Cytomegalovirus infection in the era of HAART: fewer reactivations and more immunity

Kathryn L. Springer1 and Adriana Weinberg1,2,*

Departments of 1 Medicine and 2 Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA


    Abstract
 Top
 Abstract
 Introduction
 CMV infection in patients...
 CMV infection in the...
 References
 
The incidence of cytomegalovirus (CMV) disease, once the most common and highly feared viral complication of AIDS, has dramatically decreased with the advent of highly active antiretroviral therapy (HAART). HAART-associated changes in the epidemiology of CMV disease resulted from the increase in CMV-specific immune responses coupled with the decrease in CMV reactivation. However, CMV disease continues to afflict HIV-infected patients on HAART when CD4+ cell counts fail to rise above 100 cells/mm3 and when reconstitution of normal CMV-specific immune responses does not occur. The latter scenario may lead to recurrent or de novo CMV end-organ disease, or to the recently described CMV immune recovery vitritis. HAART-associated immune reconstitution offers unique opportunities to investigate the virological and immunological correlates of protection against CMV disease. Although the full extent of CMV-specific immune reconstitution has not been defined thus far, CMV-specific interferon-{gamma} production has been shown to be significantly associated with protection against CMV reactivation and recurrent disease.

Keywords: HIV , immune reconstitution , AIDS , opportunistic infections


    Introduction
 Top
 Abstract
 Introduction
 CMV infection in patients...
 CMV infection in the...
 References
 
Cytomegalovirus (CMV) is a ubiquitous herpesvirus that generally causes asymptomatic or mildly symptomatic infection in immunocompetent hosts. In contrast, CMV infection in immunocompromised patients carries high morbidity and mortality. Before the introduction of highly active antiretroviral therapy (HAART), acquired immunodeficiency syndrome (AIDS) patients constituted the largest group severely affected by CMV, with a 10% annual incidence of sight- or life-threatening disease.1,2 The introduction of HAART in 1995–1996 caused a significant reduction in the incidence of AIDS-associated opportunistic infections including CMV.3 At the same time, new manifestations of opportunistic infections were identified and classified as immune recovery syndromes. We compare the clinical spectrum of CMV before and after HAART, while focusing on immune reconstitution.


    CMV infection in patients with HIV before the introduction of HAART
 Top
 Abstract
 Introduction
 CMV infection in patients...
 CMV infection in the...
 References
 
Overview of clinical and epidemiological characteristics

CMV disease typically occurs when latent virus reactivates in AIDS patients with <100 CD4+ T cells/mm3. CMV infection in patients with <100 CD4+ cells/mm3 can be asymptomatic, or can cause non-specific symptoms such as fever and malaise or localized end-organ disease.4 The most common manifestation of CMV in HIV-infected individuals was retinitis, which occurred in 40% of AIDS patients and represented 85% of all CMV end-organ diseases.1 Gastrointestinal tract manifestations accounted for 10% of CMV disease in AIDS patients and the remainder consisted of neurological disorders, pneumonitis, hepatitis and adrenalitis.

Antiviral therapy against CMV relies on several effective drugs, such as ganciclovir, foscarnet and cidofovir. Due to intense immunosuppression and frequent viral reactivations, CMV disease tended to have a relentlessly progressive course5 and, therefore, patients with sight- or life-threatening manifestations were typically maintained on low-dose antiviral therapy indefinitely.6 However, the virus frequently developed resistance to the antivirals, causing relapse of clinical symptoms.7,8

Both symptomatic and asymptomatic CMV infections were associated with increased risk of death in AIDS patients.9 This might be due to organ failure related to CMV end-organ disease; because CMV active infection might be a marker of extremely severe immunosuppression, which ultimately leads to the fatal outcome of the patient; or because CMV infection might have down-regulatory effects on the immune system and thus predispose to death.

