TO FEMALE TRANSMISSION OF HIV
TO MALE TRANSMISSION OF HIV
TRANSMISSION AND THE GENETIC DIVERSITY OF HIV
THE SPREAD OF HIV/AIDS
When AIDS first arose in
the United States in the early 1980s, it was dubbed "gay-related
immunodeficiency disease" (GRID) because it appeared to afflict only
homosexual and bisexual men. As more cases were diagnosed, however, it
became apparent that one did not have to be gay or even male in order
to acquire HIV. So dramatically has the face of AIDS changed that P.J.
Hitchcock, Chief of the Sexually Transmitted Diseases Branch at the United
States National Institute of Allergy and Infectious Diseases, estimates
that today, world-wide, more women than men are infected with HIV. This
estimate is based upon a number of scientific studies which showed that
in heterosexual transmission of HIV women are at least twice as susceptible
The World Health Organization
estimates that heterosexual transmission has accounted for 75% of the
HIV infections in adults world-wide.(2)
The remaining 25% are primarily due to the use of contaminated blood and
blood products, needle sharing by intravenous drug users, and homosexual/bisexual
transmission. Heterosexual intercourse has been the dominant route of
transmission in Africa, Asia, South America, Central America and the Caribbean.
Indeed, in the United States, AIDS ceased being primarily a disease of
gay men in the early 1990s. Data from the United States Centers for Disease
Control and Prevention show that the proportion of new cases reported
among homosexual/bisexual men decreased from 47.3% in 1993 to 43.3% in
1994. While the rate of AIDS among American gay males decreases, there
has been a recorded increase among women and minority groups. Women accounted
for 18.1% of total AIDS cases in 1994, up from 16.2% in 1993. In the same
years, the number of American Blacks with AIDS increased from 36.1% to
39% of total new cases, while Hispanics with AIDS increased from 17.7%
Only in Canada and the developed
nations of Europe and Australasia does AIDS remain a disease where the
majority of those afflicted are gay. Even in these countries, however,
HIV is making its way into the heterosexual population. In England and
Wales, AIDS projections for 1995 to 1999 indicate that the number of new
cases among homosexuals and bisexuals will drop by 7% but there will be
a rise of 29% among intravenous drug users and a 25% increase due to heterosexual
transmission of the virus.(4)
The Canadian Public Health Association estimates that currently one in
10,000 Canadians is living with AIDS, and one in 1,000 is currently infected
with HIV. The number of cases of AIDS in Canada attributed to heterosexual
activity continues to rise at a faster rate than for any other risk category.
In 1991, the number of women diagnosed with AIDS in Canada was one third
of the number of reported cases among women in the previous ten years
combined. Many women have been identified as HIV-positive when visiting
doctors during the course of pregnancy. In British Columbia and the Yukon,
one pregnant woman in 3,745 is infected; in Toronto, it is one in 1,976;
and, in Montreal one in 616.(5)
A Quebec HIV seroprevalence study conducted between July 1989 and
June 1993 revealed that one in 555 women undergoing abortion in Montreal
As of 31 December 1995,
women comprised 6.2% of all diagnosed cases of AIDS in Canada. The coast-to-coast
distribution of female AIDS cases, however, is quite uneven. Women comprise
2.8% of the AIDS cases in British Columbia, 4.8% in Alberta, 4.5% in Ontario;
but 10.1% in Quebec and in the Atlantic provinces.(7)
Further, Health Canada data, compiled to 31 December 1994, show that women
comprised 19.5% (9 of 46) of the AIDS cases diagnosed in Newfoundland.(8)
It is recognized that immigration to Quebec from countries with a high
incidence of HIV infection, and intravenous drug use in Montreal have
contributed to the higher incidence of HIV infection among women in Quebec;
however, reasons for the situation in Atlantic Canada are not immediately
apparent. Clarification of this question may reveal some of the factors
that place heterosexual Canadians at risk for HIV/AIDS.
TO FEMALE TRANSMISSION OF HIV
intercourse with an HIV-positive male may result in the vaginal deposition
of HIV-contaminated semen. In this situation, the HIV is received in a
moist, warm, relatively non-oxidative environment that may protect and
prolong the life of the virus until it is able to infect susceptible host
tissue. In contrast, intercourse with an HIV-positive female may expose
the external male genitalia to HIV-contaminated vaginal secretions; however,
subsequent exposure to cold, oxygen and the drying effects of air are
likely to inactivate the virus. In addition, skin acts as an effective
barrier, leaving only a portion of the penis unprotected against possible
infection. Thus, unprotected sexual intercourse with an HIV-infected partner
puts females at greater risk than males.
