EC line was sensitive to HIV-1 in the pres-
ence of whole semen resulting in a two-fold increase
in infectivity.
100
Others have shown that seminal
plasma can upregulate expression of proinflammato-
ry cytokines in human genital epithelium raising the
possibility of the role of seminal plasma in enhanc-
ing STI, including HIV-1, in the FGT.
101,102
Trans-
forming growth factor b1 (TGF-b1) concentration in
human seminal plasma is one of the highest mea-
sured in biological fluids.
103
When deposited into
the FGT, TGF-b in seminal plasma plays both proin-
flammatory and immunosuppressive roles in prepar-
ing the FGT for the conceptus.
103
We have recently
observed that semen from men infected with HIV
may contain different concentrations of TGF-b,
depending on the stage of infection, and this in turn
may induce differential responses in the FGT (J.K.
Kafka and C. Kaushic, unpublished).
Conclusions
The FGT is a unique mucosal environment and a
key target site for heterosexual HIV-1 transmission.
The mucosal ECs are key sentinels that serve the
dual function of forming the primary barrier as well
as being the first responders to HIV-1 in the event of
a breach. Recent studies show that these cells
express TLRs and other receptors that can respond
directly and rapidly to HIV-1 exposure. Several other
biological factors secreted in the FGT, such as SLPI,
lactoferrin, defensins and trappin elafin, provide
intrinsic protection against HIV-1 infection. Discrete
KAUSHIC ET AL.
American Journal of Reproductive Immunology 63 (2010) 566–575
570 ª 2010 John Wiley & Sons A/S
factors such as female sex hormones, other co-infec-
tions and semen may be present differentially in the
microenvironment of the FGT and play a key role in
determining the susceptibility of the host. The com-
bination of these and other protective mechanisms
and factors that confer susceptibility in the FGT
likely determine the net outcome of HIV-1 exposure.
Understanding the FGT microenvironment and its
interactions with HIV-1 can assist in the develop-
ment of better strategies to enhance innate and
adaptive immunity and develop novel methods to
prevent HIV-1 infection.
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    • "A central issue in women's health in developing countries is choice of contraceptive with minimal effects on susceptibility to infectious diseases, in particular to human immunodeficiency virus (HIV)-1 acquisition via the female reproductive tract (FRT). Epithelial cells lining the FRT are the first line of defence against pathogens and serve not only as a physical barrier but also express a wide variety of immune mediators aiding in both innate and adaptive immunity123 . Interleukin (IL)-6, IL-8 and regulatedupon-activation-normal-T-cell-expressed-and-secreted (RANTES) are expressed in both primary and immortalised vaginal and cervical epithelial cells456. "
    Full-text · Dataset · Oct 2015 · PLoS ONE
    • "HIV-1 infection is categorized as a sexually transmitted disease as more than 85% of HIV-1 infection occurs via sexual contacts [16,17]. For transmission, HIV-1 needs to cross female and male genital, and intestinal mucosal epithelium18192021. Langerhans cells (LCs) are a subset of DCs that line the mucosa the genital tracts and are therefore the first immune cells to encounter HIV-1 [22,23]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Sexual transmission is the main route of HIV-1 infection and the CCR5-using (R5) HIV-1 is predominantly transmitted, even though CXCR4-using (X4) HIV-1 is often abundant in chronic HIV-1 patients. The mechanisms underlying this tropism selection are unclear. Mucosal Langerhans cells (LCs) are the first immune cells to encounter HIV-1 and here we investigated the role of LCs in selection of R5 HIV-1 using an ex vivo epidermal and vaginal transmission models. Results Immature LCs were productively infected by X4 as well as R5 HIV-1. However, only R5 but not X4 viruses were selectively transmitted by immature LCs to T cells. Transmission of HIV-1 was depended on de novo production of HIV-1 in LCs, since it could be inhibited by CCR5 fusion inhibitors as well as reverse transcription inhibitors. Notably, the activation state of LCs affected the restriction in X4 HIV-1 transmission; immune activation by TNF facilitated transmission of X4 as well as R5 HIV-1. Conclusions These data suggest that LCs play a crucial role in R5 selection and that immature LCs effectively restrict X4 at the level of transmission.
    Full-text · Article · Jul 2014
    • "A central issue in women's health in developing countries is choice of contraceptive with minimal effects on susceptibility to infectious diseases, in particular to human immunodeficiency virus (HIV)-1 acquisition via the female reproductive tract (FRT). Epithelial cells lining the FRT are the first line of defence against pathogens and serve not only as a physical barrier but also express a wide variety of immune mediators aiding in both innate and adaptive immunity123 . Interleukin (IL)-6, IL-8 and regulatedupon-activation-normal-T-cell-expressed-and-secreted (RANTES) are expressed in both primary and immortalised vaginal and cervical epithelial cells456. "
    [Show abstract] [Hide abstract] ABSTRACT: Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼24 nM for transactivation of the anti-inflammatory GILZ gene and ∼4-20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.
    Full-text · Article · May 2014
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