Sexually Transmitted
Diseases Of Viral Origin
Infection
with the human papillomavirus (HPV) is the most common sexually transmitted
infection (STI) in the world. HPV is a wily pathogen that causes a spectrum
of clinical diseases, all of which involve cutaneous or mucosal squamous
surfaces. From the evolutionary standpoint, HPVs are very successful infectious
agents because they induce chronic infections that have no systemic sequelae
and rarely kill the host. Instead they periodically shed large amounts of
infectious virus for transmission to naïve individuals.
The broad
spectrum of genital HPV infection includes: (i) latent infection; (ii)
clinically apparent lesions (condylomata accuminata, warts); and (iii)
HPV-associated neoplasia. Latent infections are identified by the presence of
HPV DNA in tissue samples acquired for epidemiologic study. In the absence of
tissue collection, latent infections would go unrecognized because neither microscopic
nor visible lesions are present. Overt genital warts, also known as
condyloma acuminata, are flesh-colored, pink or pigmented papules with a
frond-like surface. Sessile warts, or flat condyloma-like lesions, are less
common, accounting for only 20% of visible genital warts. Most genital warts in
men are on the penis. In women, they are found most often at the vaginal
introitus and on the labia. Most genital warts are asymptomatic. When symptoms
do occur, they are often secondary to local friction-induced irritation from
clothing or intercourse. HPV- associated neoplasias include intraepithelial
lesions of the cervix (CIN) and vulva (VIN) and invasive carcinomas at both
sites. Cervical cancer is discussed in detail in Chapter 44.
Because most
genital warts are sexually transmitted, their presence indicates risk for other
STIs. Treatment of genital warts involves cryotherapy or topical application of
agents that cause cytolysis.
Epidemiology of HPV
The primary
risk factor for HPV infection is sexual activity. It is estimated that 75% of
sexually active women will acquire latent HPV infection. Fortunately, most HPV
infections are transient; up to 90% of infections in women will resolve
spontaneously within 2 years of acquisition. Unfortunately, persistent
infection is more common with HPV genotypes that have neoplastic potential.
Although
rare, it is possible to acquire HPV through nonsexual transmission. Neonates
can become infected during delivery.
Biology of human papillomaviruses
HPV is a
member of the Papovaviridae family of DNA viruses. Other well-known members of
this family are the polyomaviruses (polio virus and SV40). Of the 130 different
HPV genotypes identified to date, about 40 are associated with genital lesions.
Types 6 and 11 are most commonly identified in genital warts, and types 16 and
18 are most closely associated with neoplasia (high-risk subtypes). HPV sub-
types 1–5 are associated with common skin warts and plantar warts.
The success
of HPV as an infectious agent is directly linked to a virus replication cycle
that effectively evades immunologic detection by the host. The virus infects
primitive keratinocytes in the basal layers of squamous epithelia followed by a
round of viral DNA replication that appears independent of the host cell cycle
(Fig. 47.1). Once the infected keratinocyte enters the proliferative
compartment of the epithelium, viral gene expression is minimal. The oncogenes E6
and E7 are highly repressed by the viral genes E1 and E2 until
the infected keratinocyte exits the cell cycle and enters the uppermost
differentiating compartment (Table 47.1). Thus, high levels of viral protein
synthesis and assembly only occur in the upper layers of the squamous
epithelium. In this infectious cycle, the virus hitches a ride in the
keratinocyte at the beginning of its journey and replicates in cells that will
terminally differentiate and die by natural causes. Thus, there is no
viral-induced cytolysis, necrosis or inflammation. Because there is no
blood-borne phase of the HPV life cycle and only minimal amounts of replicating
virus are exposed to immune defense, the virus is essentially invisible to the
host. It is only when host integration occurs with E1 and E2 disruption,
that E6 and E7 are overexpressed. E6 and E7 are
capable of interfering with important tumor suppressor proteins in the host
cell. Their overexpression is associated with neoplastic transformation,
explaining the oncogenic potential of HPV.
HPV vaccines
are effective because they circumvent the viral epithelial evasion strategies
by introducing virus antigens through an intramuscular route. An immune cascade
resulting in a robust T-cell- dependent B-cell response generates high levels
of L1 specific neutralizing antibodies and immune memory.
Genital herpes is an STD that does
not go away. Instead, the respon- sible agent, herpes simplex virus (HSV),
establishes latent genital infection in the sacral dorsal root ganglia. It can
be reactivated from latency by fever, sun exposure and hormonal changes.
Herpetic infection causes the greatest morbidity in the neonate, who acquires
it from the genital tract of the mother at delivery, and in immunocompromised
patients for whom its disseminated form can be life-threatening.
There are
two distinct serological types of HSV: HSV-1 and HSV-2. HSV-1 infection is
typically asymptomatic and nearly ubiquitous. It is transmitted by primary
infection of the respiratory tract. HSV-1 has been found in the trigeminal
ganglion of 80% of cadavers.
