I. INTRODUCTION

There are six basic principles you should know regarding sexually transmitted diseases (STDs):

1. STDs are caused by a wide variety of organisms including viruses, bacteria, fungi, and protozoans. All that they have in common is their mode of transmission.

2. STDs usually cause systemic disease.

3. The initial symptoms of an STD usually occur at the site of transmission.

4. STDs are usually clinically more apparent in males.

5. STDs can be transmitted from mother to child either in utero or during birth.

6. Patients often (not always) suffer from more than one STD at a time.

II. THE HERPES VIRUSES

The herpes virus family includes several large DNA viruses. They have a lipid coat acquired from the host cell. They are ubiquitous, but tend to be more prevalent in lower socioeconomic groups.

They can be latent (lie dormant); this occurs when the viral DNA lies dormant in the nucleus of an infected cell. Infection with herpes viruses is marked by periods of quiescence and periods of viral expression. The types of herpes viruses are as follows:

Herpes Types I and II initially invade mucosal cells, as does Varicella zoster. Soon after the initial infection, the virus infects the sensory cells of nerve ganglia, where they can remain latent. Periodically, for unknown reasons, the virus replicates in the nerve cells and reinfects epithelium. In shingles, the lesions follow the distribution of certain nerves.

Type I is oral 80-90% of the time, although in 10% of cases, it is found in the genital area. If a pregnant woman has genital lesions of Type I, she will transmit the virus to the baby 30% of the time. Type II is genital 80 to 90% of the time. The transmission rate for Type II from mother to baby is 70%.

The initial lesions of Herpes simplex are small vesicles (fluid-filled blisters). With Type II, the primary lesions tend to be the worst. These vesicles ulcerate and can persist for several weeks before healing. In general, relapses are less severe. Immunocompromised people can have complications.

Genital herpes is a very common STD in the US (it and chlamydia are probably the most common). Infection is usually for life, since the virus is integrated into the genome of the cell. Herpes can be treated with drugs such as acyclovir, which works better for Herpes simplex than for EBV, CMV, or Varicella zoster.

III. HUMAN IMMUNODEFICIENCY VIRUS (HIV) AND AIDS

• HIV is spread by sexual contact, infected blood, and from mother to infant.

• HIV has a selective tropism (preference or affinity) for cells of the immune system.

• HIV causes an irreversible and progressive course of illness leaving the host susceptible to neoplasms and opportunistic infections. (Opportunistic infections are infections that are manifested in immunosuppressed patients and not usually seen in immunocompetent individuals.)

A. Structure of HIV

HIV is a retrovirus. There are two types of retrovirus: 1) oncogenic or transforming retroviruses, which lead to neoplasms; and 2) cytopathic or lentiviruses, of which HIV is an example.

Viruses can only replicate inside of cells and only have one type of nucleic acid (either RNA or DNA). In general, DNA viruses tend to cause chronic illness and do not occur in epidemics. RNA viruses tend to cause epidemics (e.g., influenza, measles). HIV is an RNA virus.

HIV contains two strands of RNA in its innermost core, surrounded by two layers of structural proteins. Together, the RNA and these protein coats make up the nucleocapsid of the virus particle. (A virus particle is also called a virion.) Within the core is also an enzyme called reverse transcriptase.

The structural proteins in these two coats are designated "p" for protein, along with a number that indicates the molecular weight.

The outermost coat of the virus is a lipid bilayer derived from the host cell's membrane. The virus acquires this membrane as it is released (buds) from the host cell in which it replicated. Embedded in this bilayer are glycoproteins (i.e., proteins with carbohydrate chains added) that are encoded by the genome (genetic material) of the virus. These viral glycoproteins are designated by the letters "gp" plus a number indicating the molecular weight. There are two major viral glycoproteins, called gp120 and gp41 (i.e., they have molecular weights of 120,000 and 41,000, respectively).

Cross-sectional diagram of an HIV virion. Each virion expresses glycoprotein projections composed of gp120 and gp41. Within the envelope is the viral core, or nucleocapsid, which includes a layer of protein called p17 and an inner layer of a protein called p24. The HIV genome consists of two copies of single-stranded RNA, which are associated with two molecules of reverse transcriptase and proteins p7 and p9.

gp120 allows the virus to attach to T helper cells, since it binds to CD4 on the surface of the T helper cell. The affinity of gp120 for CD4 is very high. CD4 alone, however, is not sufficient to allow the virus to bind to and enter T helper cells. Recent research shows that there are important "co-receptors" on the T cells that are also necessary. These receptors normally bind chemokines, which are proteins produced by the body’s own cells. Chemokines are chemoattractants that recruit leukocytes, much like complement component C5a (see Dr. Furie’s inflammation lecture). HIV, however, uses receptors for chemokines, along with CD4, to help it bind to and invade its target leukocytes. (Editorial note: There has been a lot in the news lately about people who are at high risk for HIV but never become infected. In many of these cases, the uninfected people have a genetic defect in one of these co-receptors.)

gp41 in the viral envelope is very important for entry of the virus into host cells, since it allows the viral membrane to fuse with the membrane of the cell.

