Date Published: March 27, 2007
Publisher: Public Library of Science
Author(s): Olivier Gasser, Florian K Bihl, Marcel Wolbers, Elisabetta Loggi, Ingrid Steffen, Hans H Hirsch, Huldrych F Günthard, Bruce D Walker, Christian Brander, Manuel Battegay, Christoph Hess, Jeffrey M Jacobson
Abstract: BackgroundIn chronic HIV infection, antiretroviral therapy–induced normalization of CD4+ T cell counts (immune reconstitution [IR]) is associated with a decreased incidence of opportunistic diseases. However, some individuals remain at risk for opportunistic diseases despite prolonged normalization of CD4+ T cell counts. Deficient Epstein-Barr virus (EBV)-specific CD4+ T cell function may explain the occurrence of EBV-associated opportunistic malignancy—such as primary central nervous system (PCNS) lymphoma—despite recovery of absolute CD4+ T cell counts.Methods and FindingsAbsolute CD4+ T cell counts and EBV-specific CD4+ T cell-dependent interferon-γ production were assessed in six HIV-positive individuals prior to development of PCNS lymphoma (“cases”), and these values were compared with those in 16 HIV-infected matched participants with no sign of EBV-associated pathology (“matched controls”) and 11 nonmatched HIV-negative blood donors. Half of the PCNS lymphoma patients fulfilled IR criteria (defined here as CD4+ T cell counts ≥500/μl blood). EBV-specific CD4+ T cells were assessed 0.5–4.7 y prior to diagnosis of lymphoma. In 0/6 cases versus 13/16 matched controls an EBV-specific CD4+ T cell response was detected (p = 0.007; confidence interval for odds ratio [0–0.40]). PCNS lymphoma patients also differed with regards to this response significantly from HIV-negative blood donors (p < 0.001, confidence interval for odds ratio [0–0.14]), but there was no evidence for a difference between HIV-negative participants and the HIV-positive matched controls (p = 0.47).ConclusionsIrrespective of absolute CD4+ T cell counts, HIV-positive patients who subsequently developed PCNS lymphoma lacked EBV-specific CD4+ T cell function. Larger, ideally prospective studies are needed to confirm these preliminary data, and clarify the impact of pathogen-specific versus surrogate marker-based assessment of IR on clinical outcome.
Partial Text: The cardinal feature of HIV infection is depletion of CD4+ T cells from the circulation and from lymphoid tissue in most patients [1,2]. Immunodeficiency caused by CD4+ T cell depletion is associated with an increased risk for opportunistic diseases. The use of antiretroviral therapy (ART) has dramatically changed the course of HIV infection. ART-induced immune reconstitution (IR) is reflected by the fact that the incidence of opportunistic infections as well as several AIDS-defining malignancies decreases with treatment [3–7]. Specifically, the incidence of Epstein-Barr virus (EBV)-associated primary central nervous system (PCNS) lymphoma has dropped dramatically from 3–8 cases per 1,000 patient-years to about 1 case per 1,000 patient-years [8,9].
In a search of the Swiss HIV Cohort Study database, six HIV-positive individuals who developed PCNS lymphoma were identified (cases 1–6). Diagnosis was established via biopsy in cases 1, 2, 3, and 5, and via imaging, detection of EBV in cerebrospinal fluid, and exclusion of alternate diagnoses in cases 4 and 6. EBV-specific antibodies were detected in all PCNS lymphoma patients more than 2.5 years prior to diagnosis of lymphoma, and in all matched controls. The search criteria applied for selection of control patients are described in the Methods, and patient characteristics are summarized in Table 1.
Although PCNS lymphoma can develop in HIV-negative individuals, it much more often occurs in severely immunosuppressed HIV-infected persons (CD4+ T cell counts <50/μl). Intriguingly, since the introduction of ART, PCNS lymphoma has also been reported in individuals with CD4+ T cell counts over 200/μl or even over 500/μl [14,15]. Source: http://doi.org/10.1371/journal.pmed.0040096