Epidemiology and Current Trends

Acquired immunodeficiency syndrome (AIDS) was first recognized in the United States in the summer of 1981 when unexplained occurrences of Pneumocystis jiroveci (formerly carinii) pneumonia and Kaposi sarcoma were reported in cohorts of previously healthy homosexual men. Within months, the disease became recognized in intravenous drug users (IDUs) and soon thereafter in recipients of blood transfusion and blood products, including hemophiliacs. As the epidemiological pattern unfolded, it became clear that a microbe transmitted by sexual (homosexual and heterosexual) contact and through blood and blood products was the etiological agent of the epidemic. In 1983, human immunodeficiency virus type-1 (HIV-1, henceforth called HIV) was isolated, and in the following year it was clearly demonstrated that it, indeed, was the causal agent of AIDS. In 1985, a sensitive enzyme-linked immunosorbent assay (ELISA) test was developed, which led to the recognition of the scope of HIV infection among cohorts of individuals in the United States and elsewhere. As the disease spread, seroprevalence studies revealed the enormity of the global pandemic, with AIDS cases reported from virtually every country.

Now, 3 decades after the first report of AIDS, this disease has become one of the greatest public health challenges globally. The HIV pandemic has resulted in an estimated 64 million infections worldwide, and it has claimed the lives of more than 30 million persons (www.unaids.org). In 2008, more than 1 million persons were living with HIV/AIDS in the United States, and based on new methods of determining incidence, approximately 56,000 new HIV infections and 25,000 deaths occurred (www.cdc.org). An estimated 44% of new HIV infections are in homosexual men, 17% are in IDUs, and in 35% the infection is transmitted by heterosexual contact. The demography of newly infected individuals has changed considerably since the 1990s in the United States; HIV infection is spreading rapidly in certain populations (racial and ethnic minority populations and women of color) and decreasing (IDUs) or fluctuating in others (homosexual men).

Despite these grim statistics, noteworthy progress has also been made in recent years to contain the HIV pandemic. The incidence of HIV infection and the epidemic as a whole has declined in the United States in recent years; the incidence of AIDS and AIDS-related deaths has fallen by about 70% since 1995. This trend likely reflects reduced HIV infection rates since the mid-1980s, more widespread use of prophylactic therapies that delay the onset of AIDS, and the use of highly active antiretroviral therapy (HAART) early in the course of HIV infection.

HIV Genome, Replication, and Molecular Heterogeneity of HIV

HIV is a ribonucleic acid (RNA) virus belonging to the family of human retroviruses (Retroviridae) and the subfamily of lentiviruses. Electron microscopy shows that the HIV virion is an icosahedral structure. It contains numerous external spikes formed by the two major envelope proteins (gp120 and gp41) and one major core protein (gp24). Like other retroviruses, HIV has genes that encode the structural and enzyme proteins of the virus: env encodes the surface glycoproteins, gag encodes the core protein, and pol encodes for the enzyme responsible for reverse transcription and viral integration into the host genome. HIV also contains at least six other genes (tat, rev, nef, vif, vpr, and vpu) that encode for proteins involved in gene regulation. The replication cycle of HIV begins with high-affinity binding of the gp120 envelope protein to its receptor, the CD4 molecule, on the host cell surface (Greene and Peterlin, 2002). After gp120 binds to the CD4 molecule, it undergoes a conformational change that facilitates its binding to a co-receptor (CCR5, CXCR4) (Xiao et al., 2000). These co-receptors belong to the family of transmembrane G protein–coupled cellular receptors that determine the cellular tropism of the virus strain. Following surface attachment and fusion, the HIV genomic RNA is uncoated and internalized into the host cell. The subsequent steps in viral replication include activation of reverse transcriptase enzyme, reverse transcription of the genomic RNA into double-stranded deoxyribonucleic acid (DNA), and integration of DNA into the host cell chromosome through the action of another virally encoded enzyme—integrase. Molecular analyses of various HIV isolates from a single person over time or from cohorts of patients reveal sequence variations over many parts of the viral genome. The degree of difference in coding sequences of the viral envelope protein, for example, can vary from a few percent to 50%. The immune pressure and functional constraints on viral proteins (e.g., by antibodies) and the use of retroviral therapy influence the level of variation in viral genes and protein products.

