Research Initiative Treatment Action (RITA!); Vol 9, No. 1 Summer 2003
Jennifer Newcomb-Fernandez, PhD

Common sense tells us that viruses should be cleared from our bodies just like any other invading pathogen. However, many are not cleared entirely and are able to persist by establishing latent infection. In many cases, virus-host interactions have evolved over the millennia such that viruses reproduce, remain viable, and are transmitted, while host immune systems can contain infections and prevent severe illness or death. Examples of such viruses include herpesviruses and papillomaviruses. Herpesviruses that can establish latent and long-term infection in host humans include cytomegalovirus (CMV) or human herpesvirus 5 (HHV-5), Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8), and Epstein-Barr virus (EBV). The latter two viruses, along with certain forms of the human papillomavirus (HPV), are associated with the development of AIDS-defining cancers. These viruses avoid immune clearance using strategies such as modulating the expression and activity of major histocompatibility complex (MHC) proteins (which are involved in antigen presentation), preventing apoptosis of virally infected cells, suppressing the antiviral activity of host interferon, and interfering with cytotoxic lymphocytes (CTLs).

Many of the above activities are mediated by special viral proteins produced in infected cells. In some cases, viral proteins play other roles such as enabling viral genes to attach to cellular chromosomes during mitosis or inducing angiogenesis to ensure an enhanced blood supply to developing tumors. The possibility even exists that the immunomodulatory mechanisms used by one type of virus may actually enhance or benefit the activity or replication of other viruses. Many of these viruses (for example, HPV, CMV, and EBV) are quite common in the human population but do not always lead to the development of malignancies. Certainly, infection with HIV changes the playing field and an environment of immunosuppression may eventually tip the scale in favor of these other viruses, leading to an increased risk of cancer.

Of course, in theory, HIV is relatively new to the human immune system and a virus-host balance (such as that seen with, for example, a normal herpes infection in an otherwise healthy individual) has yet to evolve. This scenario would be difficult to envision for HIV (given the primary target of viral infection, the CD4 T cell) were it not for the insights afforded by studying long-term nonprogressors and others who have staved off disease progression in the absence of anti-HIV therapy. Nonetheless, research has shown that there is more to HIV than its ability to wipe out T cells and that HIV is associated with the development of a variety of malignancies, as discussed in this current issue. HIV has shown itself to be an elusive target, and it accomplishes this feat by using a variety of immune evasion and manipulation strategies, including several similar to those employed by other viruses as described above.

The more we come to understand viral mechanisms of immune evasion and manipulation, the better we will be able to treat the maladies and malignancies associated with chronic viral infections.

Further reading:

Johnson WE, Desrosiers RC. Viral persistance: HIV's strategies of immune system evasion. Annu Rev Med. 2002;53:499-518.

Lieberman J, Manjunath N, Shankar P. Avoiding the kiss of death: how HIV and other chronic viruses survive. Curr Opin Immunol. 2002 Aug; 14(4): 478-86.

Means RE, Choi JK, Nakamura H, Chung YH, Ishido S, Jung JU. Immune evasion strategies of Kaposi's sarcoma-associated herpesvirus. Curr Top Microbiol Immunol. 2002;269:187-201.

Mocarski ES Jr. Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion. Trends Microbiol. 2002 Jul;10(7):332-9.

O'Brien PM, Saveria Campo M. Evasion of host immunity directed by papillomavirus-encoded proteins. Virus Res. 2002 Sep;88(1-2):103-117.

Ohga S, Nomura A, Takada H, Hara T. Immunological aspects of Epstein-Barr virus infection. Crit Rev Oncol Hematol. 2002 Dec;44(3):203-15.

Vossen MT, Westerhout EM, Soderberg-Naucler C, Wiertz EJ. Viral immune evasion: a masterpiece of evolution. Immunogenetics. 2002 Nov; 54(8): 527-42.

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Copyright © 2003 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org

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