The genome of the virus is one long strand. The two ends have regions called long terminal repeats, or LTRs for short. These LTRs are the binding sites for molecules that normally activate genes in your own cells. When these molecules bind to the LTRs, they will also activate the genome of the HIV, and the virus will begin replicating.

Once the viral genome is activated, genes are transcribed to form messenger RNA, which is then translated into viral proteins. Three important genes are:

1. gag: codes for the structural proteins of the nucleocapsid

2. pol: codes for three important enzymes, reverse transcriptase, protease, and integrase.

3. env: codes for gp120 and gp41.
   

         

Genetic organization of HIV-1. The three major genes are gag, pol, and env. These genes encode polyproteins that are cleaved to form the nucleocapsid core proteins, enzymes required for replication, and the envelope glycoproteins, respectively.

In addition, some important regulatory genes are transcribed. The genes of HIV are quite unusual in that they do not code for individual proteins. Rather, they lead to production of large polyproteins, consisting of several individual proteins joined together. In this fused state, the proteins cannot function. They must be broken apart, or cleaved, in order to form individual, functional proteins. Enzymes that break these polyproteins apart are called proteases (see below for more about proteases).

B. Life cycle of HIV

First, as described, the gp120 of the virus contacts CD4 on a T helper cell. Macrophages and microglial cells (which are found in the central nervous system) also have CD4 and can be infected with HIV. When HIV first infects a person, it has a preference for invading macrophages and is called macrophage-tropic (or m-tropic). As the disease evolves, the virus mutates to preferentially infect T cells (T-tropic). Once this shift to a T-tropic strain occurs, the disease usually accelerates.  This tropism is possible because HIV needs to interact with cell surface structures in addition to CD4 to infect a host cell.  These other structures, as mentioned above,  are termed co-receptors.   Macrophages and T cells have different co-receptors, which allows HIV to discriminate between these two cell types.  The co-receptor on macrophages is called CC chemokine receptor 5 (CCR5); the co-receptor on T cells is called CXC chemokine receptor 4 (CXCR4).  Using gp41, the virus fuses with the T cell or macrophage and enters it. As the virus is internalized, its lipid and protein coats are shed. The viral single-stranded (ss) RNA is then released free into the cytoplasm of the cell.

Next, reverse transcriptase (RT) makes DNA from the ssRNA. This is the reverse of the normal process in the cell, whereby ss messenger RNA is transcribed from chromosomal DNA: hence the name reverse transcriptase. The two strands of ssRNA from the virus have now been converted into two molecules of double-stranded (ds) viral DNA. Reverse transcriptase can be inhibited by drugs such as AZT.

Now, the viral enzyme integrase causes the viral dsDNA to be inserted or fused (i.e., integrated) into a chromosome of the host cell. This integrated viral genome is called a provirus. Either of two things can now happen. The cell can remain inactive, and the provirus will just sit there. However, if the host cell is activated (look back at the immunology lecture to review how this occurs), then the virus will be activated, too. The virus will not be activated unless the cell is activated. Whatever processes activate the T cells or macrophages will also cause cellular factors to bind to the LTRs of the provirus, so it will also be activated.

Entry of HIV into cells and integration of viral DNA. Step 1: gp120 on the virus binds to CD4 on the plasma membrane of the target cell. Step 2: The viral membrane fuses with the plasma membrane of the cell, allowing entry of the HIV nucleocapsid containing the viral genome (Step 3). Step 4: The core proteins are removed, releasing ssRNA and reverse transcriptase (RT). Steps 5 and 6: RT copies the viral ssRNA, forming viral ds DNA. Step 7: The viral dsDNA travels to the nucleus of the cell and is fused into the cell’s chromosomal DNA by the viral enzyme called integrase.

