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Cytomegalovirus-Specific T Cells Persist at Very High Levels during Long-Term Antiretroviral Treatment of HIV Disease

Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
PLoS ONE (Impact Factor: 3.53). 01/2010; 5(1):e8886. DOI: 10.1371/journal.pone.0008886
Source: PubMed

ABSTRACT In healthy, HIV seronegative, CMV seropositive adults, a large proportion of T cells are CMV-specific. High-level CMV-specific T cell responses are associated with accelerated immunologic aging ("immunosenesence") in the elderly population. The impact of untreated and treated HIV infection on the frequency of these cells remains undefined.
We measured the proportion of CD4+ and CD8+ T cells responding to CMV pp65 and IE proteins was measured using flow cytometry in 685 unique HIV seronegative and seropositive individuals. The proportion of CMV-specific CD8+ T cells was consistently higher in the HIV-seropositive subjects compared to the HIV-seronegative subjects. This HIV effect was observed even in patients who lacked measurable immunodeficiency. Among the HIV-seropositive subjects, CMV-specific CD8+ T cell responses were proportionately lower during recent infection, higher during chronic untreated infection and higher still during long-term antiretroviral treated infection. The CD8+ T cell response to just two CMV proteins (pp65 and IE) was approximately 6% during long-term therapy, which was over twice that seen in HIV-seronegative persons. CMV-specific CD4+ T cell responses followed the same trends, but the magnitude of the effect was smaller.
Long-term successfully treated HIV infected patients have remarkably high levels of CMV-specific effector cells. These levels are similar to that observed in the elderly, but occur at much younger ages. Future studies should focus on defining the potential role of the CMV-specific inflammatory response in non-AIDS morbidity and mortality, including immunosenescence.