Viral reactivations

The factors that trigger CMV reactivation in AIDS patients are incompletely understood. At least one mechanism is tumour necrosis factor (TNF)-{alpha}-mediated stimulation of the host cell, leading to nuclear factor {kappa}B (NF-{kappa}B) intranuclear accumulation and activation of CMV DNA replication.10 This might explain the high prevalence of CMV reactivation in conditions associated with increased synthesis of TNF-{alpha}, such as HIV infection.

CMV reactivations were most frequent in HIV-infected individuals with <100 CD4+ cells/mm3. When monitored systematically, 45–60% of these patients developed one or more episodes of circulating CMV DNA over a period of 6–12 months.11,12 Although CMV reactivations played a crucial role in the development of end-organ disease13,14 of AIDS patients, CMV replication was sometimes asymptomatic and self-limited. The positive predictive value of finding CMV DNA in plasma and white blood cells by PCR was ~60% and 40%, respectively. High titres of circulating CMV DNA increased the risk of end-organ disease.15

Measures that prevented viraemia also decreased the incidence of the disease. Both oral and parenteral ganciclovir were successfully used for this purpose.15 However, the cost of prophylactic therapy for HIV-infected patients at risk of CMV disease before HAART was prohibitive.16

Immune responses

The integrity of the immune system is a decisive factor in the development of CMV end-organ disease. In CMV viraemic AIDS patients stratified by CD4+ counts of <50, 50–100 and >100 cells/mm3, the incidence of CMV end-organ disease over a period of 6 months was 25%, 5.5% and 1.3%, respectively.4,11 Not all individuals with AIDS and CMV reactivation progressed to end-organ disease and the factors that ultimately determined the development of symptoms are incompletely understood. CMV-seropositive AIDS patients who lacked lymphocyte proliferative responses to CMV had a higher risk of developing CMV end-organ disease,17 suggesting a protective role for cell-mediated immunity. In contrast, anti-CMV neutralizing and total antibody titres were comparable in AIDS patients to levels in healthy controls and in patients with less advanced HIV infection.18,19 Furthermore, administration of neutralizing anti-CMV monoclonal antibodies did not prevent or modify the course of the disease.20 These data argue against a protective role for CMV-specific humoral immunity. Many other immune parameters are altered in HIV-infected patients, but their contributions to the increased susceptibility of AIDS patients to CMV disease has not been adequately studied.


    CMV infection in the era of HAART
 Top
 Abstract
 Introduction
 CMV infection in patients...
 CMV infection in the...
 References
 
Clinical and epidemiological features

HAART decreases HIV replication and increases CD4+ cell count. This is associated with a marked reduction in the incidence of opportunistic infections3 and increased survival.21 The incidence of new CMV retinitis has declined by ~80%, and survival in patients with CMV retinitis has increased by 93%.22

Risk factors for CMV end-organ disease in the HAART era continue to be CD4+ counts of <50–100 cells/mm3,2325 and CMV reactivation23,26 (Table 1). In addition, an HIV viral load (VL) of >10 000 RNA copies/mL is associated with new CMV disease in HAART recipients.23


View this table:
[in this window]
[in a new window]
 
Table 1. Immunological and virological factors associated with protection against CMV disease in HIV-infected patients on HAART

 
Current guidelines recommend discontinuation of secondary prophylaxis in HAART recipients with a sustained (≥6 months) increase in CD4+ T cells to levels of >100–150 cells/mm3.27 However, there are several reports of CMV retinitis occurring or progressing in patients taking HAART in the presence of CD4+ T cell counts of >100 cells/mm3.

A new clinical entity, CMV immune recovery vitritis, has been described in HAART recipients.24,28,29 This disease is characterized by posterior chamber inflammation, macular and disc oedema, neovascularization, cataracts and epiretinal membrane formation. Loss of visual acuity is common. It occurs in 15–90% of patients with previous CMV retinitis who experience increases in the number of CD4+ cells on HAART.24,30 The immunopathogenesis of this new disease is discussed below. There are conflicting data on the response to CMV antiviral treatment,31,32 but topical corticosteroids seem to improve symptoms.31

