Effect Mechanism of action Allele ModeGene HIV entry Cytokine anti-HIV Acquired immunity, cell-mediated Acquired immunity, innate Recessive Prevents infection Knockout of CCR5 expression Recessive Accelerates AIDS (E) Increases CCR5 expression CCR5 ˜32 P1 Dominant Delays AIDS Interacts with and reduces CXCR4 I64CCR2 Homozygous Accelerates AIDS Decreases breadth of HLA class I epitope recognition A, B, C Accelerates AIDS Defects CD8-mediated T-cell clearance of HIV-1 B*35-Px HLA Codominant Delays AIDS Delays HIV-1 escape B*27 B*57 Dominant Accelerates AIDS Decreases CCL5 expression In1.1cCCL5 Recessive Delays AIDS (L) Impedes CCR5–CXCR4 transition (?) 3´ACXCL12 Dominant Accelerates P. jirovecii pneumonia (L) Alters T-cell activations (?)E3KCXCR6 Dominant Enhances infection Stimulates immune response (?)H7CCL2-CCL7-CCL11 Dominant Accelerates AIDS (E) –179TIFNG Epistatic with HLA-Bw4 Delays AIDS Clears HIV+, HLA– cells (?) 3DS1KIR3DS1 Dominant Limits infection Decreases IL-10 expression 5´AIL10 Accelerates AIDS Dominant Prevents lymphoma (L) Decreases available CCR5 Delays AIDS Genes that infuence progression to AIDS 13-34 The destruction of immune function as a result of HIV infection leads to increased susceptibility to opportunistic infection and eventually to death.
When CD4 Tcell numbers decline below a critical level, cellmediated immunity is lost, and infections with a variety of opportunistic microbes appear (Fig. 13.36). Typically, resistance is lost early to oral Candida species and to M. tuberculosis, which cause thrush (oral candidiasis) and tuberculosis, respectively. Later, patients suffer from shingles (caused by the activation of latent herpes zoster), from aggressive EBVinduced Bcell lymphomas, and from Kaposi sarcoma, a tumor of endothelial cells that probably results both from a response to cytokines produced in the infection and a herpesvirus called Kaposi sarcomaassociated herpesvirus (KSHV, or HHV8). Since the earliest recognition of AIDS, pneumonia caused by P. jirovecii (previously called P. carinii) has been the most common opportunistic infection; it was typically fatal before effective antifungal therapy was introduced. Coinfection by hepatitis C virus is common and associated with more rapid progression of hepatitis. In the final stages of AIDS, infection with cytomegalovirus or a member of the Mycobacterium avium group of bacteria is more prominent. It is important to note that not all patients with AIDS get all of these infections or tumors, and there are other tumors and infections that are less prominent but still significant. Figure 13.36 lists the most common opportunistic infections and tumors, which are typically controlled until the CD4 Tcell count drops toward zero.
infections are the major cause of death in aiDS, the most prominent being respiratory infection with P. jirovecii and mycobacteria. Host defense against most of these pathogens requires effective macrophage activation by CD4 t cells or effective cytotoxic t cells. Opportunistic pathogens are present in the normal environment, but cause severe disease primarily in immunocompromised hosts, such as aiDS patients and cancer patients. aiDS patients are also susceptible to several rare cancers, such as Kaposi sarcoma [associated with human herpesvirus 8 (HHV8)] and various lymphomas, suggesting that immune surveillance of the causative herpesviruses by t cells can normally prevent such tumors (see Chapter 16).