When the viral genome is activated, large messenger RNAs that code for more than one protein are produced. These mRNAs produce large polyproteins that must be cleaved into the individual proteins of the virus by enzymes called proteases. First, a protease provided by the host cell cleaves the polyprotein product of the pol gene to form the viral proteins called reverse transcriptase, integrase, and viral protease. The viral protease then cleaves polyproteins made by the gag and env genes into individual proteins. The env gene codes for a large 160,000 molecular weight protein that is cleaved into gp120 and gp41 by the viral protease. The viral protease can be inhibited by drugs called protease inhibitors.

At the same time that messenger RNA is being made from the proviral DNA, viral single-stranded RNA is also being produced to be packaged into new viral particles:

The viral proteins and the viral ssRNA assemble together to form the new particles. This assembly usually occurs right under the host cell membrane. The new particles then "bud" out of the cell. As the virus buds, gp120 and gp41 are inserted into the host cell membrane. The membrane then wraps around the new virion as it is released from the cell to provide its outermost coat.

C. AIDS

AIDS is staged or classified based on the number of CD4 cells in the patient's blood (indicated by a number), as well as by the types of opportunistic diseases from which the patient has suffered (indicated by a letter).

A normal CD4 T-cell count is about 1100/m l. In classifying AIDS, a count >500 is category 1, from 200-499 is category 2, and <200 is category 3.

Clinically, a patient who is asymptomatic or has an acute infection or lymphoadenopathy only is category A. Category B includes patients with diarrhea, neuropathies, fever, Candida (yeast) infections, pelvic inflammatory disease, etc. Category C is the worst, including patients suffering from "heavy-duty" opportunistic infections such as Toxoplasma, Pneumocystis carinii, Mycobacterium, etc.

Patients who are least affected would therefore be classified as "A1", whereas the sickest would be "C3". All combinations of numbers and letters are possible.

CDC CLASSIFICATION OF AIDS INDICATOR DISEASES

(1993 REVISION)

Clinical categories in individuals with documented HIV infection:

Category A (conditions listed in categories B and C must not have occurred)

• Asymptomatic:  no symptoms at time of HIV infection
• Acute infection:  glandular fever-like illness lasting a few weeks at time of infection
• Persistent generalized lymphadenopathy (PGL):  lymph node enlargement persisting for three or more months with no evidence of infection

Category B (conditions listed in category C must not have occurred)

• Bacillary angiomatosis
• Candidiasis, oropharyngeal (thrush)
• Candidisis, vulvovaginal:  persistent, frequent, or poorly responsive to therapy
• Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
• Constitutional symptoms such as fever or diarrhea lasting > 1 month
• Hairy leukoplakia, oral
• Herpes zoster (shingles) involving at least two distinct episodes or more than one dermatome
• Idiopathic thrombocytopenic purpura
• Listeriosis
• Pelvic inflammatory disease, particularly by tubo-ovarian abscess
• Peripheral neuropathy

Category C

• Candidiasis of bronchi, trachae, or lungs
• Candidiasis, esophageal
• Cervical cancer (invasive)
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptococcosis, extrapulmonary
• Cryptosporidiosis, chronic intestinal (> 1 month's duration)
• Cytomegalovirus disease (other than liver, spleen, or nodes)
• Cytomegalovirus retinitis (with loss of vision)
• Encephalopathy, HIV-related
• Herpes simplex:  chronic ulcer(s) (> 1 month's duration) or bronchitis, pneumonitis, or esophagitis
• Histoplasmosis, disseminated or extrapulmonary
• Isosporiasis, chronic intestinal (> 1 month's duration)
• Kaposi's sarcoma
• Lymphoma, Burkitt's
• Lymphoma, immunoblastic
• Mycobacterium avium complex or M. kansaii, disseminated or extrapulmonary
• Pneumocystis carinii pneumonia
• Progressive multifocal leukoencephalopathy
• Salmonella septicemia (recurrent)
• Toxoplasmosis of brain
• Wasting syndrome due to HIV

*See table above for listing of indicator diseases in each category. Categories in italics are now reported as an AIDS diagnosis.

Full-blown AIDS is defined as being HIV-positive and suffering from one or more opportunistic infections (see the chart above).

The infected CD4 cells in the peripheral blood are the tip of the iceberg. There are lots of infected cells residing in the lymph nodes, lymphoid organs (e.g., thymus, spleen), and bone marrow.

In a normal, healthy person, the ratio of CD4 T helper cells to CD8 T cytotoxic cells in the blood is about 2:1. This ratio can be reversed in AIDS. The CD4 cells may be depleted by any of several means:

• Direct infection of CD4 cells in the blood or lymphoid organs, leading to lysis by budding virus or shutdown of cell functions due to production of large amounts of virus particles or unintegrated viral DNA.

