Here we find a number of excellent reasons to expect that the vaginal
abrasion and irritation caused directly by circumcision, as well
as increased rates of chlamydia-related inflammation associated
with MGM, probably strongly increases the rate of male->female HIV
transmission.  Also see http://www.circumstitions.com/HIV.html#hetero
and http://www.cirp.org/library/anatomy/ohara/

http://jvi.asm.org/cgi/content/full/74/12/5577?view=long&pmid=10823865

Journal of Virology, June 2000, p. 5577-5586, Vol. 74, No. 12
0022-538X/00/$04.00+0

Copyright  2000, American Society for Microbiology. All rights
reserved.

Parameters of Human Immunodeficiency Virus Infection of Human
Cervical Tissue and Inhibition by Vaginal Virucides

Peter Greenhead, Peter Hayes, Patricia S. Watts, Ken G. Laing,
George E. Griffin, and Robin J. Shattock*

Department of Infectious Diseases, St. George's Hospital Medical
School, London SW17 ORE, United Kingdom

Received 20 March 2000/Accepted 24 March 2000

Abstract: Heterosexual transmission of human immunodeficiency virus
(HIV) is the most frequent mode of infection worldwide. However,
the immediate events between exposure to infectious virus and
establishment of infection are still poorly understood. This study
investigates parameters of HIV infection of human female genital
tissue in vitro using an explant culture model. In particular, we
investigated the role of the epithelium and virucidal agents in
protection against HIV infection. We have demonstrated that the
major target cells of infection reside below the genital epithelium,
and thus HIV must cross this barrier to establish infection. Immune
activation enhanced HIV infection of such subepithelial cells.

Furthermore, our data suggest that genital epithelial cells were
not susceptible to HIV infection, appear to play no part in the
transfer of infectious virus across the epithelium, and thus may
provide a barrier to infection. In addition, experiments using a
panel of virucidal agents demonstrated differential efficiency to
block HIV infection of subepithelial cells from partial to complete
inhibition. This is the first demonstration that virucidal agents
designed for topical vaginal use block HIV infection of genital
tissue. Such agents have major implications for world health, as
they will provide women with a mechanism of personal and covert
protection from HIV infection.

Introduction: Heterosexual transmission of human immunodeficiency
virus (HIV) infection occurs through mucosal surfaces and is the
major route of infection worldwide. This mode of transmission is
increasing in prevalence more rapidly than any other in the West
(31, 33, 42). Male-female transmission rates (per contact infectivity
estimated to be 0.0009 in North American women) are reported to be
approximately eight times more efficient than female-male rates,
with history of concomitant sexually transmitted diseases (STDs)
being the most strongly associated risk factor (22). Conflicting
data have been reported on the selective pressure of mucosal
transmission on the phenotypic and genotypic characteristics of
transmitted viral isolates from a heterogeneous inoculum. Predominant
isolation from peripheral blood of virus able to infect both
macrophages and CD4+ T lymphocytes (non-syncytium inducing [NSI],
M-tropic) over those that preferentially infect T lymphocytes
(syncytium inducing [SI], T-tropic), during or near to acute HIV
infection have lead to the suggestion that NSI viruses may be more
readily transmitted via mucosal routes (40). The mechanisms for
such selective transmission of HIV isolates may be one of either
selective penetration or selective amplification within the infected
host (33). Analyses of genital biopsies from HIV-infected women and
preliminary studies from this laboratory, using cervical organ
culture as a model of primary infection, have demonstrated that
HIV-infected cells reside within subepithelial mucosa, with no
evidence of HIV infection of epithelial cells (20, 21, 23, 27, 35).
Furthermore, it has been demonstrated that the primary targets of
simian immunodeficiency virus (SIV) infection, following intravaginal
infection of macaques, are cervical and vaginal subepithelial cells
(35). Such data indicate that establishment of HIV infection requires
transepithelial penetration. Whether intact genital epithelium
presents a barrier to, or is an active participant in, HIV transmission
has not been tested in primary human mucosal tissue.

Epithelium along the female genital tract differs in structural
cellular organization: the vagina and ectocervix, the site most
exposed to a natural inoculum, are composed of stratified epithelium,
whereas the endocervix is composed of a single epithelial monolayer.
Multiple mechanisms for HIV transmission across genital epithelia
have been proposed: direct HIV infection of epithelial cells,
transcytosis of HIV through epithelial cells, epithelial transmigration
of HIV-infected donor cells, uptake of HIV by intraepithelial
Langerhans cells, or circumvention of epithelium via breaches in
epithelial integrity (14, 33). Evidence for HIV infection of, or
transcytosis through, epithelial cells is derived from in vitro
studies using epithelial cell lines, which may bear little relation
to primary intact genital epithelium (1, 38). Furthermore, infection
or transcytosis in such models is dependent on cell-associated
virus, an observation at odds with efficient mucosal cell-free SIV
or feline immunodeficiency virus infection (3, 35). Strong
epidemiological association of inflammatory ulcerative venereal
disease with HIV transmission and observation that mucosal SIV
transmission may be enhanced following thinning of vaginal epithelium
by progesterone implants suggests a barrier role for genital
epithelium (18, 31). Furthermore, recent studies have demonstrated
that STDs increase both the number of CD4 cells in genital mucosa
and the expression of chemokine receptors known to function as HIV
coreceptors, thereby increasing the number of target cells (16, 24,
30). While HIV may achieve transepithelial penetration by more than
one mechanism, the relatively low incidence of per-contact infectivity
suggests that this is unlikely to reflect a constitutive mechanism.
However, male-female transmission is also influenced by factors
relating to the male partner, including seminal viral load and
incidence of STDs (31), all of which have an impact on contact
infectivity.

While condoms provide an effective barrier against transmission of
HIV and other STDs, they require the consent of the male partner,
which cannot always be negotiated by women at risk for infection.
Thus, there is an urgent need to develop prevention strategies that
are under the personal control of women. The potential of effective
topical vaginal virucides to prevent sexual transmission of HIV and
other STDs is widely recognized (8). However, proper evaluation of
the efficacy of such agents in blocking HIV infection of female
genital tissue has been hampered by the lack of appropriate
experimental models.

Thus, understanding the first critical events in genital mucosal
transmission of HIV infection is important in developing strategies
to block or limit such transmission. In this study, human genital
mucosal tissue from premenopausal seronegative women was been used
to define primary target cells for HIV infection within genital
mucosa, differential susceptibility of such tissue to M-tropic and
T-tropic HIV isolates, and the interaction of HIV with genital
epithelium. Furthermore, this in vitro model has been used to
determine the efficacy of potential vaginal virucides designed to
protect women from HIV infection.

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