Clinical disease of the nervous system accounts for a significant degree of morbidity in a high percentage of patients with HIV infection (Table 48-1). The neurologic problems that occur in HIV-infected individuals may be either primary to the pathogenic processes of HIV infection or secondary to opportunistic infections or neoplasms. Among the more frequent opportunistic diseases that involve the CNS are toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, and primary CNS lymphoma. Other less common problems include mycobacterial infections; syphilis; and infection with CMV, HTLV-1, Trypanosoma cruzi, or Acanthamoeba. Overall, secondary diseases of the CNS have been reported to occur in approximately one-third of patients with AIDS. These data antedate the widespread use of cART, and this frequency is considerably lower in patients receiving effective antiretroviral drugs. Primary processes related to HIV infection of the nervous system are reminiscent of those seen with other lentiviruses, such as the Visna-Maedi virus of sheep.

The current U.S. CDC classification system for HIV infection and AIDS categorizes people on the basis of clinical conditions associated with HIV infection and CD4+ T lymphocyte measurement. A confirmed HIV case can be classified in one of five HIV infection stages (0, 1, 2, 3, or unknown). If there was a negative HIV test within 6 months of the first HIV infection diagnosis, the stage is 0, and remains 0 until 6 months after diagnosis. Advanced HIV disease (AIDS) is classified as stage 3 if one or more specific opportunistic illness has been diagnosed (Table 48-2). Otherwise, the stage is determined by CD4 test results and immunologic criteria (Table 48-3). If none of these criteria apply (e.g., because of missing information on CD4 test results), the stage is U (unknown).

The definition and staging criteria of AIDS are complex and comprehensive and were established for surveillance purposes rather than for the practical care of patients. Thus, the clinician should not focus on whether the patient fulfills the strict definition of AIDS, but should view HIV disease as a spectrum ranging from primary infection, with or without the acute syndrome, to the asymptomatic stage, to advanced stages associated with opportunistic diseases (see “Pathophysiology and Pathogenesis,” below).

HIV is the etiologic agent of AIDS; it belongs to the family of human retroviruses (Retroviridae) and the subfamily of lentiviruses. Nononcogenic lentiviruses cause disease in other animal species, including sheep, horses, goats, cattle, cats, and monkeys. The four retroviruses known to cause human disease belong to two distinct groups: the human T lymphotropic viruses (HTLV)-1 and HTLV-2, which are transforming retroviruses; and the human immunodeficiency viruses, HIV-1 and HIV-2, which cause cytopathic effects either directly or indirectly. The most common cause of HIV disease throughout the world, and certainly in the United States, is HIV-1, which comprises several subtypes with different geographic distributions (see “Molecular Heterogeneity of HIV-1,” below). HIV-2 was first identified in 1986 in West African patients and was originally confined to West Africa. However, a number of cases that generally can be traced to West Africa or to sexual contacts with West Africans have been identified throughout the world. The currently defined groups of HIV-1 (M, N, O, P) and the HIV-2 groups A through H each are likely derived from a separate transfer to humans from a nonhuman primate reservoir. HIV-1 viruses likely came from chimpanzees and/or gorillas, and HIV-2 from sooty mangabeys. The AIDS pandemic is primarily caused by the HIV-1 M group viruses. Although HIV-1 group O and HIV-2 viruses have been found in numerous countries, including those in the developed world, they have caused much more localized epidemics. The taxonomic relationship between primate lentiviruses is shown in Fig. 48-1.

MORPHOLOGY OF HIV

Electron microscopy shows that the HIV virion is an icosahedral structure (Fig. 48-2) containing numerous external spikes formed by the two major envelope proteins, the external gp120 and the transmembrane gp41. The HIV envelope exists as a trimeric heterodimer. The virion buds from the surface of the infected cell and incorporates a variety of host proteins into its lipid bilayer. The structure of HIV-1 is schematically diagrammed in Fig. 48-2B.