• Infected cells in the thymus or bone marrow fuse with one another to form giant, multinucleated cells called syncytia. These fused cells are not functional. (Editorial note: recall that the membranes of infected cells will contain viral gp41, which promotes fusion of membranes.)

• Bone marrow and lymphoid organs becomes suppressed and do not produce mature T cells.

• Some of the infected CD4 cells will express gp120 on their surfaces and will be eliminated by T cytotoxic cells.

The collapse of the immune system in AIDS reflects the central role of the CD4 cell in the immune response. See your immunology notes to review this central role! Not only is there depletion of CD4 cells, but those that remain may not be functioning properly.

As the normal function of the CD4⁺ T helper cells is lost, B cells begin to behave abnormally. Some of them start to produce immunoglobulins, but these antibodies don’t have any particular specificity. This production of large amounts of essentially useless antibodies is called polyclonal B cell activation.   Depletion of macrophages also impairs the innate immune response (and this is a reminder from Dr. Furie that macrophages also serve an important role in acquired immunity by acting as antigen-presenting cells).

Serological profile of HIV infection

Bear in mind that there is an early and effective immune response to HIV. In fact, HIV infection is often diagnosed by assaying for these anti-HIV antibodies in the blood. When one is first infected with HIV, there is often an early, flu-like illness, which is hard to recognize as an HIV infection because the symptoms are so non-specific (e.g., fever, lymphadenopathy). This is called acute retroviral syndrome. During this time, antibodies are produced. As with any immune response, first IgM antibodies appear, then IgG. These antibodies are usually directed against the structural protein p24 or against gp160, the polyprotein that is the precursor to gp41 and gp120. The exact time frame of what happens serologically is as follows: First, p24 antigen appears in the blood. Next come IgM antibodies to p24, followed by IgG antibodies to p24. A little later, an IgG response to gp160 is seen.

Current thinking is that it would be most effective to try to eliminate HIV in this acute retroviral syndrome stage, when the body is still capable of mounting a good immune response. But the problem is that this stage is hard to recognize -- unless the patient is known to be at high risk for HIV infection, it is easy to misdiagnose.

Ultimately, the immune response is ineffective, leading to chronic disease. There is a rapid clearing of virus from the blood after acute infection, but viruses remain within CD4 T cells and macrophages. Moreover, these viruses may mutate so that the initial immune response no longer recognizes them. gp120 mutates especially rapidly. Some of these mutations may allow viruses to infect more efficiently and/or to evade the protection provided by the early immune response. As the infection proceeds, the immune response will become weaker and weaker, and it will be less able to deal with any mutant viruses that arise. Eventually, HIV gains an edge over the immune response, and the outcome is almost invariably fatal.

IV. CHLAMYDIA TRACHOMATIS

Chlamydia trachomatis is a bacterium that causes STD. It is very small and must replicate within cells (i.e., is an obligate intracellular bacterium), which led early scientists to believe it was a virus. It is one of the most common STDs in the U.S. and is probably the most common STD caused by a bacterium.  The STD is called chlamydia; this bacterium can also cause the eye disease trachoma.

A. Life cycle

Chlamydia is bimorphic, meaning that it has two different forms or stages in its life cycle. The infectious form is called the elementary body (EB). EBs infect epithelial cells of mucous membranes (e.g., lining the mouth or genital area). When they enter the cells, EBs are taken up into vacuoles that are acidic. Chlamydia can prevent fusion of lysosomes with this vacuole, so that it is not destroyed within the cell. Instead, the EB undergoes a change to become the replicating form of the bacterium, which is called a reticulate body (RB). RBs divide in the cell and accumulate to form inclusion bodies that can be seen microscopically. For unknown reasons, at some point the RBs transform back into EBs. The infected cell then lyses and releases the infectious EBs to start a new cycle of infection.

B. Diseases and their symptoms

Serotypes (which are variants) A, B, and C of Chlamydia trachomatis cause the eye infection trachoma.  In trachoma, the cornea becomes opaque and develops blood vessels (which normally are not present).  Trachoma is rare in the U.S., but it is the most common cause of blindness world-wide. Serotypes D-K cause genitourinary infections and inclusion conjunctivitis. The conjunctivitis can occur in newborns who get it from their mothers as they travel through the birth canal. All infants are given eyedrops soon after birth to prevent this infection. It can also lead to pneumonia in babies.