Viral reactivations

HAART decreases the incidence of viraemia.3335 In one study of 16 patients, HAART resulted in the disappearance of CMV DNA from circulation as detected by PCR without specific anti-CMV therapy.36 One potential mechanism is that control of HIV replication and opportunistic infections eliminates factors that would otherwise increase CMV reactivation,37 such as transactivation in cells co-infected with CMV and other pathogens or increased circulating TNF-{alpha}. In addition, we showed that CMV-specific interferon-{gamma} production by in vitro-stimulated peripheral blood mononuclear cells was associated with a decreased risk of CMV reactivation in HAART recipients, arguing in favour of immunological control of CMV replication. The two mechanisms are not mutually exclusive and might jointly contribute to the decrease in CMV reactivation.

Immune responses

During the first 3 months of HAART both memory and naive circulating CD4+ cells increase.38 There is an initial increase, followed by a decrease in circulating CD8+ cells. Activation markers on circulating T cells and TNF-{alpha} serum levels decrease.39 Three to 6 months after HAART, patients reacquire delayed type hypersensitivity responses and in vitro lymphocyte proliferation assay (LPA) to microbial antigens.40 Both cellular and humoral CMV-specific immune reconstitution has been demonstrated in HAART recipients.4143 CMV LPA responses increase with higher CD4+ cell counts and there is no significant association between nadir CD4+ cells and CMV-specific immune reconstitution (A. Weinberg, unpublished results). However, immune restoration is incomplete, as illustrated by the inconsistency of CMV-specific CD4+-mediated proliferative responses,44,45 the dissociation between in vitro mononuclear cell proliferation and cytokine production44 and the persistence of high levels of circulating CMV-specific CD8+ T lymphocytes.46 The mechanisms that account for incomplete immune reconstitution in HIV-infected patients are under investigation. There is evidence for both pathogen-specific and generalized immune defects. We described a HAART recipient with recurrent CMV retinitis despite an increase in circulating CD4+ T lymphocytes to >200 cells/mm3. This patient was unable to mount in vitro CMV-specific immune responses but had adequate Candida-specific in vitro responses,47 suggesting that CMV-specific clonal deletion or toleration might have occurred. However, there is also evidence that HAART recipients who reconstitute immunity against a ubiquitous agent such as Candida or CMV are more likely to reconstitute responses against other pathogens.48,49

At the cellular level, several mechanisms have been implicated in the immune defect observed in HAART recipients. These patients have persistently high proportions of apoptotic circulating mononuclear cells despite control of HIV replication.50 There is a marked deficit of CMV-specific CD4+ T cell production of interleukin-233,44,51,52 with downstream consequences on cell cycle progression53 and proliferation.52,54 Furthermore, there is evidence of down-regulatory activity mediated by CD4+ 55 and CD8+ 44 T cells.

The immune recovery vitritis or uveitis constitutes another example of altered immune responses in HIV-infected patients on HAART. This syndrome is characterized by exuberant retinal inflammatory infiltrates, which include CMV-specific cytotoxic T cells but also CD8+ T cells of broader specificity56 and seems to occur in the context of increased CMV-specific Th2 responses.57 In contrast, protection against CMV disease is conferred by Th1-specific cells. It is interesting to note that the eye, a segregated body compartment, but not the gastrointestinal or respiratory tract, is the main target of CMV-associated immune recovery syndrome. It is tempting to speculate that the barrier between the eye chambers and circulation might impair the ability to establish normal immune regulatory processes in patients undergoing immune reconstitution.

Although it is well accepted that competent CMV-specific responses are critical determinants of CMV infection outcome, a user-friendly immunological test that can predict protection against CMV disease is not yet available. Immune reconstitution of HIV-infected patients on HAART has offered ample opportunity to examine immune correlates of protection against CMV disease. CMV-stimulated interferon-{gamma} production measured in bulk cell culture supernatants33 or by flow cytometry in CD4+ 58 or CD8+ 59 cells has shown the best correlation with protection against CMV reactivation and disease (Table 1). Further work is needed, however, to establish the predictive value of CMV-specific interferon-{gamma} assays in clinical practice.


