AIDS results from infection by HIV. It associates with a number of defining abnormalities (Table 13.25). More than 30 million people are infected with HIV-1 worldwide. Epidemiologically,
the major risk groups for developing AIDS vary depending on geographic locale. In Africa and Asia, the major risk group is sexually active heterosexuals; women are more often infected than men (472,473). In contrast, in the United States, over 70% of cases affect men having sex with men. Another 15% develop in intravenous drug users. Other high-risk groups include prostitutes, hemophiliacs, children born to HIV-positive mothers, patients transfused with infected blood or blood products, and heterosexual contacts of any of the above groups (474). HIV-infected mothers pass the virus transplacentally, at the time of delivery through the birth canal or through breast milk. AIDS especially affects Hispanics and African Americans (475). The AIDS patient population in the United States is disproportionately male, black, and poor (476). Women represented 18% of all cases in the United States in 1994. Sexual transmission is now the dominant route by which women become infected (477). Substantial declines have occurred in AIDS incidence and death in recent years (475), probably due to an increased awareness in at-risk populations and the introduction of antiretroviral therapies.

Since 1996, profound changes have taken place in the epidemiology, clinical presentation, complications, and management of HIV infections, largely due to the introduction of highly active antiretroviral treatment (HAART). As a result, gastrointestinal complications have dramatically decreased and there has been a substantial decline in the number of opportunistic infections associated with the infection (478). However, while HAART is effective in suppressing opportunistic infections, the antiretroviral medications cause GI side effects in up to 10% of cases (479). Currently, drug-induced side effects and nonopportunistic diseases are among the most common causes of GI symptoms in HIV-positive patients (478,480).

Two HIVs exist: HIV-1 and HIV-2; both belong to the lentivirus family of nononcogenic retroviruses. HIV-1 is the predominant virus in the United States, Europe, and eastern Africa. HIV-2 infection predominates in parts of western Africa. Many fewer AIDS cases develop in HIV-2–infected than in HIV-1–infected populations. Viral transmission is similar for both viruses, except that perinatal transmission occurs less frequently in HIV-2 infections. HIV-2 also has a longer latency period before AIDS appears, the course is less aggressive, and the mortality rate is less than in HIV-1 infection. HIV-2–infected patients typically have a lower viral load and higher CD4 counts than HIV-1–infected individuals. HIV easily mutates leading to the emergence of new viral strains that can resist immune attack or drug therapy or alter the clinical or histopathologic features of the disease. The number of active replicating viruses is proportional to the number of CD4+ lymphocytes.

The virion contains two single RNA strands, structural proteins, and the enzymes required for viral replication. HIV genes encode core proteins (GAG), reverse transcriptase, protease, an endonuclease (Pol), and envelope glycoproteins (Env). At least five other genes exert regulatory functions that may affect viral pathogenicity: vif, tat3, rev, nef, and vpr. The viruses use the enzyme reverse transcriptase to transcribe viral RNA into proviral DNA in host cells. The proviral DNA resides in the cells during viral latency. The lipid envelope surrounding the viral core derives from the host cell surface as the virions bud from the infected cell. As a result, this lipid envelope contains host membrane protein remnants as well as the viral envelope glycoprotein gp120 and the transmembrane protein gp41, two proteins involved in viral attachment and entry into host cells (481).

The CD4 protein and its coreceptor, CXCR4, and possibly CD26 on helper T-cell surfaces, serve as high-affinity receptors for the viral envelope gp120, mediating rapid, firm, cellular attachments. T-cell trophic viruses requiring CXCR4 for entry are termed X4 viruses (482).

Some HIV strains (named R5 viruses to reflect their coreceptor requirement) bind to macrophages via the β chemokine receptor CCR5 (483,484,485). Genetic polymorphisms in the chemokine receptor genes that mediate HIV disease progression affect disease expression (486). Cells with an absent or reduced CCR5 expression or a CCR5 mutation have a reduced sensitivity to HIV infection (487), and these cells are resistant to HIV infection even in the face of a high risk of infection (487).

The most common mode of HIV-1 infection is sexual transmission through the anogenital mucosa. Monocytes, macrophages, dendritic cells, and CD4+ T lymphocytes are the primary viral targets (481). The virus is initially acquired via one of the following: Rectal mucosal tears, M cells overlying lymphoid follicles, direct infection of the rectal epithelium, or infection of lamina propria dendritic cells (488) subjacent to the anorectal epithelium. HIV-1 viruses adhering to the luminal membranes of rectal M cells are endocytosed and delivered to
intraepithelial lymphocytes, macrophages, and the mononuclear cells of the lymphoid follicles (489). The infected cells fuse with CD4+ lymphocytes and spread into deeper tissues. Within 2 days of the initial infection, viruses can be detected in draining internal iliac lymph nodes. Shortly thereafter, systemic dissemination occurs.

The gastrointestinal mucosa serves as an important reservoir for HIV, with lamina propria macrophages frequently harboring the virus (489,490). The gastrointestinal epithelium and lamina propria are also a rich source of CD4+ T cells. There are also abundant CD4+ T cells in the regional lymph nodes. The intestinal mucosa becomes profoundly and selectively depleted of CD4+ cells within days of the infection, even before similar changes occur in peripheral lymphoid tissues. In contrast, CD8+ T cells increase early in the infection and then display increased levels of activation antigens and abnormal MHC-restricted HIV-specific and -nonspecific cytotoxic abilities. A specific increase in apoptotic CD8+ T cells eventually leads to their depletion (490). A nearly complete absence of CD4+ intraepithelial lymphocytes and decreased CD11+ intraepithelial lymphocytes characterize the intestinal mucosa of severely ill AIDS patients (491).

Host factors also play a major role in the pathogenesis of HIV-related disease. A complex network of endogenous cytokines provides a delicate balance between HIV induction and suppression. The β-chemokines RANTES, MIP-1α, and MIP-1β act as suppressors of macrophage-trophic HIV strains (492) and elevated β-chemokine expression levels probably help control HIV load and replication in individuals who do not progress to AIDS (493).

Acute HIV-1 infection is a transient symptomatic illness associated with high viral titers and a robust immunologic antiviral response (494). Signs and symptoms of an acute HIV-1 infection occur within days to weeks of the initial viral exposure, and include the first gastrointestinal symptoms. The most common systemic signs and symptoms include fever, fatigue, a rash, headache, lymphadenopathy, pharyngitis, myalgia, arthralgia, aseptic meningitis, retro-orbital pain, weight loss, depression, GI distress, night sweats, and oral or genital ulcers. The acute illness lasts for a few days to more than 10 weeks, but averages <14 days in length (495). Since the early signs and symptoms are nonspecific, acute HIV-1 infections are frequently confused with other viral illnesses. Initial laboratory studies may show lymphopenia and thrombocytopenia, but atypical lymphocytes are infrequent. Standard serologic tests only become positive 3 to 4 weeks after the initial infection (496). Severe and prolonged symptoms correlate with rapid disease progression (497). After the initial infection, there is a rapid viremia with widespread viral dissemination, seeding of lymphoid organs (498), and entrapment by follicular dendritic cells (499). Individuals with the highest viral loads have the highest rates of disease progression (500).