Natural History of HIV Disease

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.


  1. Acuda SW, Sebit MB: Serostatus surveillance testing of HIV-I infection among Zimbabwean psychiatric inpatients in Zimbabwe. Cent Afr J Med 42:254-257, 1996
  2. American Psychiatric Association: Practice Guideline for the Treatment of Patients with HIV/AIDS. Am J Psychiatry 157 (suppl):1-62, 2000
  3. Ayuso-Mateos JL, Montanes F, Lastra I, et al: HIV infection in psychiatric patients: an unlinked anonymous study. Br J Psychiatry 170:181-185, 1997
  4. Barnes R, Felker B, Sloan K, et al: Safety of valproic acid treatment in patients with hepatitis C. Poster presented at the 40th annual meeting of the American College of Neuropsychopharmacology, Waikoloa, HI, December 9, 2001
  5. Barre-Sinoussi F, Chermann JC, Rey F, et al: Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immunodeficiency syndrome. Science 220:868-871, 1983
  6. Broder S, Merigan TC, Bolognesi D (eds): Textbook of AIDS Medicine. Baltimore, MD, Williams & Wilkins, 1994
  7. Brunette MF, Mercer CC, Carlson CL, et al: HIV-related services for persons with severe mental illness: policy and practice in New Hampshire community mental health. J Behav Health Serv Res 27:347-353, 2000
  8. Carey MP, Carey KB, Kalichman SC: Risk for human immunodeficiency virus (HIV) infection among persons with severe mental illnesses. Clin Psychol Rev 17:271-291, 1997
  9. Carmen E, Brady SM: AIDS risk and prevention for the chronic mentally ill. Hosp Community Psychiatry 41:652-657, 1990
  10. Chuang HT, Atkinson M: AIDS knowledge and high-risk behaviour in the chronic mentally ill. Can J Psychiatry 41:269-272, 1996
  11. Cividini A, Pistorio A, Regazzetti A, et al: Hepatitis C virus infection among institutionalized psychiatric patients: a regression analysis of indicators of risk. J Hepatol 27:455-463, 1997
  12. Community Research Initiative on AIDS: HIV/hepatitis C co-infection: confronting twin epidemics., accessed January 2000
  13. Corbitt G, Crosdale E, Bailey A: Protracted sero-conversion in haemophiliacs in whom infection is confirmed by p24 antigen detection and/or positive HIV PCR, in Abstracts, 7th International Conference on AIDS, Florence, Italy, 1991, p 387
  14. Cournos F, McKinnon K: HIV seroprevalence among people with severe mental illness in the United States: a critical review. Clin Psychol Rev 17:259-269, 1997
  15. Cournos F, Guido JR, Coomaraswamy S, et al: Sexual activity and risk of HIV infection among patients with schizophrenia. Am J Psychiatry 151:228-232, 1993
  16. Fernandez F, Levy JK: The use of molindone in the treatment of psychotic and delirious patients infected with the human immunodeficiency virus: case reports. Gen Hosp Psychiatry 15:31-35, 1993
  17. Gallo RC, Salahuddin SZ, Popovic M, et al: Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 224:500-503, 1984
  18. Goodman LA, Fallot RD: HIV risk-behavior in poor urban women with serious mental disorders: association with childhood physical and sexual abuse. Am J Orthopsychiatry 68:73-83, 1998
  19. Hanson M, Kramer TH, Gross W, et al: AIDS awareness and risk behaviors among dually disordered adults. AIDS Educ Prev 4:41-51, 1992
  20. Hardy AM: National health interview survey data on adult knowledge about AIDS in the United States. Public Health Rep 105:629-634, 1990
  21. Herbert B: Woman battering and HIV infection, in Abstracts (TP500), HIV Infection in Women: Setting a New Agenda. Washington, DC, Philadelphia Sciences Group, 1995
  22. Horwath E: Psychiatric and neuropsychiatric manifestations, in AIDS and People With Severe Mental Illness: A Handbook for Mental Health Professionals. Edited by Cournos F, Bakalar N. New Haven, CT, Yale University Press, 1996, pp 57-73
  23. Horwath E, Cournos F, McKinnon K, et al: Illicit-drug injection among psychiatric patients without a primary substance use disorder. Psychiatr Serv 47:181-185, 1996
  24. Kalichman SC, Kelly JA, Johnson JR, et al: Factors associated with risk for HIV infection among chronic mentally ill adults. Am J Psychiatry 151:221-227, 1994
  25. Katz RC, Watts C, Santman J: AIDS knowledge and high risk behaviors in the chronic mentally ill. Community Ment Health J 30:395-402, 1994
  26. Keet IP, Krol A, Koot M, et al: Predictors of rapid progression to AIDS in HIV-1 seroconverters. AIDS 7:51-57, 1993
  27. Kelly JA: HIV risk reduction interventions for persons with severe mental illness. Clin Psychol Rev 17:293-309, 1997
  28. Kelly JA, Murphy DA, Bahr GR, et al: AIDS/HIV risk behavior among the chronic mentally ill. Am J Psychiatry 149:886-889, 1992
  29. Levy J: Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 57:183-189, 1993
  30. Liberman RP, Mueser KT, Wallace CJ, et al: Training skills in the psychiatrically disabled: learning coping and competence. Schizophr Bull 12:631-647, 1986