    Footnotes
 
* Correspondence address. UCHSC, 4200 E 9th Ave., Denver, CO 80262, USA. Tel: +1-303-315-4624; Fax: +1-303-315-1787; Email: adrianna.weinberg{at}uchsc.edu


    References
 Top
 Abstract
 Introduction
 CMV infection in patients...
 CMV infection in the...
 References
 
1 . Drew, W. L. (1988). Cytomegalovirus infection in patients with AIDS. Journal of Infectious Diseases 158, 449–56.[ISI][Medline]

2 . Jacobson, M. A. & Mills, J. (1988). Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Clinical findings, diagnosis, and treatment. Annals of Internal Medicine 108, 585–94.[ISI][Medline]

3 . Palella, F. P., Jr, Delaney, K. M., Moorman, A. C. et al. (1998). Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New England Journal of Medicine 338, 853–60.[Abstract/Free Full Text]

4 . Gerard, L., Leport, C., Flandre, P. et al. (1997). Cytomegalovirus (CMV) viremia and the CD4+ lymphocyte count as predictors of CMV disease in patients infected with human immunodeficiency virus. Clinical Infectious Diseases 24, 836–40.[ISI][Medline]

5 . Jacobson, M. A., Kramer, F., Bassiakos, Y. et al. (1994). Randomized phase I trial of two different combination foscarnet and ganciclovir chronic maintenance therapy regimens for AIDS patients with cytomegalovirus retinitis: AIDS Clinical Trials Group Protocol 151. Journal of Infectious Diseases 170, 189–93.[ISI][Medline]

6 . Jacobson, M. A. (1997). Treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. New England Journal of Medicine 337, 105–14.[Free Full Text]

7 . Weinberg, A., Jabs, D. A., Chou, S. et al. (2003). Mutations conferring foscarnet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Journal of Infectious Diseases 187, 777–84.[CrossRef][ISI][Medline]

8 . Jabs, D. A., Enger, C., Dunn, J. P. et al. (1998). Cytomegalovirus retinitis and viral resistance: ganciclovir resistance. CMV Retinitis and Viral Resistance Study Group. Journal of Infectious Diseases 177, 770–3.[ISI][Medline]

9 . Spector, S. A., Wong, R., Hsia, K. et al. (1998). Plasma cytomegalovirus (CMV) DNA load predicts CMV disease and survival in AIDS patients. Journal of Clinical Investigation 101, 497–502.[Abstract/Free Full Text]

10 . Docke, W. D., Prosch, S., Fietze, E. et al. (1994). Cytomegalovirus reactivation and tumour necrosis factor. Lancet 343, 268–9.[ISI][Medline]

11 . Shinkai, M., Bozzette, S. A., Powderly, W. et al. (1997). Utility of urine and leukocyte cultures and plasma DNA polymerase chain reaction for identification of AIDS patients at risk for developing human cytomegalovirus disease. Journal of Infectious Diseases 175, 302–8.[ISI][Medline]

12 . Rasmussen, L., Zipeto, D., Wolitz, R. A. et al. (1997). Risk for retinitis in patients with AIDS can be assessed by quantitation of threshold levels of cytomegalovirus DNA burden in blood. Journal of Infectious Diseases 176, 1146–55.[ISI][Medline]

13 . Bowen, E. F., Sabin, C. A., Wilson, P. et al. (1997). Cytomegalovirus (CMV) viraemia detected by polymerase chain reaction identifies a group of HIV-positive patients at high risk of CMV disease. AIDS 11, 889–93.[CrossRef][ISI][Medline]

14 . Dodt, K. K., Jacobsen, P. H., Hofmann, B. et al. (1997). Development of cytomegalovirus (CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test. AIDS 11, F21–8.[CrossRef][ISI][Medline]

15 . Spector, S. A., McKinley, G. F., Lalezari, J. P. et al. (1996). Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. Roche Cooperative Oral Ganciclovir Study Group. New England Journal of Medicine 334, 1491–7.[Abstract/Free Full Text]