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    ABSTRACT: ENGLISH ABSTRACT: Introduction: Reactivation of human cytomegalovirus (HCMV) infection in individuals infected with human immunodeficiency virus (HIV) may lead to life-threatening end-organ diseases (EOD). The EOD becomes clinically apparent when a critical number of cells in the affected organs become damaged as a consequence of HCMV-infection. Treatment of the HCMV-associated disease at this point may not be effective. Therefore, early detection of HCMV reactivation may be useful to guide pre-emptive therapy. Aim: The aim of this study was to determine whether there is a point at which the HCMV-specific cellular immune response breaks down, as determined by the interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay, and HCMV reactivation occurs in HIV-positive, antiretroviral therapy (ART)-naïve individuals in a South African setting. This was done in relation to the CD4+ T cell count and the HCMV viral load as determined by real-time polymerase chain reaction (qPCR). Materials and methods: Fifty-two (52) HIV-infected, ART-naïve subjects were recruited from primary healthcare centres that they attended for the management of their HIV infection. Heparinised blood samples were collected to quantify the HCMV-specific cellular immune response using the IFN-γ-ELISPOT assay and to determine the HCMV IgG serostatus. Ethylenediaminetetraacetic acid (EDTA) blood samples were collected for the determination of the CD4+ T cell counts and the HCMV viral loads. Results: All 52 subjects recruited were confirmed to be HIV-HCMV co-infected based on their HCMV IgG serostatus. The results of 34 subjects with completed data sets were analysed. The CD4+ T cell counts of these subjects ranged from 10 to 784 cells/μl. Twenty-two (22) (65%) subjects had positive HCMV IFN-γ-ELISPOT results with 94% having no detectable HCMV viral loads. All subjects (28) with a CD4+ T cell count above 100 cells/μl had undetectable HCMV viral loads. Two of the six subjects with CD4+ T cell counts <100 cells/μl had detectable HCMV viral loads. There was no statistically significant association between the CD4+ T cell counts and the HCMV IFN-γ-ELISPOT results. Conclusion: No specific point could be determined when there is loss of integrity of the HCMV-specific cellular immune response in HIV-positive individuals. Low CD4+ T cell counts did not correlate with HCMV IFN-γ-ELISPOT results suggesting that the HCMV-specific cellular immunity did not necessarily break down at low CD4+ T cell counts. Nevertheless, a CD4+ T cell count above 100 cells/μl appeared to be protective against viraemia as determined by the HCMV viral load qPCR. The IFN-γ-ELISPOT assay was employed as a tool to determine the integrity of the HCMV-specific cellular immune response in HIV-positive individuals. However, the IFN-γ-ELISPOT assay should be used in conjunction with the CD4+ T cell count and the HCMV viral load qPCR to determine when there is loss of integrity of the HCMV-specific cellular immune response and HCMV reactivation occurs. This may assist clinicians in their choice of management and appropriate pre-emptive treatment in the HIV-HCMV co-infected individual at a risk for HCMV reactivation. AFRIKAANSE OPSOMMING: Inleiding: Heraktivering van menslike sitomegaalvirus (MSMV) in menslike immuniteitsgebreksvirus (MIV)-MSMV ko-geïnfekteerde individue kan lei tot dodelike end-orgaan siektes (EOS). Die EOS word klinies duidelik wanneer 'n kritieke aantal selle in die organe beskadig raak as gevolg van die MSMV-infeksie. Behandeling van die MSMV-verwante siekte op hierdie punt mag moontlik nie meer effektief wees nie. Daarom kan die vroeë opsporing van MSMV heraktivering nuttig wees in die gebruik van voorkomende terapie. Doel: Die doel van hierdie studie is om die punt te bepaal wanneer die MSMV-spesifieke sellulêre immuun reaksie afgebreek word met behulp van die interferon gamma (IFN-γ) ensiem-gekoppelde immunospot (ELISPOT) toets en MSMV heraktivering voorkom in MIV-positiewe, antiretrovirale terapie (ART)-naïewe individue in' n Suid-Afrikaanse instelling. Dit word gedoen in verhouding met die CD4+ T sel telling en die MSMV virale lading. Materiale en metodes: Twee-en-vyftig (52) MIV-geïnfekteerde, ART-naïewe pasiënte is vanaf primêre gesondheidsentrums, wat hul bywoon vir die behandeling van hul MIV infeksie, genader. Gehepariniseerde bloedmonsters is gebruik om die MSMV-spesifieke sellulêre immuun reaksie met behulp van die IFN-γ-ELISPOT toets en die MSMV IgG serostatus te bepaal. Etileendiamientetra-asynsuur (EDTA) bloed monsters is versamel vir die bepaling van hul CD4+ T sel telling en hul MSMV virale lading met behulp van die ―real-time‖ polimerase kettingreaksie (qPKR) waardes. Resultate: Al 52 pasiënte is bevestigde MIV-MSMV ko-infeksies, gebasseer op hul serologiese status. Die resultate van 34 pasiënte met voltooide data is ontleed. Die CD4+ T sel tellings van hierdie pasiënte het gewissel 10-784 selle/μl. Twee-en-twintig (22) (65%) pasiënte het positiewe MSMV IFN-γ-ELISPOT resultate met 94% wat ‗n negatiewe qPKR resultate. Alle pasiënte (28) met 'n CD4+ T-seltelling bo 100 selle/μl het' n negatiewe qPKR resultate. Twee van die ses pasiënte met 'n CD4+ T-seltelling <100 selle/μl het waarneembare MSMV virale ladings oor die qPKR. Daar was geen statisties beduidende assosiasie tussen die CD4+ T sel tellings en die MSMV IFN-γ-ELISPOT resultate nie. Gevolgtrekking: Geen spesifieke punt wanneer die MSMV-spesifieke sellulêre immuun reaksie afgebreek word kon in MIV-positiewe individue bepaal word nie. Lae CD4+ T sel tellings het nie ooreengestem met die MSMV IFN-γ-ELISPOT resultate nie en dui daarop dat die MSMV-spesifieke sellulêre immuniteit nie noodwendig afgebreek word teen 'n lae CD4+ T sel tellings nie. Tog blyk 'n CD4+ T-seltelling bo 100 selle/μl om beskerming teen viremie te bied. Die meriete van die gebruik van die IFN-γ-ELISPOT toets die integriteit van die MSMV-spesifieke sellulêre immuun response in MIV-positiewe individue te bepaal, is waargeneem in die opgehoopte data. Tog kan die gebruik van die IFN-γ-ELISPOT toets in samewerking met die CD4+ T sel telling en die MSMV virale lading meer voordelig in die bepaling van 'n punt wanneer die MSMV-spesifieke sellulêre immuun reaksie afbreek en herstel plaasvind. Dit kan help om klinici in hul keuse van bestuur en gepaste voorkomende behandeling in die MIV-MSMV mede-geïnfekteerde individu op 'n risiko vir herstel. Thesis (MScMedSc)--University of Stellenbosch, 2011.
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