Natural History of HIV Infection and Neuro-HIV Disease

The hallmark of HIV disease is the profound immunodeficiency resulting from a progressive loss or dysfunction of the subset of T lymphocytes referred to as helper or inducer T cells. This subset of T lymphocytes is phenotypically defined by the presence on their surface of the CD4 molecules that serve as the primary cellular receptor for HIV. A co-receptor (CCR5 or CXCR4, see previous section) must also be present together with CD4 for efficient fusion and entry of HIV into the target cells, leading to progressive dysfunction and depletion of CD4⁺ T cells. Depletion of these cells leads to a high risk of opportunistic infectious diseases and neoplasms. Some features of AIDS, such as neurological abnormalities (encephalopathy, dementia), cannot be explained entirely by the immunosuppressive effect of HIV, since they can arise before the development of severe immunological impairment.

The current Centers for Disease Control and Prevention (CDC) classification system of HIV-infected adolescents and adults categorizes persons on the basis of clinical conditions associated with HIV infection and CD4⁺ T-cell counts. The system is based on three ranges of such lymphocyte counts and three clinical categories, making a total of nine mutually exclusive categories (Table 53A.1). HIV disease follows a progressive course; once individuals have had a clinical condition in category B (or C), their disease cannot again be classified into a lower category (A or B). AIDS-defining conditions were originally designed for surveillance purposes, and clinicians should not focus on whether AIDS is present but instead should view HIV disease as a spectrum ranging from primary infection through asymptomatic stage to advanced disease.

The stage of systemic HIV infection influences both the risk and the nature of neurological disease; hence CD4⁺ T-cell count provides critical information that helps guide the evaluation (Fig. 53A.1). In early infection (corresponding to CD4⁺ T-cell counts >500/mL) and excess immune stimulation, autoimmune disorders such as demyelinating neuropathies may develop. During midstage infection (CD4⁺ T-cell counts of 200-500/mL), primary HIV-related disorders such as HIV-associated neurocognitive dysfunction (HAND) and certain opportunistic infections such as varicella-zoster virus (VZV) radiculitis (shingles) may appear. In advanced HIV infection (CD4⁺ T-cell count <200/mL), the risk of dementia, myelopathy, and painful neuropathy increases further, and patients become increasingly vulnerable to major opportunistic infections (OIs) such as cerebral toxoplasmosis, progressive multifocal leukoencephalopathy (PML), and cryptococcal meningitis, as well as to neoplasms—in particular, primary central nervous system lymphoma (PCNSL).

Fig. 53A.1 Systemic and neurological events in human immunodeficiency virus (HIV) infection. Temporal sequence is approximate and indicates the increasing risk of systemic and neurological complications as HIV infection advances. CMV-E, Cytomegalovirus encephalitis; CMV-PR, CMV polyradiculitis; CNS, central nervous system; CSF, cerebrospinal fluid; ITP, idiopathic thrombocytopenic purpura; OIs, opportunistic infections; PML, progressive multifocal leukoencephalopathy; PNS, peripheral nervous system.

Neuropathogenesis of HIV Disease

HIV-infected individuals can experience a variety of neurological abnormalities due either to the direct effects of the HIV or to the consequences of immunosuppression. Opportunistic infection is the major sequela of an altered immune system. Other neurological complications that are the indirect effect of the infection or treatment include neoplasm, cerebrovascular disease, toxic and metabolic disturbances, and the neurological side effects of antiretroviral and other therapies.

Neurons lack the conventional surface receptor for HIV binding and fusion and therefore are not directly infected by the virus. The main cell types infected in the brain in vivo are those of the monocyte-macrophage lineage. These include monocytes that have migrated into the brain from the peripheral blood, perivascular macrophages, and resident microglial cells (Sabri et al., 2003; Yadav and Collman, 2009). Although there have been reports of infrequent HIV infection of astrocytes, there is no convincing evidence that brain cells other than those of monocyte-macrophage lineage can be productively infected in vivo (Price and Spudich, 2008). Nevertheless, in vitro infection of a neural cell line has been reported (Klein et al., 1999), and it appears that galactosylceramide on the neuronal surface is an essential component of the HIV gp120 receptor; antibodies to galactosylceramide inhibit HIV entry into the neural cell lines. Some studies have demonstrated that viral entry is due in part to the ability of virus-infected and immune-activated macrophages to induce adhesion molecules such as vascular adhesion molecule 1 (VCAM-1) on brain endothelium. Other studies have demonstrated that HIV gp120 enhances the expression of intercellular adhesion molecule 1 (ICAM-1) in glial cells; this effect may facilitate entry of HIV-infected cells into the CNS and may promote syncytia formation (Fig. 53A.2).

