Clinical Manifestations

Neurologic abnormalities, which occur in the majority of HIV-infected individuals, may be caused by opportunistic infections, neoplasms, or may be the direct result of HIV infection. Approximately one third of patients with AIDS are diagnosed with central nervous system infections and neoplasms such as toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, CMV, HTLV-1, tuberculosis, syphilis, and primary central nervous sytem lymphoma (Fauci and Lane 1991) at some time in the course of their disease. However, the vast majority of HIV-infected individuals experience some form of an inflammatory, demyelinating, or degenerative neurologic abnormality that appears to be a direct affect of HIV-1 (Table 1). (Geleziunas et al. 1992). Patients with AIDS often develop an HIV-induced encephalopathy, which is an AIDS-defining condition known as AIDS dementia complex (ADC) (Price et al. 1988). ADC is characterized by the presence of dementia, motor and behavioral abnormalities, and seizures. ADC is the initial AIDS-defining illness in approximately 10% of patients. Nearly two thirds of all HIV-infected patients are ultimately diagnosed with clinically significant ADC (Geleziunas et al. 1992). Autopsies suggest that 80–90% of patients have histologic evidence of central nervous system involvement (Price and Brew 1988).

Central nervous system abnormalities are also seen in SIV-infected rhesus monkeys, up to 50% of which develop a characteristic lesion that is not associated with an opportunistic infection (Simon et al. 1994). In all rhesus monkeys tested, SIV can be detected in the brain within the first 2 weeks of infection, and becomes established in the central nervous system (Chakrabarti et al. 1991). A perivascular accumulation of macrophages in meninges and gray and white matter of cerebrum, cerebellum, brain stem, and spinal cord is the most frequently observed anomaly. Multinucleated giant cells are frequently found in association with these perivascular macrophages, but they can also be found in the neuropil. Spongiosis, vascular dilatation, and endothelial hypertrophy often accompany the macrophage infiltrates, and occasional neutrophils and lymphocytes are present in the perivascular cuffs. Macrophages within the infiltrates contain SIV RNA and protein, and virions are present within intracytoplasmic vacuoles. Foci of gliosis, not usually associated with blood vessels or inflammation, can also be found in any part of the neuropil. These lesions are similar to the subacute encephalopathy/encephalitis seen in HIV-infected individuals. However, peripheral neuropathies, and the characteristic vacuolar myelopathy seen in some AIDS patients, are not seen in SIV-infected macaques.

Cell Tropism

HIV is present in the brains and cerebrospinal fluid of most infected individuals whether or not they have overt neurologic manifestations. In the brain, the principal HIV-infected cell types are of the monocyte/macrophage lineage that have migrated from the peripheral blood as well as resident microglial cells (for review, see Gartner et al. 1986; Koening et al. 1986; Wiley et al. 1986; Price et al. 1988; Rosenberg and Fauci 1989a; Levy 1993). There are conflicting reports on HIV infection of other neural cells. HIV-specific nucleic acids and proteins have been infrequently reported in astrocytes and neurons. Certain HIV isolates can infect astrocytes and neuroglial cells in vitro in addition to macrophages and microglial cells. Although HIV entry into brain macrophages and microglial cells occurs via CD4, in vitro infection of other neuronal cells may occur by a CD4-independent mechanism; galactosyl ceramide may be an alternate HIV receptor on CD4^– neuronal cells (Bhat et al. 1991; Harouse et al. 1991).

Certain strains of HIV isolated from the brain or cerebrospinal fluid of individuals with neurologic symptoms have biological properties that distinguish them from viruses isolated from the blood of individuals who do not have neurologic symptoms (for review, see Levy 1993). In general, brain-derived isolates are M-tropic. These viruses replicate efficiently in fresh blood CD4⁺ T cells but cause minimal cytopathicity. They generally grow to high titer in macrophages, but grow poorly in established T-cell, B-cell, or monocyte cell lines. There are differences between blood-derived and brain-derived HIV strains obtained from a single individual, indicating that the virus may have adapted to the brain rather than simply showing tropism for cells of macrophage/monocyte origin. The sequences of viral genomes isolated from the brain and lymphoid tissue suggest that the brain-derived viruses form a lineage distinct from those in the rest of the body. The relative contributions of selection for neurotropism and chance founder effects to this diversity remain to be assessed.

Studies of neurological disease in SIV-infected rhesus monkeys also support a role for M-tropic virus. The development of primary SIV encephalitis is associated with the presence of viral variants that replicate efficiently in macrophages (Desrosiers et al. 1991). If monkeys are infected with a clone of SIV that replicates poorly in macrophages, encephalitis is observed only in those animals from which M-tropic virus can be isolated (Mori et al. 1992). As in HIV, variants with high replicative capacity for microglial cells found in the brain are distinct biologically and genetically not only from T-cell-adapted viruses present in lymphoid compartments, but also from M-tropic viruses present in other tissues (Kodama et al. 1993 and unpubl.). The development of tissue-adapted viral genotypes may be important for the development of neurological disease in SIV-induced AIDS and perhaps in HIV-induced AIDS as well.

Mechanisms of Neuronal Damage

Pathologically, ADC is characterized by lesions in the white matter and neuronal loss. The precise mechanisms by which HIV causes these abnormalities are not known. Since HIV does not infect neurons in vivo, it is unlikely that direct viral replication within these cells accounts for their loss. However, viral proteins may play a part in neuronal cytotoxicity since gp120 and Tat protein have been shown to be toxic for neurons in culture (for review, see Geleziunas et al. 1992; Levy 1993). The effects of gp120 on neuronal cell growth might be due to its ability to bind to receptors for neuronal growth factors, since some sequence similarity exists between a portion of gp120 and both neuroleukin and vasoactive intestinal peptide. The significance of these similarities awaits experimental testing.

Some neuronal toxicity may be caused by cytokines released by infected macrophages or microglial cells (for review, see Geleziunas et al. 1992; Levy 1993). A number of cytokines, including TNF-α, IL-6, IL-1, TGF-β, and endothelin, all of which have the potential to damage neural tissue, can be induced by HIV infection of monocyte/macrophages and microglial cells. Astrocytes may play a part in cytokine-mediated damage of neuronal cells. In this regard, TNF-α has been found to be toxic for bovine oligodendrocytes and for rat neurons when infused in high concentrations into rat brains. The importance of HIV, as either a direct or indirect cause of ADC, is supported by the fact that treatment with an anti-HIV agent, AZT, can markedly reduce the severity of neurological symptoms (Vago et al. 1993), an effect that is particularly dramatic in children (Pizzo et al. 1988).