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- W2321884458 abstract "HIV infection is characterized by a loss of immunological function and the development of severe opportunistic infections such as cytomegalovirus. To determine the frequency of cytomegalovirus-specific CD4 T cells in healthy and HIV-infected individuals, we examined peripheral blood mononuclear cells from 10 HIV-negative and 55 HIV-positive individuals for antigen-induced intracellular cytokine responses. We found that HIV suppression with antiretroviral therapy leads to a normalization of previously increased cytomegalovirus-specific CD4 T cells, indicating the efficient control of an opportunistic pathogen. Cytomegalovirus is one of the most frequent opportunistic pathogens in patients with AIDS [1]. Untreated HIV infection is characterized by a progressive loss of immunological function and the development of severe opportunistic infections [2]. More than 90% of patients with HIV have been infected at some time with cytomegalovirus. It is therefore important to identify HIV-infected patients with low CD4 cell counts who are at greatest risk of developing cytomegalovirus disease and to treat HIV effectively before cytomegalovirus disease becomes established. Little is known about the role of virus-specific CD4T cells in maintaining immunity against cytomegalovirus [3]. It is now possible to quantitate antigen-specific CD4 lymphocytes by flow cytometry [4]. Using this method, we studied cytomegalovirus-specific CD4 lymphocyte responses in HIV-negative and HIV- infected individuals after in-vitro stimulation with lysate of cytomegalovirus-infected human fibroblasts. For each analysis, cells were gated on CD4 cell expression and up to 20 000 gated events were acquired for the detection of responding versus non-responding T cells after 6 h of in-vitro antigen stimulation. Responding CD4 T cells were defined by intracellular TNF-α or IFN-γ production and CD69 expression. Quantitation was corrected for background reactivity seen with control antigen stimulation. In 10 healthy cytomegalovirus-positive HIV-negative individuals, cytomegalovirus-specific T cells were detected at a mean responder frequency of 1.16/μl CD69 CD4 T cells of peripheral blood IFN-γ and 1.15/μl TNF-α-producing T cells (Fig. 1, group G). The staining could be inhibited by pre-incubation with blocking monoclonal antibodies to IFN-γ and TNF-α. As expected, cytomegalovirus-specific CD4 T cells could not be demonstrated in three healthy HIV-negative cytomegalovirus-negative individuals and in 10 HIV-positive cytomegalovirus-negative subjects (Fig. 1, group F).Fig. 1.: Cytomegalovirus-specific CD4 T cells per microlitre of peripheral blood in HIV-infected (group A: long-term non-progressors; group B: untreated; group C: highly active antiretroviral therapy less than one year; group D: highly active antiretroviral therapy more than one year with detectable viral load; group E: highly active antiretroviral therapy more than one year without detectable viral load; group F: cytomegalovirus seronegative) and HIV-negative control group (group G). Filled bars: IFN-γ-producing CD4 CD69 T cells; hatched bars: TNF-α-producing CD4 CD69 T cells. After the subtraction of background reactivity seen with control lysate, the percentage of responding cells was multiplied with the absolute CD4 cell number, resulting in the absolute number of antigen-specific cells. There are no significant differences between IFN-γ and TNF-α-producing CD4 T-cell numbers within the same group. Mean numbers are indicated, standard error of the mean is shown above the bars.However, the frequency of cytomegalovirus-specific CD4 T cells producing IFN-γ and TNF-α from 45 HIV-positive cytomegalovirus-positive individuals was significantly increased (P = 0.009; Mann–Whitney) compared with the HIV-negative population. For a more detailed analysis, HIV-positive cytomegalovirus-positive subjects were divided into five groups according to time since initiation of antiretroviral therapy and HIV viral load: None of the patients had detectable cytomegalovirus viraemia in the Roche Amplicor assay or clinical signs suspicious of cytomegalovirus disease. Group A consisted of three HIV-infected long-term non-progressors defined as asymptomatic, untreated HIV-1 infection for more than 10 years with CD4 cell counts greater than 500 cells/μl (mean 655/μl) and viral loads of less than 10 000 copies/ml (mean 188). Cytomegalovirus-specific T cells were detected in all HIV-positive individuals at a mean frequency of 9.25/μl IFN-γ and 7.99/μl TNF-α-producing T cells (Fig. 1, group A). Group B consisted of nine HIV-infected subjects without antiretroviral treatment. (CD4 