Fig. 53A.2 Human immunodeficiency virus encephalitis. Microglial nodule (arrow) containing multinucleated giant cells. (H&E, ×200.)

The R5 (CCR5 co-receptor) virus strains that are macrophage-tropic preferentially gain access into the brain rather than R4 (CXCR4 co-receptor) strains. HIV-infected individuals who are heterozygous for CCR5-del.32 (co-receptor gene with 32-base deletion) appear to be relatively protected against the development of HIV encephalopathy, compared to persons with homozygous wild-type CCR5 (Weiss et al., 1999). Distinct HIV envelope sequences are also linked with the clinical manifestation of HAND (McArthur et al., 2010).

Both white-matter changes and neuronal loss are observed in HIV infection. It is unlikely that direct infection of neurons or glial cells accounts for this cell loss. Rather, the brain pathology is thought to be due to a combination of direct effects, either toxic or function-inhibitory, of virus or viral antigens on neuronal cells and effects of a variety of neurotoxins released from the infiltrating monocytes, resident microglial cells, and astrocytes (McArthur et al., 2010; Price and Spudich, 2008; Scaravilli et al., 2007; Yadav and Collman, 2009). Neurotoxins can be released from monocytes as a consequence of other HIV-associated infections or immune activation. Activated monocyte-derived neurotoxic factors have been reported to injure neurons via the N-methyl-d-aspartate (NMDA) receptor. Additionally, HIV gp120 and tat shed by virus-infected monocytes and a variety of cytokines including tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-6, interferon alpha (IFN-α), and endothelin can contribute directly or indirectly to the neurotoxic effects in HIV infection. Activation of microglial cells, leading to increased production of eicosanoids, nitric oxide, and quinolinic acid, may also be neurotoxic.

Astrocytes may play diverse roles in HIV neuropathogenesis. Astrocytosis and reactive gliosis occur in brains of HIV-infected individuals; TNF-α and IL-6 have been shown to induce astrocyte proliferation. In addition, astrocyte-derived IL-6 can induce HIV expression in infected cells in vitro. Older HIV-infected individuals and those with the E4 allele for apolipoprotein E (APOE) appear to have an increased risk of HIV encephalitis and polyneuropathy (Corder et al., 1998). Neuropsychiatric abnormalities may rapidly improve following the initiation of antiretroviral therapy, indicating that HIV or products are involved in the neuropathogenesis of these disorders and suggesting that the dominant changes are either structural or functional at the synapses and dendritic spines (Yadav and Collman, 2009).

Antiretroviral Therapy and Its Effect on Neuro-HIV Disease

The dynamics of in vivo HIV production and turnover have been quantified using mathematical modeling in the setting of HAART. Treatment with effective HAART typically results in precipitous decline in the level of plasma viremia, often by well over 95% within a few weeks. The number of CD4⁺ T cells increases concurrently. Combination antiretroviral therapy is the cornerstone of management of HIV infection (Fauci and Lane, 2006). Suppression of HIV replication prolongs and improves the quality of life in patients with HIV infection.

Following the widespread use of HAART in the United States since 1996, dramatic declines have been noted in the incidence of most AIDS-defining conditions, including neurological diseases. Reconstitution of immune defenses with HAART has enabled some patients to discontinue secondary prophylaxis against CNS opportunistic pathogens. Primary neurological diseases can be prevented or delayed by successful HAART (Geraci and Simpson, 2001; Sacktor et al., 2006), although the evolution of drug-resistant viral strains may limit the sustained benefits of antiretroviral therapy (D’Aquila et al., 2003).

Once the decision has been made to initiate therapy, the physician must decide which drugs to use as the first therapeutic regimen. Initial choice of drugs will determine the immediate response to therapy, and it will have implications regarding options for future therapeutic regimens. The goal of treatment is to achieve a viral load of fewer than 50 copies/mL within 4 to 6 months of initiation (Gazzard et al., 2008). The two options for initial therapy most commonly in use today involve a three-drug regimen from two different antiretroviral classes (Table 53A.2). Recommendations regarding specific regimens are evolving. Combination therapy must be employed.