16 . Paltiel, A. D., Goldie, S. J., Losina, E. et al. (2001). Preevaluation of clinical trial data: the case of preemptive cytomegalovirus therapy in patients with human immunodeficiency virus. Clinical Infectious Diseases 32, 783–93.[CrossRef][ISI][Medline]

17 . Schrier, R. D., Freeman, W. R., Wiley, C. A. et al. (1995). Immune predispositions for cytomegalovirus retinitis in AIDS. The HNRC group. Journal of Clinical Investigation 95, 1741–6.[ISI][Medline]

18 . Lucht, E., Sundqvist, V. A., Linde, A. et al. (1994). Presence of autologous neutralizing antibodies against cytomegalovirus (CMV) in serum of human immunodeficiency virus type 1-infected patients shedding CMV in saliva. Journal of Infectious Diseases 169, 1096–100.[ISI][Medline]

19 . Boppana, S. B., Polis, M. A., Kramer, A. A. et al. (1995). Virus-specific antibody responses to human cytomegalovirus (HCMV) in human immunodeficiency virus type 1-infected persons with HCMV retinitis. Journal of Infectious Diseases 171, 182–5.[ISI][Medline]

20 . Jabs, D. A., Gilpin, A. M., Min, Y. I. et al. (2002). HIV and cytomegalovirus viral load and clinical outcomes in AIDS and cytomegalovirus retinitis patients: monoclonal antibody cytomegalovirus retinitis trial. AIDS 16, 877–87.[CrossRef][ISI][Medline]

21 . Murphy, E. L., Collier, A. C., Kalish, L. A. et al. (2001). Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease. Annals of Internal Medicine 135, 17–26.[Abstract/Free Full Text]

22 . Kempen, J. H., Jabs, D. A., Wilson, L. A. et al. (2003). Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clinical Infectious Diseases 37, 1365–73.[CrossRef][ISI][Medline]

23 . Erice, A., Tierney, C., Hirsch, M. et al. (2003). Cytomegalovirus (CMV) and human immunodeficiency virus (HIV) burden, CMV end-organ disease, and survival in subjects with advanced HIV infection. AIDS Clinical Trials Group Protocol 360. Clinical Infectious Diseases 37, 567–78.[CrossRef][ISI][Medline]

24 . Jabs, D. A., Van Natta, M. L., Kempen, J. H. et al. (2002). Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. American Journal of Ophthalmology 133, 48–61.[CrossRef]

25 . Labetoulle, M., Goujard, C., Frau, E. et al. (1999). Cytomegalovirus retinitis in advanced HIV-infected patients treated with protease inhibitors: incidence and outcome over 2 years. Journal of Acquired Immune Deficiency Syndromes 22, 228–34.[ISI][Medline]

26 . Salmon-Ceron, D., Mazeron, M. C., Chaput, S. et al. (2000). Plasma cytomegalovirus DNA, pp65 antigenaemia and a low CD4 cell count remain risk factors for cytomegalovirus disease in patients receiving highly active antiretroviral therapy. AIDS 14, 1041–9.[CrossRef][ISI][Medline]

27 . Kaplan, J. E., Masur, H. & Holmes, K. K. (2002). Guidelines for preventing opportunistic infections among HIV-infected persons—2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Morbidity and Mortality Weekly Report: Recommendations and Reports 51, 1–52.

28 . Whitcup, S. M., Fortin, E., Lindblad, A. S. et al. (1999). Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis. Journal of the American Medical Associaton 282, 1633–7.[CrossRef]

29 . Karavellas, M. P., Plummer, D. J., Macdonald, J. C. et al. (1999). Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. Journal of Infectious Diseases 179, 697–700.[CrossRef][ISI][Medline]

30 . Wright, M. E., Suzman, D. L., Csaky, K. G. et al. (2003). Extensive retinal neovascularization as a late finding in human immunodeficiency virus-infected patients with immune recovery uveitis. Clinical Infectious Diseases 36, 1063–6.[CrossRef][ISI][Medline]

