HIV targets host CD4 T lymphocytes by identifying certain surface molecules and attaching to and entering the cells (Staprans and Feinberg 1997). This begins the process of using the viral reverse transcriptase enzyme to transcribe viral RNA to DNA, which allows the virus to use the host cell’s machinery to make new whole viral particles, called virions. These virions spread rapidly to uninfected lymphocytes, where they replicate more copies of HIV. As the host produces circulating antibodies against HIV, the host is said to seroconvert. Although the immune system may initially contain the infection, the course is set for chronic persistent viral replication. Without treatment, eventually there is near complete destruction of the CD4 T lymphocyte population in the vast majority of infected people. Current knowledge suggests that a person’s initial viral “setpoint,” the capacity of his or her immune system to limit viral replication, is the strongest predictor of untreated disease progression (Mellors et al. 1996).

The range and severity of symptoms in primary HIV infection varies considerably, with an acute 1-month mononucleosis-like viral syndrome developing in about 40%­60% of patients (Levy 1993). Symptoms can include fever, headache, lymphadenopathy, malaise, myalgia, rash, stiff neck, and other meningeal signs and symptoms, accompanied by transient intense viremia and an acute fall in CD4 T cell count in the peripheral blood from its normal range of 800­1,200 cells per cubic millimeter (Staprans and Feinberg 1997). The more severe this syndrome is, the more likely that the untreated patient will progress rapidly to AIDS (Keet et al. 1993). Clinicians are now hoping to slow down progression to AIDS by initiating highly active antiretroviral treatment (HAART) during primary infection, and recent evidence suggests that such treatment may provide a unique window for enhancing the body’s own immune response to HIV. However, primary infection often goes undetected and HAART requires longterm near-perfect adherence with multiple drugs taken several times daily.

Once the symptoms of primary infection subside and an antiviral immune response appears, patients usually enter a chronic, clinically asymptomatic or minimally symptomatic state despite continuous active viral replication. This period may last only a few years in some infected individuals, but the majority of HIV-positive patients develop overt immunodeficiency in approximately 10 years, with a small cohort demonstrating sustained long-term (>10 years) symptom-free HIV infection (Lifson et al. 1991; Staprans and Feinberg 1997). During chronic infection, the development of symptoms, a low CD4 cell count, and a high viral load should initiate a discussion between clinician and patient about antiretroviral treatment.

The patient’s ability to adhere to the regimen is, of course, pivotal to the decision. The spectrum of HIV-associated illnesses that eventually develops includes constitutional symptoms (e.g., weight loss, fatigue, fever, night sweats) and involvement of multiple organ systems. Opportunistic infections (OIs) are multiple and can occur throughout the body. These include fungal infections (e.g., oral or esophageal candidiasis [thrush]), PCP, and mycobacterial infections (e.g., tuberculosis and Mycobacterium avium complex). Cancers, such as Kaposi’s sarcoma and lymphoma, are other manifestations of severe immunosuppression. Prophylactic regimens can reduce the occurrence of many OIs in immunocompromised patients.

Neuropsychiatric Manifestations
HIV infection presents a spectrum of neuropsychiatric sequelae that can pose diagnostic and treatment quandaries to clinicians. In patients with serious and persistent psychiatric illness, some of the early, subtle neuropsychiatric symptoms may be difficult to differentiate from preexisting symptoms of their psychiatric illness. HIV is neurotropic (O’Brien 1994), enters the CNS soon after infection (Resnick et al. 1988), and can acutely induce headache and meningeal signs as already noted.

Long-term clinical sequelae of CNS infection range from subtle neurocognitive impairment to frank dementia, and their incidence increases with HIV illness progression. OIs and neoplasms that follow immunosuppression can also affect the CNS, resulting in mood disorders, psychosis, cognitive disorders, delirium, and other neuropsychiatric abnormalities. In addition, prescribed and recreational psychoactive substance use may create neuropsychiatric complications, and must be considered in the differential diagnosis of patients who present with new mental status changes (McDaniel et al. 1997).

HIV-related neurocognitive disorders are diagnoses of exclusion made after other etiologies have been ruled out through a comprehensive evaluation. Common cognitive disorders in HIV infection include minor cognitive­ motor disorder (MCMD) and HAD. MCMD is a mild syndrome of motor and/or cognitive dysfunction with minimal impairment in functioning (McDaniel et al. 1997) and is characterized by at least two of the following features: impaired attention or concentration, mental slowing, impaired memory, slowed movements, impaired coordination, personality change, irritability, and lability. MCMD does not necessarily progress to the more severe disorder of HAD (Masliah et al. 1996).

HAD is a subcortical dementia, and criteria for its diagnosis include acquired abnormality in two or more cognitive domains causing functional impairment; acquired abnormality in motor performance or decline in motivation or emotional control; no clouding of consciousness (delirium); and no confounding etiology. Although the exact pathophysiology of HAD remains unclear, HAD is relatively common, particularly in more advanced stages of HIV infection (McDaniel et al. 1997). Patients may also have neuropsychiatric impairments verifiable by testing that do not meet criteria for MCMD or HAD but that may result in functional impairment.

Psychiatric symptoms due to HIV-related medical conditions tend to occur in advanced stages of illness with significant evidence of immunosuppression and CD4 cell counts below 200 (American Psychiatric Association 2000). Therefore, among patients with advanced HIV disease who have a preexisting severe mental illness, psychiatric changes should not be attributed to a relapse until a complete medical workup has ruled out other causes. Mental status changes due to a medical etiology can include shifts in level of consciousness characteristic of delirium, cognitive impairment, mood changes, and psychotic symptoms.

The differential diagnosis (Wainberg et al. 2000) includes not only the neuropsychiatric manifestations of HIV itself but also OIs (toxoplasmosis, cryptococcus, tuberculous meningitis), lymphoma, and delirium from metabolic derangement, substance use, or drug toxicity (McDaniel et al. 1997).

Milton L. Wainberg, M.D.
Francine Cournos, M.D.
Karen McKinnon, M.A.
Alan Berkman, M.D.

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