HSV-2 has a
predilection for genital disease, although HSV-1 infections of the genitalia
and HSV-2 infections of the oral cavity do occur. HSV-2 is much more likely
than HSV-1 to become a latent infection of the sacral ganglion and to cause
neonatal disease.
Patients
with herpetic infections present with three clinical scenarios: primary
first episode, nonprimary first episode and recurrent episodes.
These presentations inform our understanding of the biology and epidemiology of
genital HSV infections. First episodes describe the initial recognition by the
patient or health-care provider that a genital herpes infection is occurring.
In primary first episodes, no HSV antibodies can be detected in acute phase
serum samples, demonstrating that there has been no prior HSV infection. HSV
antibodies will be present at the time of the first recognized genital herpes
outbreak in nonprimary first episodes. Recurrent episodes require recognition
that the patient has had a prior episode(s) of symptomatic HSV. The severity of
clinical manifestations and the incidence of complications at presentation vary
according to whether the infection is primary, nonprimary or recurrent.
Primary
genital HSV disease is typically the most severe although it can be totally
asymptomatic. Over 80% of patients with primary genital HSV will have local
painful penile or vulvar lesions, dysuria, urethral or vaginal discharge and
painful inguinal adenopathy. The mean duration of viral shedding from
mucocutaneous lesions in primary genital HSV-2 infections is 2–3 weeks.
Nonprimary first infections tend to be milder than primary first infections,
presumably because acquired humoral and cellular immunity partially contain
infectious spread.
Recurrent
genital HSV-2 disease typically involves painful recrudescence of the
mucocutaneous lesions on the penis or vulva and cervix. Local viral shedding
occurs at the site of lesions, although cervical shedding has also been
documented in the absence of visible cervical lesions. Systemic symptoms are
absent. The mean duration of symptoms and viral shedding is much shorter with
recurrences.
Medications
that inhibit viral DNA synthesis have been developed to treat the symptoms of
HSV infection. Treatment will stop viral DNA replication and spread but will
neither prevent latent infections nor eradicate the virus.
Abstinence
from sexual contact with an infected partner when lesions are visible is the
only way to prevent genital HSV infection. Unfortunately, even this is not
completely protective because trans- mission
can occur during
asymptomatic viral shedding.
Condoms are also not completely protective. The penile shaft may be
partially exposed to the vulva during intercourse using a condom. In addition,
HSV is capable of penetrating latex.
Epidemiology of genital HSV
infection
Symptomatic
genital HSV infection accounts for 2–4% of visits to STD clinics in the UK and
the USA. Genital HSV infections are reported more commonly among Caucasians
than non-Caucasians. A higher prevalence of anti-HSV antibodies is noted with
decreasing age at first coitus and with increasing number of sexual partners. The
incidence of neonatal herpes is about 1 in 7500 live births.
Biology of HSV
HSV is a
member of the herpesvirus class of DNA viruses. Herpes- viridae include the two
serotypes of HSV, cytomegalovirus (CMV), varicella zoster (chickenpox,
shingles) and Epstein–Barr virus (mono- nucleosis, chronic fatigue syndrome).
Herpesviruses would be better called “complex” rather than “simplex” because
they have the most complicated structure and replication cycles of all the
viruses.
Genital HSV
is acquired by sexual contact with contaminated secretions or lesions.
Herpesviruses are very susceptible to desiccation and extremes of temperature,
making transmission by fomites very rare. Once the virus has gained access to
mucosal cells, it destroys the host DNA during productive replication of its
own and kills the cell. HSV spreads by contiguity to adjacent cells and tracks
toward autonomic nerve endings. Mucosal and skin cells infected with HSV
produce serous transudates that result in the classic vesicles seen in the
disorder.
Following
primary genital mucocutaneous infection, HSV virions travel to the dorsal root
ganglia of the sacral plexus (S2–S4) via the intra-axonal
route. Here, they persist in a nonreplicative state until reactivation.
Reactivation is heralded by a dramatic increase in viral DNA synthesis. This is
followed by spread of virus back down the sensory neurons to the skin.
HSV in pregnancy and the neonate
Ninety per
cent of women with primary genital HSV-2 infection shed virus from their cervix
during the acute infection. This level drops to 70% both in women with primary
genital HSV-1 infection and in women with nonprimary first episodes of genital
HSV-2 infection. These numbers stand in stark contrast to the 12–20% rate of
cervical shedding among women with recurrent external genital lesions. There-
fore, it is not surprising that 50% of pregnant women with primary genital HSV
will transmit infection to the neonate while only 5% of women with recurrent
genital HSV will do so. Neonatal herpetic infec- tions are life-threatening.
They may be prevented with appropriate use of cesarean delivery.