Urethritis from Chlamydia causes a discharge, which is usually more obvious in males. As a consequence, males usually seek medical treatment earlier than females. There also may be localized lymphadenopathy.  Important point: Very often, a patient will have both Chlamydia and gonorrhea. Gonorrhea is usually treated with penicillin, which is not effective against Chlamydia (which is sensitive to tetracycline). So often after treatment for gonorrhea, the patient will still have what is referred to as a nongonococcal urethritis, which is due to accompanying infection with Chlamydia that was not wiped out by the penicillin. (Penicillin inhibits the synthesis of bacterial cell walls, but Chlamydia has no cell wall and is therefore unaffected by this antibiotic). Penicillin is the drug of choice for gonorrhea and the symptoms of gonorrhea are usually more severe, so patients are usually treated with penicillin first. However, it is important to have these patients come back for a follow-up visit to make sure that there is no lingering chlamydial infection. If the disease is left untreated in males, it can cause, in addition to urethritis, generalized infections of the genitourinary tract and testicular infections.

In women, the symptoms are often less apparent, resulting in a delay in seeking treatment. The disease can cause inflammation of the cervix (cervicitis), uterus, and Fallopian tubes. Untreated Chlamydia infections can lead to infertility as a consequence of destruction of the epithelial cells lining the Fallopian tubes. These cells have cilia (hair-like projections) which beat back and forth and help move the egg from the ovary to the uterus.

Patients with urethritis due to Chlamydia can end up with conjunctivitis due to transmission of the bacterium by the genital-ocular route (appetizing thought, isn’t it?).

As mentioned, Chlamydia also causes the eye disease trachoma, although this is rarely seen in the U.S. In trachoma, the bacterium causes ulceration of the cornea, which leads to its infiltration with blood vessels. The cornea can become opaque.

Chlamydia is diagnosed by culture. Since it must replicate within cells, cell cultures are needed to grow it in the laboratory.

V. GONORRHEA

Gonorrhea is caused by infection with the bacterium Neisseria gonorrhoea. The bacterium first infects mucosa at the point of entry in the body. If untreated, regional lymphadenopathy and then systemic disease may result. The symptoms of gonorrhea are similar to those of infection with Chlamydia, except that they tend to be more severe and there is a high incidence of arthritis in gonorrhea. Infections with Neisseria usually progress more rapidly than those with Chlamydia.   Gonorrhea is the major cause of pelvic inflammatory disease in the female.

Gonorrhea is diagnosed by culture. Since it does not require cells for its growth, it can be cultured in the lab in a simple growth medium.

There has been a recent increase in penicillin-resistant gonorrhea.

VI. SYPHILIS

In the U.S., there have been ups and downs in the incidence of syphilis.  We are now in a period where the incidence is relatively low.  It is caused by Treponema pallidum, which is a spirochete, or spiral-shaped bacterium. Treponema is quite long (10-20 mm, compared with the 7 mm diameter of a red blood cell), but very narrow (0.2 mm). Because these bacteria are so thin, they cannot be seen in a conventional microscope. A special, "dark-field" microscope must be used, where the illumination comes from below, and one sees the shadow of the spirochete. Treponema pallidum has never been cultured in the laboratory. Blood tests for syphilis used to be required for marriage licenses, but this is no longer done.

A. Stages of syphilis

Syphilis, if untreated, is a long, chronic illness that can affect many organ systems. It may have many manifestations and may mimic other diseases. It is characterized by periods of relapse and remission (i.e., no symptoms). Untreated syphilis is marked by three stages:

Primary syphilis: Treponema multiplies locally at the site of infection to form a lesion called a chancre. The chancre is full of mononuclear cells (i.e., macrophages and lymphocytes). The chancre may last about 2-6 weeks, after which it heals by itself. The spirochetes spread, but the patient remains asymptomatic.

Secondary syphilis: If untreated, the disease may progress. A lot of patients don't make the connection between the initial chancre and the symptoms of secondary syphilis. Secondary syphilis may be marked by a rash, genital lesions called condylomata lata, and invasion of the spirochetes into the heart, kidney, nervous system, etc. Secondary syphilis can last for years, but there are periods of relapse and remission. Generally the relapses occur further apart as the disease progresses, until the patient enters a latent period that can last from 3 to 30 years.

Tertiary syphilis: This stage usually occurs in the elderly (just because the course of the disease is so long) and is very rare in the U.S. It was common in pre-antibiotic days, but most patients now are successfully treated in the earlier stages of the disease. A striking feature of the disease in this stage is the gumma, which is a granuloma or collection of macrophages (see your notes from the inflammation lecture).

Syphilis can be treated successfully with penicillin or tetracycline, given by injection.  There are no known antibiotic-resistant strains of T. pallidum.