Microbiology, Lec 24.

Genital Warts.

This topic came up because I have gotten a number of questions about these viruses. It is also of interest because it is one type of virus that has been implicated in causing cancer.

Genital warts is an emerging viral disease (see Table 35.3 and lec. 22) and may be the most common sexually transmitted disease, rivaling genital herpes (lec. 23). Genital warts are caused by a human papillomavirus (HPV). There are about 60 HPVs known and they all cause tumors (malignant and/or benign). Warts are benign tumors of the skin. Papillomaviruses are members of the Papovavirus group (see Fig. 18.1 page 374). HPVs are spread by direct contact with other humans with warts.

The HPV that causes genital warts is very closely related to viruses that can cause cancer (e.g. HPV-16). The most serious type of cancer associated with HPVs is cervical cancer. In the USA it accounts for about 7% of all cancers in females (5000 deaths annually). Worldwide, there are about 500,000 new cases of cervical cancer reported per year.

HPVs are ds DNA viruses (their genomes are circular, see handout, fig. 59-4 and Fig. 18.1 page 374) that don't always cause a lytic or a true lysogenic cycle. They can infect a cell and cause it to multiply more rapidly than normal; the virus is either incorporated into the host chromosome or else multiplies as a plasmid. Thus, the rapid multiplication of the host cell results in proliferation of the virus, much as in a lysogenic virus.

The mechanism by which some Papillomaviruses cause cancer has been hard to study because these viruses cannot (so far) be grown in cultured human cells. It is known that the proteins coded for by E6 and E7 (See handout fig. 59-4) bind to human proteins that are responsible for suppressing cell division (coded for by "anti-oncogenes"). It is not known if papillomaviruses can cause cancer alone or whether chemical, physical of viral co-factors are needed.

The scariest thing about the pandemic of genital warts is that the cancer causing forms may be just as easily transmitted as the wart-causing varieties (they are often both found in patients with cervical cancer) - no one really knows at this time.

AIDS and HIV

Let's talk about another major viral disease, acquired immune deficiency syndrome (AIDS). AIDS is caused by the human immuno-deficiency virus (HIV), which is a retrovirus. Figure 36.8 shows a cross-section through HIV. Note that there are two copies of the single stranded RNA genome and several enzymes in the inner core of the virus. The enzymes include integrase, reverse transcriptase, protease and ribonuclease. Retro viruses got their name because they reverse the usual flow of information,
DNA ---> RNA ---> protein, to

RNA ---> DNA ---> RNA ---> protein.

Show how this is done in retroviruses - compare to the influenza virus (see Fig. 18.5).....

Epidemiology of AIDS...

We are in the midst of an AIDS pandemic (see Fig. 36.7). HIV is spread by direct contact with bodily fluids such as blood, semen and vaginal secretions. Passage of these fluids into the blood of an uninfected person leads to infection. There is absolutely no evidence that casual contact or insect bites can spread HIV. Thus, AIDS is most often spread via sex or sharing of needles during IV drug use. Figure 6.1 from Fan et al. (2000) shows the progression of the AIDS epidemic in the U.S.A.

Fan, H., R.F. Conner & L.P. Villarreal. 2000. AIDS, science and society, 3rd ed. Jones and Bartlett Publishers, Boston.

Once HIV is in the body it preferentially binds (via gp120) to cells with CD4 glycoproteins on their membranes (e.g. helper T-Cells and macrophages). Once inside the cell, the RNA is reverse transcribed (via HIV's reverse transcriptase) into DNA and the viral RNA is destroyed by the viral ribonuclease. The ds DNA is then integrated into the host cell's DNA via the viral enzyme integrase. In this "provirus" state (= latent infection, lec. 23) HIV can be copied along with the rest of the host's DNA (see Figs. 36.10 & 18.5d). It can also lead to the almost continuous production of more HIV by some infected macrophages (= persistent infection, lec. 23).

New HIV are made via transcription of the provirus leading to mRNA that codes for the various viral proteins . Many of the viral proteins are produced as one long polypeptide (a polyprotein) that is later cut into the various active viral proteins by the HIV protease. New anti-AIDS drugs called protease inhibitors bind to the HIV protease thereby directly inhibiting its function. This prevents the virus from maturing and becoming infective. As long as we're discussing treatment, I should mention AZT (azidothymidine, Fig. 30.9). AZT is a nucleoside analog of thymidine (T) that is preferentially incorporated, by reverse transcriptase, into the DNA copy of viral RNA. It causes DNA replication to cease when it is incorporated into DNA. AZT works because our own DNA polymerases don't efficiently incorporate AZT into our own DNA.

Problems with AZT:

1) AZT-resistant variants of HIV arise (via mutated reverse transcriptase) in those treated for long periods of time

2) side effects because some AZT is incorporated into our own DNA.

One reason that vaccines for AIDS haven't been successful is that reverse transcriptase is a sloppy enzyme (with no repair functions) and thus new variants of HIV arise continuously via mutation.

Despite all of the research on AIDS it is still not really understood how HIV destroys the immune system. It is known that over time the number of T-helper cells declines until they reach such a low point that the body can be overrun with opportunistic infections (see Table 36.3 and Fig. 4.9 from Fan et al., 2000).

Sequencing studies have shown that HIV is related to a bunch other retroviruses of the lentivirus class. HIV probably evolved in central Africa over the last few hundred to thousands of years and may be endemic to certain human populations in Africa. Recent changes in human social behavior and population spread have probably helped it to spread into populated areas of Africa and the rest of the world over the last 20 years. There is no evidence (although theories abound!) that HIV was bio-engineered in a germ warfare lab, or that it came from sexual interactions between humans and animals.

A good current discussion of the possible origins of HIV1 and HIV2 can be found in :

B.H. Hahn et al. 2000. AIDS as a Zoonosis: Scientific and Public Health Implications. Science 287: 607-614.