31 . Song, M. K., Azen, S. P., Buley, A. et al. (2003). Effect of anti-cytomegalovirus therapy on the incidence of immune recovery uveitis in AIDS patients with healed cytomegalovirus retinitis. American Journal of Ophthalmology 136, 696–702.[CrossRef]

32 . Kosobucki, B. R., Goldberg, D. E., Bessho, K. et al. (2004). Valganciclovir therapy for immune recovery uveitis complicated by macular edema. American Journal of Ophthalmology 137, 636–8.[CrossRef]

33 . Weinberg, A., Wohl, D. A., MaWhinney, S. et al. (2003). Cytomegalovirus-specific IFN-gamma production is associated with protection against cytomegalovirus reactivation in HIV-infected patients on highly active antiretroviral therapy. AIDS 17, 2445–50.[CrossRef][ISI][Medline]

34 . Para, M. F., Kalish, L. A., Collier, A. C. et al. (2001). Correlates of change in cytomegalovirus viremia in patients with advanced human immunodeficiency virus infection who require transfusion. Journal of Infectious Diseases 183, 1673–7.[CrossRef][ISI][Medline]

35 . O'Sullivan, C. E., Drew, W. L., McMullen, D. J. et al. (1999). Decrease of cytomegalovirus replication in human immunodeficiency virus infected patients after treatment with highly active antiretroviral therapy. Journal of Infectious Diseases 180, 847–9.[CrossRef][ISI][Medline]

36 . Deayton, J., Mocroft, A., Wilson, P. et al. (1999). Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral therapy in the absence of specific anti-CMV therapy. AIDS 13, 1203–6.[CrossRef][ISI][Medline]

37 . Skolnik, P. R., Kosloff, B. R. & Hirsch, M. S. (1988). Bidirectional interactions between human immunodeficiency virus type 1 and cytomegalovirus. Journal of Infectious Diseases 157, 508–14.[ISI][Medline]

38 . Autran, B., Carcelain, G., Li, T. S. et al. (1997). Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277, 112–6.[Abstract/Free Full Text]

39 . Lederman, M. M., Connick, E., Landay, A. et al. (1998). Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. Journal of Infectious Diseases 178, 70–9.[ISI][Medline]

40 . Connick, E., Lederman, M. M., Kotzin, B. L. et al. (2000). Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response. Journal of Infectious Diseases 181, 358–63.[CrossRef][ISI][Medline]

41 . Li, T. S., Tubiana, R., Katlama, C. et al. (1998). Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 351, 1682–6.[CrossRef][ISI][Medline]

42 . Komanduri, K. V., Viswanathan, M. N., Wieder, E. D. et al. (1998). Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nature Medicine 4, 953–6.[ISI][Medline]

43 . Deayton, J. R., Sabin, C. A., Britt, W. B. et al. (2002). Rapid reconstitution of humoral immunity against cytomegalovirus but not HIV following highly active antiretroviral therapy. AIDS 16, 2129–35.[CrossRef][ISI][Medline]

44 . Weinberg, A., Wohl, D. A., Barrett, R. J. et al. (2001). Inconsistent reconstitution of cytomegalovirus-specific cell-mediated immunity in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy. Journal of Infectious Diseases 184, 707–12.[CrossRef][ISI][Medline]

45 . Jacobson, M. A., Schrier, R., McCune, J. M. et al. (2001). Cytomegalovirus (CMV)-specific CD4+ T lymphocyte immune function in long-term survivors of AIDS-related CMV end-organ disease who are receiving potent antiretroviral therapy. Journal of Infectious Diseases 183, 1399–404.[CrossRef][ISI][Medline]

46 . Villacres, M. C., Lacey, S. F., La Rosa, C. et al. (2001). Human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy maintain activated CD8+ T cell subsets as a strong adaptive immune response to cytomegalovirus. Journal of Infectious Diseases 184, 256–67.[CrossRef][ISI][Medline]