The HIV virus readily infects
CD4 T-lymphocytes(9) because
the HIV viral envelope has a protein structure that dovetails with the
CD4 structure (receptor site) on the lymphocyte cell wall. The cells on
the surface of the female genital tract (the epithelial cells) lack CD4
receptor sites; however, T-lymphocytes are attracted to the vaginal and
cervical epithelia if inflammation or lesions are present. Accordingly,
it is believed that women are more apt to acquire an HIV infection if
there are perturbations to the epithelium lining of the genital tract.
This theory has been verified by studies that show women with sexually
transmitted diseases (STDs), which cause lesions and inflammation, have
a much higher risk of HIV infection.(10)
In addition to T-lymphocytes,
macrophages and Langerhans cells, both key immune system cells, bear CD4
receptor sites. In animal studies, these cells have been observed to be
present in the tissue immediately under the epithelial cells. Further,
the epithelial layer has been observed to swell and thin during different
phases of the menstrual cycle. Theoretically, a microscopic lesion in
the epithelial layer could provide HIV with the opportunity of coming
in contact with the CD4-bearing cells below. It has also been observed
that women with cervical ectopy, a condition that disrupts the epithelial
lining, are particularly vulnerable to HIV infection. It is currently
believed that both the cervix and vagina can provide sites for the entry
The foregoing describes
infection by free viral particles. There also appears to be some evidence
that infection can be accomplished by intracellular-HIV present in lymphocytes
carried with semen. Electron micrograph studies have shown that the infected
lymphocytes attach to the epithelial cells of the female genital tract.
Intracellular HIV particles settle to the bottom of the cells and are
then released to the spaces between the lymphocytes and the epithelial
cells. The epithelial cells, without the benefit of CD4-receptor sites,
then engulf viral particles and become infected. Although these studies
were conducted with human cell lines derived from the cervix, animal studies
indicate that intracellular virus may be far less infectious than free
virus. Specifically, macaques monkeys were easily infected with simian
immunodeficiency virus (SIV), the simian cousin of HIV, when small doses
of free SIV were placed in their vaginas. In contrast, no infections occurred
when large doses of lymphocyte-associated SIV were applied in an identical
fashion to a second test group of macaques.(12)
TO MALE TRANSMISSION OF HIV
Separate studies designed
to estimate the per-contact probability of female to male transmission
of HIV have shown that Thai and Kenyan males who engage in sex with local
prostitutes are, at a minimum, 31 times more likely to acquire HIV than
are North American males who engage in sex with local prostitutes.(13),(14),(15)
This very large difference in infection probability has allowed researchers
to probe into the reasons why the incidence of heterosexual AIDS is much
higher in developing countries and to determine the factors that place
men at risk.
Sexual exposure, including
the number of partners, the frequency of intercourse, and the frequency
of prostitute contact in some populations may differ between countries.
The observed differences in HIV-1 seroprevalence, however, would require
profound differences in sexual activity, for which there are few supportive
data. This realization has led researchers to look for factors that either
increase infectivity or render exposed individuals more susceptible to
In the Kenyan study, the
sexual health of 293 men who frequented Nairobi prostitutes (85% HIV-positive)
was followed. Newly acquired HIV infection was associated with frequent
prostitute contact, with the acquisition of genital ulcer disease, and
with being uncircumcised. After a single sexual exposure, 43% of all uncircumcised
men who acquired an ulcer became HIV-positive. In contrast, all of the
circumcised study subjects who did not acquire an ulcer remained free
of HIV infection. Data analysis indicated that lack of circumcision was
a greater risk factor than acquisition of a genital ulcer.
In the Thai study of 1,115,
21-year-old male military conscripts, sex with female prostitutes was
identified as the principal source of HIV infection. Surveys of the local
prostitute population revealed very high rates of STDs, with seropositivity
rates of: HIV, 51%; syphilis, 37%; genital herpes, 80%; and chanchroid
ulcerative disease, 21%. Active infection rates were: chlamydia infection,
30%; gonorrhoea infection 24%; and genital ulcer disease, 9%. For sexually
active military conscripts, the highest rate of HIV seroconversion occurred
among men who reported both a high frequency of contact with prostitutes
and a high rate of STDs. Transmission probability was, however, still
quite high for men who frequented prostitutes but did not report STDs.
The effect of circumcision on the risk of infection could not be determined
as circumcision is very uncommon in Buddhist Thailand.
