Germinal Center B-Cell Hyperplasia. The majority of the lymphomas that arise in patients with preserved CD4 T-cell counts are not associated with EBV or KSHV. The increased risk for lymphoma in these patients may be related to the profound germinal center B cell hyperplasia that occurs in HIV infection. The high level of proliferation and somatic mutations that occur in germinal center B cells set the stage for chromosomal translocations and mutations involving tumor-causing genes. In fact, the aggressive B-cell tumors that arise outside the setting of severe T cell depletion in HIV-infected individuals, such as Burkitt lymphoma and diffuse large B cell lymphoma, often are associated with mutations in oncogenes such as MYC and BCL6 that bear the molecular hallmarks of “mistakes” during the attempted diversification of immunoglobulin genes in germinal center B cells.
Several other EBV-related proliferations also merit mention. Hodgkin lymphoma, an unusual B-cell tumor associated with a pronounced tissue inflammatory response (Chapter 12), also occurs at increased frequency in HIV-infected individuals. In virtually all instances of HIV-associated Hodgkin lymphoma, the characteristic tumor cells (Reed-Sternberg cells) are infected with EBV. Many (but not all) HIV patients with Hodgkin lymphoma have low CD4 counts at the time of disease presentation. EBV infection also is responsible for oral hairy leukoplakia (white projections on the tongue), which results from EBV-driven squamous cell proliferation of the oral mucosa (Chapter 15).
Other Tumors. In addition to KS and lymphomas, patients with AIDS also have an increased occurrence of carcinoma of the uterine cervix and of anal cancer. Both of these tumors are highly associated with human papilloma virus infection, which is poorly controlled in the setting of immunosuppression.
Involvement of the CNS is a common and important manifestation of AIDS. Ninety percent of patients demonstrate some form of neurologic involvement at autopsy, and 40% to 60% have clinically apparent neurologic dysfunction. Importantly, in some patients, neurologic manifestations may be the sole or earliest presenting feature of HIV infection. Lesions include a self-limited presumed viral meningoencephalitis or aseptic meningitis, vacuolar myelopathy, peripheral neuropathies, and, most commonly, a progressive encephalopathy called HIV-associated neurocognitive disorder (Chapter 23).
Effect of Anti-Retroviral Drug Therapy on the Course of HIV Infection
The advent of new drugs that target the viral reverse transcriptase, protease, and integrase enzymes has changed the clinical face of AIDS. When a combination of at least three effective drugs is used in a motivated, compliant patient, HIV replication is reduced to below the threshold of detection (<50 RNA copies/mL) and remains there as long as the patient adheres to therapy. Once the virus is suppressed, the progressive loss of CD4+ T cells is halted, and the peripheral CD4+ T-cell count slowly increases, often returning to a normal level. With the use of these drugs, the annual death rate from AIDS in the United States has decreased from a peak of 16 to 18 per 100,000 individuals in 1995–1996 to less than 4 per 100,000. Many AIDS-associated disorders, such as opportunistic infections with http://ebooksmedicine.net
P. jiroveci and Kaposi sarcoma, now are uncommon. Effective anti-retroviral therapy also has reduced the transmission of the virus, especially from infected mothers to newborns.