47 . Johnson, S. C., Benson, C. A., Johnson, D. W. et al. (2001). Recurrences of cytomegalovirus retinitis in a human immunodeficiency virus-infected patient, despite potent antiretroviral therapy and apparent immune reconstitution. Clinical Infectious Diseases 32, 815–9.[CrossRef][ISI][Medline]

48 . Weinberg, A. & Pott, G. B. (2003). Immunity to human immunodeficiency virus (HIV) in children with chronic HIV infection receiving highly active antiretroviral therapy. Clinical and Diagnostic Laboratory Immunology 10, 821–5.[Abstract/Free Full Text]

49 . Weinberg, A., Pawhwa, S., Oyomopito, R. et al. (2004). Anitmicrobial-specific cell-mediated immune reconstitution in children with advanced HIV infection on HAART. Clinical Infectious Diseases 39, 107–14.[CrossRef][ISI][Medline]

50 . Weinberg, A., Edelstein, C. L., Jesser, R. D. et al. (2003). Apoptosis of circulating mononuclear cells down regulates CMV cell-mediated immunity in HIV-infected patients on HAART. In Abstracts of the Ninth International Cytomegalovirus Workshop and First International Betaherpesvirus Workshop, Maastricht, The Netherlands, 2003. Abstract k.08, p. 91. Conference Agency Limburg, Maastricht, The Netherlands.

51 . Sieg, S. F., Bazdar, D. A., Harding, C. V. et al. (2001). Differential expression of interleukin-2 and gamma interferon in human immunodeficiency virus disease. Journal of Virology 75, 9983–5.[Abstract/Free Full Text]

52 . Iyasere, C., Tilton, J. C., Johnson, A. J. et al. (2003). Diminished proliferation of human immunodeficiency virus-specific CD4+ T cells is associated with diminished interleukin-2 (IL-2) production and is recovered by exogenous IL-2. Journal of Virology 77, 10900–9.[Abstract/Free Full Text]

53 . Sieg, S. F., Harding, C. V. & Lederman, M. M. (2001). HIV-1 infection impairs cell cycle progression of CD4+ T cells without affecting early activation responses. Journal of Clinical Investigation 108, 757–64.[Abstract/Free Full Text]

54 . Sieg, S. F., Bazdar, D. A. & Lederman, M. M. (2003). Impaired TCR-mediated induction of Ki67 by naive CD4+ T cells is only occasionally corrected by exogenous IL-2 in HIV-1 infection. Journal of Immunology 171, 5208–14.[Abstract/Free Full Text]

55 . Aandahl, E. M., Michaelsson, J., Moretto, W. J. et al. (2004). Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. Journal of Virology 78, 2454–9.[Abstract/Free Full Text]

56 . Mutimer, H. P., Akatsuka, Y., Manley, T. et al. (2002). Association between immune recovery uveitis and a diverse intraocular cytomegalovirus-specific cytotoxic T cell response. Journal of Infectious Diseases 186, 701–5.[CrossRef][ISI][Medline]

57 . Stone, S. F., Price, P., Tay-Kearney, M. L. et al. (2002). Cytomegalovirus (CMV) retinitis immune restoration disease occurs during highly active antiretroviral therapy-induced restoration of CMV-specific immune responses within a predominant Th2 cytokine environment. Journal of Infectious Diseases 185, 1813–7.[CrossRef][ISI][Medline]

58 . Lilleri, D., Piccinini, G., Genini, E. et al. (2004). Monitoring of human cytomegalovirus (HCMV)-specific CD4+ T cell frequency by cytokine flow cytometry as a possible indicator for discontinuation of HCMV secondary prophylaxis in HAART-treated AIDS patients. Journal of Clinical Virology 29, 297–307.[CrossRef][ISI][Medline]

59 . Jacobson, M. A., Maecker, H. T., Orr, P. L. et al. (2004). Results of a cytomegalovirus (CMV)-specific CD8+/interferon-gamma+ cytokine flow cytometry assay correlate with clinical evidence of protective immunity in patients with AIDS with CMV retinitis. Journal of Infectious Diseases 189, 1362–73.[CrossRef][ISI][Medline]