Male genital ulceration
present at the time of exposure to an HIV-positive woman could act as
a portal of entry. Genital ulcers, however, are very painful and it is
thought that very few men afflicted in this way would engage in sexual
intercourse. Rather, it is thought that genital ulcer disease raises the
infectivity of an HIV-infected woman by increasing virus shedding in the
female genital tract. Researchers have been able to isolate HIV from the
surface of genital ulcers, and it is postulated that this condition attracts
HIV-infected lymphocytes and macrophages to the ulcer and results in high
concentrations of infectious virus in vaginal secretions. It is believed
that other STDs may also potentiate female to male HIV transmission in
a similar fashion.
In addition to the Kenyan
investigation, other studies have indicated that lack of circumcision
places males at greater risk for HIV.(16),(17)
Evidence indicates that the male portal of entry for HIV is the glans
urethra and the epidermis of the glans penis and/or subprepuce. It has
been suggested that the prepuce (foreskin) may physically trap infected
vaginal secretions and provide a hospitable environment that enhances
viral survival. Minor inflammatory conditions are more common in uncircumcised
males, and the foreskin may be more susceptible to traumatic epithelial
disruption during sexual intercourse; both conditions could attract susceptible
lymphocytes and macrophages and place them in contact with HIV.
TRANSMISSION AND THE GENETIC DIVERSITY OF HIV
HIV is characterized by
large genetic flexibility, which has given rise to drug resistance and
escape from immune responses, and has confounded attempts to develop an
effective vaccine.(18) To
date, nine genetically distinct subtypes of HIV have been identified and
designated subtypes A through H, and O.(19)
In Japan and the developed countries of North America, Europe, and Australasia,
virtually all HIV infections among homosexuals/ bisexuals and intravenous
drug users are due to HIV-B. In contrast, B is the least prevalent subtype
in Africa, where subtypes A, C, D, and E predominate and are spread by
heterosexual transmission. A situation of considerable scientific interest
has been identified in south-east Asia, where intravenous drug users are
infected with subtype B, while the afflicted heterosexual population is
infected with E.
The segregation of subtype
B and E between two distinct population groups prompted Thai researchers
to quantify the male to female risk of transmission for each of these
subtypes. This two-year study monitored the HIV status of women whose
male partners were infected with either HIV-E or HIV-B. During the course
of this study, 70% of the women with HIV-E infected partners became infected
themselves, while only 26% of the women with HIV-B infected partners did
so. The researchers suggested that HIV-E presents a higher risk of heterosexual
transmission than HIV-B, and they postulated that the very high rate of
spread of HIV/AIDS in Thailand might be due to the high heterosexually
infectious nature of HIV-E.(20)
A study conducted at the
Harvard School of Public Health in Boston has given additional weight
to the theory that subtypes B and E differ in infectivity. Langerhans
cells were isolated from the vagina, cervix, breast and penile foreskin
and successfully grown in pure cell cultures. These cell lines were then
challenged with either HIV-B or E. It was observed that HIV-B demonstrated
very poor growth while HIV-E grew "quite well," particularly
on the Langerhans cell lines derived from the female genital tract.(21)
Work at the Pasteur Institute and the University of Alabama have shown
that it is much easier to infect a chimpanzee vaginally with subtype E
than with subtype B. An animal study at the University of California has
shown that when monkeys are vaginally inoculated with SIV, the virus localizes
in Langerhans cells.(22)
At the September 1995, Third
International Conference on AIDS in Asia and the Pacific, it was suggested
that there are two distinct HIV-1 epidemics. In developed countries, subtype
B is spread primarily through blood and homosexual sex. The second epidemic
is occurring primarily in developing countries, and it is driven by non-B
subtypes through vaginal sex. It was feared that developed countries will
experience a more severe heterosexual epidemic if other HIV subtypes spread
into these populations. On this point, it should be noted that subtype
E has been identified in Uruguayan military personnel recently returned
from a peace-keeping mission in Cambodia,(23)
while subtypes A, D and E have been isolated from American servicemen
returning from Thailand, Kenya and Uganda.(24)
American servicemen are routinely tested for HIV; however, HIV testing
is voluntary for civilians returning from holiday or business abroad.
Therefore, even though non-B subtypes are being detected among military
personnel, epidemiologists believe that civilian travel represents the
greater risk for the introduction of highly infectious strains of HIV
into the heterosexual populations of developed countries.
In South America, Central
America, and the Caribbean, HIV/AIDS is primarily a disease of heterosexuals,
with subtype B the causative agent. This observation is at odds with the
theory that B is less transmissible by heterosexual sex than the other
HIV subtypes. As yet there are no strong scientific data to explain this
discrepancy; however, epidemiologists have suggested that heterosexual
anal intercourse might be more common in those parts of the world,(25)
circumcision less common, and STDs, particularly the ulcerative type,
less well controlled.
