That Complicate Acquired Immunodeficiencies

Certain malignant tumors are associated with HIV disease, organ transplantation, and other acquired immunodeficiency states. Most of these malignancies fall into one of only three types: Kaposi's sarcoma, lymphomas, and carcinomas arising from anal or cervical epithelium. They tend to metastasize, meaning jump to new areas, and be difficult to treat. Evidence indicates that viruses are a factor in their causation. A popular theory is that certain viral antigens, perhaps with the aid of cytokines, cause rapid multiplication of a host cell type. A mutation to malignancy then occurs among the rapidly dividing cells, the result of insertion of viral DNA into their genome, or other carcinogen. Finally, the malignant cell escapes detection and destruction by immune surveillance because of defective cellular immunity, and it is able to multiply without restraint.

Kaposi's Sarcoma

Kaposi's sarcoma (figure 29.12) is an unusual tumor arising from blood or lymphatic vessels in multiple locations. Formerly, it was seen rarely and mainly in older men of Mediterranean and Eastern European origin. It also occurs among all age groups in certain parts of tropical Africa. It is not associated with immunodeficiency in any of these varieties.

Figure 29.12 Kaposi's Sarcoma Two lesions are shown on a person's foot.

Coincident with the spread of HIV, the tumor began to appear in young men with HIV disease, and the incidence rose dramatically. Among a group of never-married San Francisco men, the incidence of Kaposi's sarcoma was 2,000 times as high in 1984 as it was in the period before HIV became widespread. The tumor was so common among AIDS patients that it became an AIDS-defining condition, even though it generally appeared before the development of severe immunodeficiency. One of the many unsolved mysteries about this tumor is that its incidence among AIDS patients has fallen dramatically since the adoption of condom use and safer sex practices.

Besides HIV disease, Kaposi's sarcoma is often associated with the use of medications to suppress the immune system in organ transplant patients. Indeed, the incidence of Kaposi's sarcoma is more than 400 times as high in transplant patients as in the general public. Another peculiarity of the tumor is that it can sometimes disappear if a patient's organ graft is rejected, suggesting a strong influence for cellular immunity.

In 1994, scientists at Columbia University detected a previously unknown herpesvirus in Kaposi's sarcomas, named Kaposi's sarcoma associated herpesvirus (KSHV), or human her-pesvirus-8 (HHV-8). The virus can be detected in essentially all cases of Kaposi's sarcoma, whether associated with immunodeficiency or not. It is also strongly associated with certain malignant tumors, including multiple myeloma. Serological evidence of infection is present in about 25% of the healthy adult United States population. HHV-8 has been detected in the saliva of patients with HIV disease and Kaposi's sarcoma, and in semen of healthy men. Although there is still much to be learned about the role HHV-8 plays in Kaposi's sarcoma, the virus appears to be necessary for formation of the tumor, but additional factors must be present for the tumor to develop. ■ multiple myeloma, p. 456

In Kaposi's sarcoma, HHV-8 infects the endothelial cells that line blood and lymphatic vessels and persists there mostly in a latent form, only a small percentage of the infected cells evidencing a lytic infection at any one time. Presence of the virus is associated with two dramatic changes that result in tumor formation: (1) The cells assume a spindle shape and proliferate; (2) Extensive formation of new blood vessels occurs. These

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changes are probably due to release from the host cells of the cytokines normally responsible for stimulating cell growth and new vessel formation. This release of cytokines appears to be due largely to a gene product of latent HHV-8. The changes typically seen in cancers and other malignant tumors are usually not present—namely, proliferation of a single clone of microscopically abnormal cells with abnormal chromosomes, and origin in a single location with later distant metastases. When malignant changes occur in Kaposi's sarcoma, as they do occasionally, the abnormal clone of cells does not contain the HHV-8 genome, showing that some other factor than the virus is responsible for the transformation.

Only in a fraction of individuals infected with both HHV-8 and HIV-1 develop Kaposi's sarcoma, but that fraction is enormously greater than with those infected only with HHV-8. Why is HHV-8 infection so much more likely to result in Kaposi's sarcoma in patients with HIV-1 disease? Scientists around the world, hard at work on this question, have discovered some clues. Tat, the protein product of the HIV tat gene, is released from infected T lymphocytes and enhances proliferation of endothelial cells. The Tat of HIV-2 does not have the same effect, and there is no increase in Kaposi's sarcoma in patients with HIV-2 disease. Many of the molecular details of the interaction of the two viruses are now known and undoubtedly will lead to new treatment options and better understanding of how malignancy develops.

B-Lymphocytic Tumors of the Brain

Lymphomas are a group of malignant tumors that arise from lymphoid cells. Most of these tumors arise from B lymphocytes, although T-lymphocytic lymphomas also occur. B-cell lymphomas are 60 to 100 times as common in AIDS patients as in the general public, and 60 times as frequent in individuals with organ transplants. Intense, sustained replication of lymphoid cells is a constant feature of HIV. As stated at the beginning of this chapter, HIV was first isolated from a patient with the lym-phadenopathy syndrome, a condition in which the lymph nodes are markedly enlarged for 3 months or more, now known to be a prelude to AIDS. The lymph node enlargement reflects proliferation of lymphoid cells in response to high-level unregulated cytokine release and to the HIV gp41 (TM) antigen. Also in HIV disease, sustained replication of T cells occurs as billions of new cells are produced each day to replace those destroyed by HIV. In contrast to Kaposi's sarcoma, with B-lymphocytic tumors there is no epidemiologic evidence of involvement of a sexually transmitted infection.

Epstein-Barr virus (EBV), however, plays a role in many of the B-cell lymphomas associated with AIDS, present in essentially all those that involve the brain. Lymphomas rarely arise in the brain except in AIDS patients. EBV is also present in all the B-cell lymphomas that occur in transplant patients. The EBV-related tumor, Burkitt's lymphoma, is at least 1,000 times as frequent among AIDS patients as in the general public, representing about one-fourth of all the lymphomas associated with AIDS. EBV probably plays an indirect role in B-cell lymphoma formation rather than being the direct cause. HIV infection causes activation of latent EBV infection, with release of the virus to infect new B lymphocytes. This, in turn, causes polyclonal

754 Chapter 29 HIV Disease and Complications of Immunodeficiency

B-cell proliferation and increased life span. Malignant B-cell clones are thought to arise from this population of rapidly dividing cells. ■ Epstein-Barr virus, Burkitt's lymphoma, p. 727

Cervical and Anal Carcinoma

Carcinoma (cancer) of the uterine cervix in women and carcinoma of the anus in women and gay men are strongly associated with human papillomaviruses (HPV) types 16 and 18. The cells involved in these cancers are epithelial cells and, therefore, differ from those in Kaposi's sarcomas and lymphomas. HPV is transmitted during sexual activity and infects the cervical and anal epithelium, appearing to cause increased replication of the cells by blocking expression of a cellular gene responsible for controlling cell growth. In HIV disease, organ transplantation, and other immunodeficient conditions, HPV replication increases with the decline of the host's cellular immunity. Precancerous changes can be demonstrated in the anal cells of HIV-positive gay men twice as frequently as in gay men who are HIV negative, and six times as frequently among HIV-positive gay men with low CD4+ T-cell counts as in HIV-positive gay men with high CD4+ T-cell counts. Interestingly, even before the arrival of HIV, the incidence of anal carcinoma in gay men exceeded the incidence of cervical carcinoma in women. One important implication of these findings is that women who engage in anal intercourse should be screened for precancerous lesions of the cervix and anus, and gay men for lesions of the anus, at least twice yearly if they are HIV positive. ■ human papillomavirus infections, p. 654

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