Clinical Disease Manifestations Of Hivassociated Cognitive Impairments

Virus invades the brain early after exposure to HIV and likely before the development of humoral and cellular immune responses (Koenig et al., 1986; Michaels et al., 1988; Gartner, 2000; Aquaro et al., 2005). An aseptic meningitis is known to occur and is characterized by nuchal rigidity, fever, and altered mentation (Brown et al., 1992; Huang et al., 2005). In most patients, the HIV-seroconversion reaction is commonly subclinical and often passes unnoticed; others may present with a mild influenza-like illness and rarely a mononucleosis-like syndrome (Martin et al., 1992; Beckett and Forstein, 1993; Huang et al., 2005). A portion of these individuals will develop headaches, fever, myalgia, anorexia, rash, and/or diarrhea within the first 2 weeks (Schacker et al., 1996; Lindback et al., 2000; Tyrer et al., 2003; Pilcher et al., 2004). Prior to seroconversion, the acute phase of viral infection is characterized by a rapid HIV-mediated loss of memory CD4+CCR5+ T cells within the mucosal tissues that results in potentially irreversible immune suppression (Veazey et al., 1998; Brenchley et al., 2004; Mehandru et al., 2004; Derdeyn and Silvestri, 2005). During this acute HIV infection, high levels of vire-mia and viral shedding at mucosal sites occur. Genital and oral ulcers, cancers, and coinfections with a number of sexually transmitted microbial pathogens, including herpes simplex and hepatitis viruses, syphilis, and gonorrhea, can also manifest during the HIV sero-conversion reaction (Stamm et al., 1988; Bagdades et al., 1992; Kinloch-de Loes et al., 1993; Bollinger et al., 1997).

The transition from the acute to chronic phase of infection is accompanied by generation of HIV-1-specific adaptive immune responses (Cao et al., 1995; Poluektova et al., 2004; Draenert et al., 2006). Initially, HIV-specific cytotoxic CD8+ T-cell responses and humoral responses (for example, neutralizing antibodies) function to reduce viral replication to a set-point level that is characteristic of chronic HIV infection (Borrow et al., 1997; Schmitz et al., 1999; Letvin and Walker, 2003; Montefiori et al., 2003; Goulder and Watkins, 2004; Koup, 2004). Although this is a robust initial immune response, it is not enough to eradicate virus infection (Musey et al., 1997; Oxenius et al., 2004; Draenert et al., 2006). Continuous low-level or restricted infection of naive CD4+ T cells and mononuclear phagocytes (monocytes, tissue macrophages, and dendritic cells) during acute infection effectively evades immune surveillance (Zhang et al., 1999; Blankson et al., 2000). The persistence of these quiescent but infected cellular reservoirs makes it difficult to eradicate HIV infection.

Despite early HIV nervous system infection, most infected individuals remain neurologically intact until late stages of AIDS. After years of viral infection and associated profound losses in CD4+ T lymphocytes and viral loads, infected patients commonly succumb to behavioral, motor, and cognitive impairment. During the early days of the AIDS epidemic, cases of unexplained diffuse and often profound neurological impairment were reported in patients who were in the advanced stages of disease (Snider et al., 1983; Nielsen et al., 1984; Navia et al., 1986a, 1998). Neurological manifestations were ascribed to HIV-1 infection itself following the identification of virus in brains at autopsy from neurologically impaired individuals (Koenig et al., 1986; Navia et al., 1986a; Price and Brew, 1988; Price et al., 1988; Cherner et al., 2002).

Dementia is perhaps the most common manifestation of HIV disease, the resultant neuropsychiatric consequences termed by a variety of names: HIV-1 dementia, HIV-1 encephalopathy (the name used commonly for infected children), HIV-associated cognitive/motor complex, AIDS dementia complex, and now, most commonly, HIV-1 associated dementia (HAD) (Swindells et al., 1999; Wilkie et al., 2003; Griffin et al., 2004; Weed and Steward, 2005; Worlein et al., 2005). A clinical diagnosis is based on findings of developmental delays, psychomotor slowing, forget-fulness, personality changes, and decreased knowledge acquisition (Beckett and Forstein, 1993; Sidtis et al., 1993; Sacktor and McArthur, 1997; Schifitto et al., 2001; Cysique et al., 2006). Before use of antiretroviral therapy (ART), HAD developed in 20%-50% of AIDS patients, indicating that HIV-associated central nervous system (CNS) disease does not manifest in all infected individuals. Currently with ART, the rates of disease are around 7%-10%. The more serious neurological manifestations typically occur in patients with high peripheral viral loads, generally when an individual has advanced immune suppression and systemic HIV disease or AIDS (Beckett and Forstein, 1993; Martin-Garcia and Rodriguez-Scarano, 2005). Dementia related to direct HIV infection of the brain is only one of the protean manifestations of AIDS that may be associated with decline in mental status in an infected person. Among the complications of AIDS that must be considered in the differential diagnosis of dementia are the direct effect of HIV on the CNS, opportunistic fungal, viral, and or parasitic infections, neoplasm (lymphoma), ischemic or hemorrhagic lesions, and metabolic abnormalities. These include, for example, toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy (PML), and tuberculosis, among others (Kure et al., 1991; Manzardo et al., 2005). Although there are no definitive tests for HAD, diagnosis is most commonly made following exclusion of common opportunistic and cancerous brain diseases, with screening tests such as neuropsychological test batteries for psychomotor speed and the HIV Dementia Scale (Power et al., 1995; Davis et al., 2002; Cysique et al., 2006). A variety of biomarkers have been discovered in recent years, but none are used in clinical practice (Genis et al., 1992; Gelbard et al., 1994; Mellors et al., 1997; Sporer et al., 2004; McArthur et al., 2005; Schifitto et al., 2005).

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