For HIV-associated brain disease, drugs that have good blood-brain barrier penetration should be preferred (see Table 53A.2). Following the initiation of therapy, one should monitor virological (HIV RNA levels) and immunological (CD4⁺ counts) responses periodically. The HIV RNA levels in serum generally reflect viral levels in CSF, at least until late stages of the HIV disease. In terminal stages, the CNS compartment may harbor slightly different and divergent HIV strains, with different degrees of drug susceptibility (Ellis et al., 2007; Liu et al., 2006; McArthur et al., 2010; Price and Spudich, 2008). In an attempt to determine an optimal therapeutic regimen, antiretroviral drug susceptibility through genotyping or phenotyping of HIV quasispecies has been attempted. Maximal suppression of viral replication is the goal of therapy, not just to prevent the disease progression but also to prevent the appearance of drug-resistant HIV quasispecies. The principles of current therapy for HIV infection are well articulated in publications of the U.S. Department of Health and Human Services (see updates at www.aidsinfo.nih.gov/guidelines/). As HAART has become widely available and has prolonged the life of patients with AIDS, an increasingly commonly observed manifestation was noted, characterized by a paradoxical clinical deterioration following therapy referred to as the immune reconstitution inflammatory syndrome (IRIS) and attributed to immunological recovery. Although typically observed with opportunistic infection, it may also occur as a response to noninfectious antigens. In the CNS, IRIS has been well described with Cryptococcus neoformans cytomegalovirus and PML. Patients with IRIS either present with clinical deterioration of a recognized infection following initiation of HAART, or the neurological disease may first manifest upon immunological recovery following the initiation of effective antiretroviral therapy. Neuroimaging generally shows worsening of previously observed lesions, frequently with contrast enhancement. Neuropathological findings at autopsy or from brain biopsy specimens reveal severe inflammatory reaction, with intraparenchymal and perivascular infiltration by lymphocytes (predominantly CD8⁺ T lymphocytes) and macrophages (Gray et al., 2005). The symptoms mostly regress with continued HAART, although a short course of high-dose parenteral corticosteroids (Riedel et al., 2006) has been suggested as effective in abrogating the response. Death may complicate IRIS (Gray et al., 2005).

Clinical Spectrum of Neuro-HIV Disease

The high prevalence and striking diversity of neurological disorders complicating AIDS were recognized early in the epidemic (Berger et al., 1987a). Clinical description of neurological OIs and malignancies predominated in early reports, but it also became clear that AIDS was associated with distinct neurological syndromes such as dementia and painful neuropathy that appeared to result solely from HIV. It also became recognized that the risk of neurological complications increased with the progression of HIV infection and decline of CD4⁺ counts. Clinically apparent neurological disease develops in approximately half of HIV-infected patients. Neuropathological abnormalities are nearly universal in patients dying with AIDS, suggesting subclinical disease, underdiagnosis, or both in many cases. Neurological disorders cause significant morbidity and mortality, and they may be the AIDS-defining illnesses in previously asymptomatic HIV disease or, occasionally, herald unrecognized HIV infection. Nervous system complications may directly threaten life as well as impair a patient’s ability to work or comply with complex HAART regimens necessary to manage HIV disease optimally. These disorders affect every level of the neuraxis, and a given patient may suffer more than one HIV-associated neurological disease.

The neurological complications of HIV infection occur at all stages of the disease (Simpson and Berger, 1996). Disorders of both the CNS and peripheral nervous system (PNS) can complicate HIV infection from the period after initial infection through the end stages of the severe immunosuppression. These neurological complications can be classified in a number of ways. A classification based on the underlying pathophysiology and HIV disease stages is summarized in Fig. 53A.1 and Table 53A.3. Clinicians must be aware of the possibility that more than one nervous system site can be involved at the same time, and deficits from one site may be masked by other lesions elsewhere in the neuraxis. The clinician must also be vigilant for other common conditions that are not necessarily associated with HIV or AIDS. Experience in large HIV clinics indicates that the diagnosis of neurological complications of HIV infection and AIDS is far from an academic exercise. Rather, precise diagnosis is critical, and it frequently leads to specific therapy with resultant reduction in morbidity and mortality and in preservation of meaningful function and quality of life. Fig. 53A.3 summarizes a diagnostic algorithm for CNS manifestations in HIV-infected patients.

Table 53A.3 Major HIV-Associated CNS Disorders Classified by Neuroanatomical Localization