  31. Lifson AR, Buchbinder SP, Sheppard HW, et al: Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics. J Infect Dis 163:959-965, 1991
  32. Masliah G, Achim CL, DeTeresa R, et al: The patterns of neurodegeneration in HIV encephalitis. Journal of NeuroAIDS 1:161-173, 1996
  33. McDaniel JS, Purcell DW, Farber EW: Severe mental illness and HIV-related medical and neuropsychiatric sequelae. Clin Psychol Rev 17:311-325, 1997
  34. McDermott BE, Sautter FJ, Winstead DK, et al: Diagnosis, health beliefs, and risk of HIV infection in psychiatric patients. Hosp Community Psychiatry 45:580-585, 1994
  35. McKinnon K, Cournos F: HIV infection linked to substance use among hospitalized patients with severe mental illness. Psychiatr Serv 49:1269, 1998
  36. McKinnon K, Cournos F, Sugden R, et al: The relative contributions of psychiatric symptoms and AIDS knowledge to HIV risk behaviors among people with severe mental illness. J Clin Psychiatry 57:506-513, 1996
  37. McKinnon K, Cournos F, Herman R, et al: AIDS-related services and training in outpatient mental health care agencies in New York. Psychiatr Serv 50:1225-1228, 1999
  38. McKinnon K, Wainberg ML, Cournos F: HIV/AIDS preparedness in mental health care agencies with high and low substance use disorder caseloads. J Subst Abuse 13:127-135, 2001
  39. Mellors JW, Rinaldo CR Jr, Gupta P, et al: Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272:1167-1170, 1996
  40. Menon AS, Pomerantz S: Substance use during sex and unsafe sexual behaviors among acute psychiatric inpatients. Psychiatr Serv 48:1070-1072, 1997
  41. Meyer JM: Prevalence of hepatitis A, hepatitis B and HIV among hepatitis C seropositive state hospital patients: results from Oregon State Hospital. J Clin Psychiatry (in press)
  42. Mulder RT, Ang M, Chapman B, et al: Interferon treatment is not associated with a worsening of psychiatric symptoms in patients with hepatitis C. J Gastroenterol Hepatol 15: 300-303, 2000
  43. National Digestive Diseases Information Clearinghouse: Chronic hepatitis C: current disease management. Available at: Accessed February 17, 2003
  44. National Institutes of Health Consensus Development Conference Panel: Management of hepatitis C. Hepatology 26:2S-10S, 1997
  45. O'Brien WA: Genetic and biologic basis of HIV-1 neurotropism, in HIV, AIDS and the Brain. Edited by Price RW, Perry SW. New York, Raven, 1994, pp 47-70
  46. O'Brien WA, Hartigan PM, Martin D, et al: Changes in plasma HIV-1 RNA and CD4 + lymphocyte counts and the risk of progression to AIDS. N Engl J Med 334:426-431, 1996
  47. Oliveira SB: Avalia'o do comportamento sexual, conhecimentos e atitudes sobre AIDS, dos pacientes internados no instituto de psiquiatria da UFRJ, in O Campo da Aten'o Psicossocial. Edited by Venncio AT, Leal EM, Delgado PG. Rio de Janeiro, Te Cor, 1997, pp 343-351
  48. Oquendo M, Tricarico P: Pre- and post-HIV test counseling, in AIDS and People With Severe Mental Illness: A Handbook for Mental Health Professionals. Edited by Cournos F, Bakalar N. New Haven, CT, Yale University Press, 1996, pp 97-112
  49. Otto-Salaj LL, Heckman TG, Stevenson LY, et al: Patterns, predictors and gender differences in HIV risk among severely mentally ill men and women. Community Ment Health J 34:175-190, 1998
  50. Otto-Salaj LL, Kelly JA, Stevenson LY, et al: Outcomes of a randomized smallgroup HIV prevention intervention trial for people with serious mental illness. Community Ment Health J 37:123-144, 2001
  51. Resnick L, Berger JR, Shapshak P, et al: Early penetration of the blood brain barrier by HTLV-III/LAV. Neurology 38:9-15, 1988
  52. Rosenberg SD, Goodman LA, Osher FC, et al: Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness. Am J Public Health 91:31-37, 2001
  53. Sewell DD, Jeste DV, McAdams LA, et al: Neuroleptic treatment of HIV-associated psychosis. Neuropsychopharmacology 10:223-229, 1994
  54. Staprans SI, Feinberg MB: Natural history and immunopathogenesis of HIV-1 disease, in The Medical Management of AIDS, 5th Edition. Edited by Sande MA, Volberding PA. Philadelphia, PA, WB Saunders, 1997, pp 29-56
  55. Susser E, Miller M, Valencia E, et al: Injection drug use and risk of HIV transmission among homeless men with mental illness. Am J Psychiatry 153:794-798, 1996
  56. Varmus H: Retroviruses. Science 240:1427-1435, 1988
  57. Vento S, Garofano T, Renzini C, et al: Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 338:286-290, 1998
  58. Wainberg ML, Forstein M, Berkman A, et al: Essential medical facts for mental health practitioners, in What Mental Health Practitioners Need to Know about HIV and AIDS. Edited by Cournos F, Forstein M. San Francisco, CA, Jossey-Bass, 2000, pp 3-15
  59. Warner GC: Molecular insights into HIV-1 infection, in The Medical Management of AIDS, 5th Edition. Edited by Sande MA, Volberding PA. Philadelphia, PA, WB Saunders, 1997, pp 17-28

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