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In vitro priming recapitulates in vivo HIV-1 specific T cell responses, revealing rapid loss of virus reactive CD4+ T cells in acute HIV-1 infection
New York University School of Medicine.
Partners AIDS Research Center.
Partners AIDS Research Center.
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
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2009 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 1, e4256- p.Article in journal (Refereed) Published
Abstract [en]

Background: The requirements for priming of HIV-specific T cell responses initially seen in infected individuals remain to be defined. Activation of T cell responses in lymph nodes requires cell-cell contact between T cells and DCs, which can give concurrent activation of T cells and HIV transmission. Methodology: The study aim was to establish whether DCs pulsed with HIV-1 could prime HIV-specific T cell responses and to characterize these responses. Both infectious and aldrithiol-2 inactivated noninfectious HIV-1 were compared to establish efficiencies in priming and the type of responses elicited. Findings: Our findings show that both infectious and inactivated HIV-1 pulsed DCs can prime HIV-specific responses from na�ve T cells. Responses included several CD4+ and CD8+ T cell epitopes shown to be recognized in vivo by acutely and chronically infected individuals and some CD4+ T cell epitopes not identified previously. Follow up studies of acute and recent HIV infected samples revealed that these latter epitopes are among the earliest recognized in vivo, but the responses are lost rapidly, presumably through activation-induced general CD4+ T cell depletion which renders the newly activated HIV-specific CD4+ T cells prime targets for elimination. Conclusion: Our studies highlight the ability of DCs to efficiently prime na�ve T cells and induce a broad repertoire of HIV-specific responses and also provide valuable insights to the pathogenesis of HIV-1 infection in vivo.

Place, publisher, year, edition, pages
2009. Vol. 4, no 1, e4256- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-18850DOI: 10.1371/journal.pone.0004256OAI: diva2:221903
Original Publication: R.L. Sabado, D.G. Kavanagh, D.E. Kaufmann, Karlhans Fru Che, E. Babcock, E. Rosenberg, B. Walker, J. Lifson, N. Bhardwaj and Marie Larsson , In vitro priming recapitulates in vivo HIV-1 specific T cell responses, revealing rapid loss of virus reactive CD4+ T cells in acute HIV-1 infection, 2009, PLoS ONE, (4), 1, e4256. Licensed under Creative Commons Available from: 2009-06-10 Created: 2009-06-05 Last updated: 2011-10-10Bibliographically approved
In thesis
1. Immunomodulatory Effects of Human ImmunodeficiencyVirus (HIV-1) on Dendritic Cell and T cell Responses: Studies of HIV-1 effects on Dendritic cell functionality reflected in primed T cells
Open this publication in new window or tab >>Immunomodulatory Effects of Human ImmunodeficiencyVirus (HIV-1) on Dendritic Cell and T cell Responses: Studies of HIV-1 effects on Dendritic cell functionality reflected in primed T cells
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human immunodeficiency virus (HIV)-1 is the causative agent of acquired immune deficiency syndrome (AIDS) worldwide. Till date there are no vaccines or cure for this infection as the virus has adapted myriad ways to remain persistent in the host where it causes severe damage to the immune system. Both humoral and cellular immune responses are mounted against HIV-1 during the initial phase of infection but fail to control viral replication as these responses are severely depleted during disease progression. Of great importance in HIV-1 research today is the in depth understanding of the types of immune responses elicited, the mechanisms behind their decline and how these responses can be  maintained overtime.

The focus of this thesis was to examine the possibility of priming HIV-1 specific T cell responses in vitro from whole viral particles and in detail, scrutinize the type of T cell responses and epitope specificities generated. Next was to investigate in vitro the factors responsible for impaired immune responses in HIV-1 infected individuals. We were also interested in understanding the underlying mechanisms through which HIV-1 initiate suppression of T cell functionality.

Results showed that using HIV-1 pulsed monocyte derived dendritic cells (DCs), we were able to prime HIV-1 specific CD4+ and CD8+ T cells from naïve T cells in vitro. The epitopes primed in vitro were located within the HIV-1 envelope, gag, and pol proteins and were confirmed ex vivo to exist in acute and chronically infected individuals. We established that many of the novel CD4+ T cell epitopes primed in vitro also existed in vivo in HIV-1 infected individuals during acute infection. These responses declined/disappeared early on, which is in line with HIV-1 preferential infection of HIV-1 specific CD4+ T cells.

Besides declining HIV-1 specific T cell responses, many HIV-1 infected individuals also have impaired T cell functionality. We established that one reason behind the decline and impairment in immune responses was the increased expression of inhibitory molecules PD-1, CTLA-4, and TRAIL on HIV-1 primed T cells. These T cells had the capacity to suppress new responses in a cell-cell contact dependent manner. The ability of the HIV-1 primed T cells to proliferate was severely impaired and this condition was reversed after a combined blockade of PD-1, CTLA-4 and TRAIL. Furthermore, more inhibitory molecules TIM-3, LAG-3, CD160, BLIMP-1, and FOXP3 were also found increased at both gene and protein levels on HIV-1 primed T cells. Additionally, we showed decreased levels of functional cytokines IL-2, IFN-γ and TNF-α, and the cytolytic proteins perforin and granzyme in DC T cell priming cocultures containing HIV-1. This could be as a result of the decreased T cell activation or impaired production by T cells. The mechanisms responsible for the elevated levels of inhibitory molecules emanated mainly from the P38MAPK/STAT3 pathways. Blockade of these pathways in both allogeneic and autologous DC-T cell assays significantly suppressed expression of inhibitory molecules and subsequently rescued T cell proliferation.

In conclusion, HIV-1 pulsed DCs have the capacity to prime HIV-1 specific responses in vitro that do exist in HIV-1 infected individuals and we found evidence that many of these responses were eliminated rapidly in HIV-1 infected individuals. HIV-1 triggers through P38MAPK/STAT3 pathway the synthesis of inhibitory molecules, namely CTLA-4, PD-1, TRAIL, TIM-3, LAG-3, CD160, and suppression associated transcription factors FOXP3, BLIMP-1 and DTX1. This is followed by decreased T cell proliferation and functionality which are much needed to control viral replication.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 67 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1256
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-71279 (URN)978-91-7393-093-2 (ISBN)
Public defence
2011-09-02, Eken, ingång 65, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2011-11-28Bibliographically approved

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