THE SPREAD OF HIV/AIDS
In Canada, the most common
STDs are chlamydia infection, genital herpes, and venereal warts, with
gonorrhoea following in a distant fourth place. The Canadian effort to
check the spread of STDs has been particularly successful with syphilis;
chanchroid ulcerative disease is now virtually never seen in Canadians,
except for individuals returning from African or Asian trips. Since the
acquisition of a venereal infection is a significant HIV risk factor,
a strong program to combat STDs is an essential component of the war against
AIDS. Also of particular importance is the proper use of condoms. Condoms
have been proven effective in reducing the transmission risk of both STDs
and in Canada they are both available and affordable. In Africa and south-east
Asia, frequent prostitute contact has been identified as an HIV risk factor.
Any form of casual or anonymous sex places an individual at risk of sexually
transmitted diseases; however, sex with Canadian prostitutes should carry
considerably less risk than sex with prostitutes in developing countries
because of the lower rates of HIV and STDs in Canada, because condoms
are recognized and used as an essential tool of the trade, and because
of sexual health education programs that have been focused on target groups.
Male circumcision is one factor in HIV risk reduction where Canada may
start to fall behind, however. The medical benefits of this procedure
have been a matter of debate for decades, and recently some Canadian provinces
have removed circumcision from the list of procedures paid for by provincial
health care plans. This decision may have to be reconsidered in light
of recent findings that lack of circumcision poses an increased risk for
the acquisition of HIV.
All HIV subtypes are characterized
by a high mutation rate that has endowed this virus with the ability to
develop drug resistance quickly. Similarly, the ability to mutate and
the existence of nine distinct subtypes have severely frustrated attempts
to develop an effective vaccine. Although strong research efforts are
continuing in these areas, another proposed line of attack is chemically
and/or biologically to challenge the virus at the point of heterosexual
transmission, where the virus is particularly vulnerable. Condoms can
perform this role; however, many women cannot negotiate safe-sex practices
with their partner. It is argued that if the heterosexual path of HIV
transmission is to be cut, women must have access to and control over
the use of topical microbiocides effective against both HIV and STDs.
The commercially available
spermicide nonoxynol-9 (N-9), has received a great deal of attention as
a potential vaginal microbiocide for blocking the male to female transmission
of HIV. N-9 is a detergent that cripples microbes by disrupting their
outer membranes. A capsule has been developed that can release N-9 to
the vagina within three minutes of insertion, and continues delivering
the compound for up to six hours. Clinical trials of this microbiocide
are to be underway in early 1996. Another detergent microbiocide, C316,
has been found to be effective against a broader spectrum of pathogens
than N-9; it is currently undergoing vaginal suppository safety testing.
A San Diego pharmaceutical company has tested the compound n-Docosanol
in monkeys. This chemical permits HIV to attach to vaginal epithelial
cells but inhibits the passage of genetic material out of the virus. The
United States Food and Drug Administration has found that some sulphated
polysaccharides are effective in binding to HIV and thereby preventing
binding to vaginal epithelial cells. The final avenue of research involves
buffering vaginal pH at mildly acidic levels. Work at Harvard University
has shown that HIV is inactivated by the naturally acidic environment
of the vagina. Since semen is alkaline, within eight seconds of ejaculation
vaginal pH is raised to neutrality, providing HIV with a "window
of opportunity." A variety of buffering agents are being screened
and tested to find one or more that will inactivate HIV without disturbing
the natural microflora of the vagina, or irritating mucosal sufaces.(28)
In the United States, the
National Institute of Allergy and Infectious Diseases is attempting biologically
to cut HIV transmission by the development of vaccines to induce mucosal
immunity. In animal studies, rhesus monkeys who had received an intramuscular
inoculation of killed SIV virus vaccine followed by a series of oral booster
doses were found to be immune to a vaginal challenge from SIV. Clinical
trials are now being carried out in which human volunteers are receiving
an intramuscular inoculation followed by oral doses of a vaccine containing
synthetic copies of HIV envelope proteins. These trials are on-going and
data are not yet available.
Until a cure for HIV/AIDS
is in use, the best defence against the disease continues to be knowledge.
The federal and provincial governments are all active in the promotion
of education and prevention initiatives that run the breadth of behavioural
change (promotion of abstinence, monogamy, reduction in the number of
sexual partners) to safe-sex instruction, to the avoidance of shared needles
(for drugs and steroids). Knowledge of how the virus is transmitted allows
individuals to make personal choices and, most important, makes everyone
responsible for his or her own sexual health.
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