Strategies for optimizing targeting and delivery of mucosal HIV vaccines

Ahlers, Jeffrey D.; Belyakov, Igor M.

doi:10.1002/eji.200939269

Cited by 24 publications

(20 citation statements)

References 137 publications

(146 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, Ag presentation by HLA-I or HLA-II molecules is mandatory for the development of a cognate T cell response (47). However, the qualitative response of a DC-based vaccine will be determined primarily by the adjuvants used, because these are DC activators (29,30). The most widely used DCmaturation stimulus in immunotherapy is the proinflammatory mixture ITIP (14,20); however, our results show that it only boosts HLA-I Ag presentation when DC mature during viral capture.…”

Section: Discussionmentioning

confidence: 76%

“…Because vaccine adjuvants boost immune responses, mainly because they are DC activators (29,30), we wondered whether timing of maturation during Ag loading affected viral capture and transmission to HIV-1-susceptible cells. Thus, we compared the viral uptake and trans-infection abilities of DC matured with LPS (iDC+LPS) or with ITIP (iDC+ITIP) during viral capture with those DC fully matured before HIV-1 incubation.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

HIV-1 Capture and Antigen Presentation by Dendritic Cells: Enhanced Viral Capture Does Not Correlate with Better T Cell Activation

Rodriguez-Plata

Urrutia

Cardinaud

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

During HIV-1 infection, dendritic cells (DC) facilitate dissemination of HIV-1 while trying to trigger adaptive antiviral immune responses. We examined whether increased HIV-1 capture in DC matured with LPS results in more efficient Ag presentation to HIV-1–specific CD4+ and CD8+ T cells. To block the DC-mediated trans-infection of HIV-1 and maximize Ag loading, we also evaluated a noninfectious integrase-deficient HIV-1 isolate, HIVNL4-3ΔIN. We showed that higher viral capture of DC did not guarantee better Ag presentation or T cell activation. Greater HIVNL4-3 uptake by fully LPS-matured DC resulted in higher viral transmission to target cells but poorer stimulation of HIV-1–specific CD4+ and CD8+ T cells. Conversely, maturation of DC with LPS during, but not before, viral loading enhanced both HLA-I and HLA-II HIV-1–derived Ag presentation. In contrast, DC maturation with the clinical-grade mixture consisting of IL-1β, TNF-α, IL-6, and PGE2 during viral uptake only stimulated HIV-1–specific CD8+ T cells. Hence, DC maturation state, activation stimulus, and time lag between DC maturation and Ag loading impact HIV-1 capture and virus Ag presentation. Our results demonstrate a dissociation between the capacity to capture HIV-1 and to present viral Ags. Integrase-deficient HIVNL4-3ΔIN was also efficiently captured and presented by DC through the HLA-I and HLA-II pathways but in the absence of viral dissemination. HIVNL4-3ΔIN seems to be an attractive candidate to be explored. These results provide new insights into DC biology and have implications in the optimization of DC-based immunotherapy against HIV-1 infection.

show abstract

Section: Discussionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

HIV-1 Capture and Antigen Presentation by Dendritic Cells: Enhanced Viral Capture Does Not Correlate with Better T Cell Activation

Rodriguez-Plata

Urrutia

Cardinaud

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…For HIV vaccines this will require immunization strategies that generate sufficient numbers of high-avidity effector memory CD8 ϩ CTL armed and ready at mucosal sites of infection and CD4 ϩ and CD8 ϩ central memory T cells capable of being rapidly recalled in a second wave of attack to curtail primary infection and prevent dissemination from mucosal compartments. 8,[60][61][62][63][64][65] The role of cytokines, type I and type II IFNs in regulating effector function and transition to memoryThe production of inflammatory cytokines and in particular the induction of the IFN-␥/IL-12-signaling axis plays a key role in the STRATEGIES FOR OPTIMIZING VACCINE T-CELL MEMORY 1683 BLOOD, 4 MARCH 2010 ⅐ VOLUME 115, NUMBER 9For personal use only. on May 11, 2018. by guest www.bloodjournal.org From coordinate regulation of the transcriptional programs that guide CD4 ϩ Th1 and CD8 ϩ T-cell effector and effector/memory differentiation.…”

mentioning

confidence: 99%

Memories that last forever: strategies for optimizing vaccine T-cell memory

Ahlers

Belyakov

2010

Blood

Self Cite

137

134

View full text Add to dashboard Cite

For acute self-limiting infections a vaccine is successful if it elicits memory at least as good as the natural experience; however, for persistent and chronic infections such as HIV, hepatitis C virus (HCV), human papillomavirus (HPV), and human herpes viruses, this paradigm is not applicable. At best, during persistent virus infection the person must be able to maintain the integrity of the immune system in equilibrium with controlling replicating virus. New vaccine strategies are required that elicit both potent high-avidity CD8 ؉ T-cell effector/memory and central memory responses that can clear the nidus of initial virus-infected cells at mucosal surfaces to prevent mucosal transmission or significantly curtail development of disease. The objective of an HIV-1 T-cell vaccine is to generate functional CD8 ؉ effector memory cells at mucosal portals of virus entry to prevent viral transmission. In addition, long-lived CD8 ؉ and CD4 ؉ central memory cells circulating through secondary lymphoid organs and resident in bone marrow, respectively, are needed to provide a concerted second wave of defense that can contain virus at mucosal surfaces and prevent systemic dissemination. Further understanding of factors which can influence long-lived effector and central memory cell differentiation will significantly contribute to development of effective T-cell vaccines. In this review we will focus on discussing mechanisms involved in T-cell memory and provide promising new approaches toward expanding current vaccine strategies to enhance antiviral memory. (Blood. 2010;115:1678-1689) IntroductionA common defining characteristic of immune memory is that it is both selective and parsimonious. After resolution of primary infection a small somewhat constant fraction of cells remain depending upon initial precursor frequency and the balance between T-cell receptor (TCR) signal strength and prosurvival signals received. 1,2 Memory cells are homeostatically maintained in a progrowth state poised to respond rapidly to secondary infection. The fidelity of memory and effectiveness to thwart disease is reflected in the multifunctional character of the recalled response. Memory T cells are heterogenous in terms of phenotype, function, and anatomical locations. [3][4][5] Understanding cytokine and costimulatory signals that influence transcriptional programs regulating T-cell differentiation and memory is key to manipulating vaccine responses. Furthermore, defining different subpopulations of memory CD8 ϩ T cells by differentiation and activation markers representative of transcriptional programs associated with protective recall responses will be key to predicting vaccine efficacy.To date, strategies for targeted delivery of vaccines and inclusion of cytokines, chemokines, and immunomodulatory molecules for enhancing the magnitude of immune responses and memory have been mostly empirical. For HIV-1 vaccines this has involved the expression of HIV-1 genes, cytokines, and chemokines by in vivo delivery of plasmid DNA and recombinant v...

show abstract

“…Vaccine success will depend significantly, but not exclusively on immunogens; it will also be critical to factor in how these immunogens are presented to the immune system, i.e. the choice of vaccine vectors and vector combinations, adjuvantation and routes of delivery [37]. Which vaccine strategy is the best can be only decided by protection of humans against HIV-1 infection and/or AIDS and this, in turn, can only be answered in efficacy trials.…”

Section: Summary Perspectivementioning

confidence: 99%