REPLICATION CYCLE OF HIV

HIV is an RNA virus whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase. The replication cycle of HIV begins with the high-affinity binding of the gp120 protein via a portion of its V1 region near the N terminus to its receptor on the host cell surface, the CD4 molecule (Fig. 48-3). The CD4 molecule is a 55-kDa protein found predominantly on a subset of T lymphocytes that are responsible for helper function in the immune system. It is also expressed on the surface of monocytes/macrophages and dendritic/Langerhans cells. Once it binds to CD4, the gp120 protein undergoes a conformational change that facilitates binding to one of two major co-receptors. The two major co-receptors for HIV-1 are CCR5 and CXCR4. Both receptors belong to the family of seven-transmembrane-domain G protein–coupled cellular receptors, and the use of one or the other or both receptors by the virus for entry into the cell is an important determinant of the cellular tropism of the virus. Certain dendritic cells (DCs) express a diversity of C-type lectin receptors on their surface—one of which is called DC-SIGN—that also bind with high affinity to the HIV gp120 envelope protein, allowing DCs to facilitate virus spread to CD4+ T cells. Following binding of the envelope protein to the CD4 molecule associated with the above-mentioned conformational change in the viral envelope gp120, fusion with the host cell membrane occurs via the newly exposed gp41 molecule penetrating the plasma membrane of the target cell and then coiling upon itself to bring the virion and target cell together (Fig. 48-4). Following fusion, uncoating of the capsid protein shell is initiated—a step that facilitates reverse transcription and leads to formation of the preintegration complex, composed of viral RNA, enzymes, and accessory proteins and surrounded by capsid and matrix proteins (Fig. 48-3). As the preintegration complex traverses the cytoplasm to reach the nucleus, the viral reverse transcriptase enzyme catalyzes the reverse transcription of the genomic RNA into DNA, resulting in the formation of double-stranded proviral HIV-DNA. At the preintegration steps of the replication cycle, the viral genome is vulnerable to cellular factors that can block the progression of infection. In particular, the cytoplasmic tripartite motif-containing protein 5-α (TRIM5-α) is a host restriction factor that interacts with retroviral capsids (Fig. 48-3). Although the exact mechanisms of action of TRIM5-α remain unclear, the HIV-1 capsid is not recognized by the human form of TRIM5-α. Thus this host factor is not effective in restricting HIV-1 replication in human cells. The apolipoprotein B mRNA editing enzyme (catalytic polypeptide-like 3 [APOBEC3]) family of cellular proteins also inhibits progression of virus infection after virus has entered the cell and prior to entering the nucleus (Fig. 48-3). APOBEC3 proteins, which are incorporated into virions and released into the cytoplasm of a newly infected cell, bind to the single minus-strand DNA intermediate and deaminate viral cytidine, causing hypermutation of retroviral genomes. HIV has evolved a powerful strategy to protect itself from APOBEC. The viral protein Vif targets APOBEC3 for proteasomal degradation.

With activation of the cell, the viral DNA accesses the nuclear pore and is exported from the cytoplasm to the nucleus, where it is integrated into the host cell chromosomes through the action of another virally encoded enzyme, integrase (Fig. 48-3). HIV provirus (DNA) integrates into the nuclear DNA preferentially within introns of active genes and regional hotspots. This provirus may remain transcriptionally inactive (latent) or it may manifest varying levels of gene expression, up to active production of virus.

Cellular activation plays an important role in the replication cycle of HIV and is critical to the pathogenesis of HIV disease (see “Pathogenesis and Pathophysiology,” below). Following initial binding, fusion, and internalization of the nucleic acid contents of virions into the target cell, incompletely reverse-transcribed DNA intermediates are labile in quiescent cells and do not integrate efficiently into the host cell genome unless cellular activation occurs shortly after infection. Furthermore, some degree of activation of the host cell is required for the initiation of transcription of the integrated proviral DNA into either genomic RNA or mRNA. This latter process may not necessarily be associated with the detectable expression of the classic cell-surface markers of activation. In this regard, activation of HIV expression from the latent state depends on the interaction of a number of cellular and viral factors. Following transcription, HIV mRNA is translated into proteins that undergo modification through glycosylation, myristoylation, phosphorylation, and cleavage. The viral particle is formed by the assembly of HIV proteins, enzymes, and genomic RNA at the plasma membrane of the cells. Budding of the progeny virion through the lipid bilayer of the host cell membrane is the point at which the core acquires its external envelope and where the host restriction factor tetherin can inhibit the release of budding particles (Fig. 48-3). Tetherin is an interferon (IFN)-induced type II transmembrane protein that interferes with virion detachment, although the HIV accessory protein Vpu counteracts the effect through direct interactions with tetherin. During or soon after budding, the virally encoded protease catalyzes the cleavage of the gag-pol precursor to yield the mature virion. Progression through the virus replication cycle is profoundly influenced by a variety of viral regulatory gene products. Likewise, each point in the replication cycle of HIV is a real or potential target for therapeutic intervention. Thus far, the reverse transcriptase, protease, and integrase enzymes as well as the process of virus–target cell binding and fusion have proved clinically to be susceptible to pharmacologic disruption.