T-cell counts 88–1502/μl, mean 558/μl; viral loads 114–367 000 copies/ml, mean 77 289 copies/ml). Mean cytomegalovirus-specific CD4 T cells in this group were 8.11/μl blood IFN-γ-producing CD4 T cells and 7.61/μl blood TNF-α-producing CD4 T cells (Fig. 1, group B). Group C consisted of 10 HIV-infected individuals on antiretroviral therapy for less than one year (CD4 T-cell counts 165–629/μl, mean 348/μl; viral loads < 50–1080 copies/ml, mean 226 copies/ml). In this group the mean responder frequencies were 2.32/μl IFN-γ and 2.96/μl TNF-α. HIV-1-infected subjects treated with highly active antiretroviral therapy (HAART) for more than one year were divided into two groups: group D with detectable viral loads (CD4 T-cell counts 75–615/μl, mean 335/μl; viral loads 104–75 000 copies/ml, mean 17 726 copies/ml) and group E with undetectable viral loads (CD4 T-cell counts 117–911/μl, mean 427/μl; viral loads < 50 copies/ml). The mean cytomegalovirus-specific CD4 T-cell frequency was 0.65/μl blood for IFN-γ-producing CD4 T cells and 0.73/μl blood for TNF-α-producing CD4 T cells in group D. In group E, we detected 0.76/μl blood IFN-γ-producing CD4 T cells and 0.94/μl blood TNF-α-producing CD4 T cells. There were no significant (P > 0.05, Mann–Whitney) differences in cytomegalovirus responses in long-term treated patients between group D and group E. We expected to find reduced cytomegalovirus-specific CD4 T cells in HIV patients compared with HIV-uninfected subjects. Surprisingly, the number of cytomegalovirus-specific CD4 T cells from HIV-positive cytomegalovirus-positive individuals was significantly increased, and the frequency distribution within these groups of HIV-positive individuals was broad (range 0–11.29%, mean 0.85%) compared with the HIV-negative population. Among the 45 HIV-positive cytomegalovirus-positive individuals tested, 11 (24.4%) had a more than threefold increase in the frequency of IFN-γ-producing cytomegalovirus-specific T cells over the mean frequency observed in HIV-negative subjects for IFN-γ. Only 13 (28.8%) of the remaining HIV-positive cytomegalovirus-positive subjects revealed lower numbers than the lowest observed in HIV-negative subjects. We found strong cytomegalovirus-specific CD4 T-cell responses in untreated HIV disease. This observation may reflect an immune response against a chronic pathogen boostered by periodic low-grade cytomegalovirus replication in latently infected hosts, in which the proliferation of cytomegalovirus-specific CD4 T cells is able to counterbalance the destruction of cytomegalovirus-activated lymphocytes caused by HIV-1, thereby maintaining an effective anti-cytomegalovirus-response as long as possible. An implication of these findings is that antigen availibility is the most important factor for the survival and function of antigen-specific T helper cells. Cytomegalovirus-specific CD4 T cells were either undetectable or detectable at very low frequency in subjects with long-term HAART-mediated viral suppression (groups D, E). This observation supports the assumption that cytomegalovirus-specific T cells are progressively lost from the recirculating pool with prolonged HIV suppression. Cytomegalovirus-specific CD4 T cells decrease after initiating HAART as a result of the successful restoration of an effective immune response against cytomegalovirus. The subsequent reduction of cytomegalovirus antigen results in the elimination of proliferation stimuli for cytomegalovirus-specific T helper cells and the predominance of multiple other T-cell specificities [3,5]. Our results show that cytomegalovirus-specific CD4 T cells can persist with or without therapy against HIV-1 infection. This indicates that these cells can be generated during HIV-1 infection. Cytomegalovirus-specific CD4 T cells are not necessarily eliminated or suppressed by ongoing HIV replication, even when it is accompanied by a CD4 T-cell decline. Reconstitution of effective CD4 T-cell responses against cytomegalovirus in HIV patients after HAART results in immunological control of cytomegalovirus replication, as HAART can not directly inhibit cytomegalovirus. These promising findings support the idea of vaccination strategies against several pathogens, and ultimately HIV itself. Volker Grosse Alexander Schulte Klaus Weber Myriam Mendila Roland Jacobs Reinhold E. Schmidt Hans Heiken" @default.
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- W2321884458 date "2002-05-01" @default.
- W2321884458 modified "2023-09-26" @default.
- W2321884458 title "Normalization of cytomegalovirus-specific CD4 T cells in HIV-1-infected individuals receiving antiretroviral therapy" @default.
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