Dendritic Cell-Based Immunotherapies to Fight HIV: How Far from a Success Story? A Systematic Review and Meta-Analysis
Abstract
:1. Introduction
2. Results
2.1. Study Screening and Characteristics
2.2. Meta-Analysis and Meta-Regression Results
3. Discussion
3.1. Immune Responses Elicited by the Experimental Vaccines
3.2. The Role of Host Genomic and Trascriptomic Background
3.3. Recommendations for Future Protocols
4. Material and Methods
4.1. Literature Search Strategy and Study Selection
4.2. Statistical Analysis
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Ref. | Country, City, Year | Inclusion Criteria | Recruited Individuals’ ART Status | Baseline CD4+ T cell count * | Vaccine Doses | Periodicity | Vaccine Administration Form | Anatomical Site (Vaccine Application) | Adverse Effects |
---|---|---|---|---|---|---|---|---|---|
[7] | USA, Stanford, 1998 | Asymptomatic HIV-1 infection CD4+ T cell counts >350/mm3 | naive | NR | 6 | Monthly | intravenous injection | NR | None reported |
[8] | Brazil, Recife, 2004 | Age of ≥18 years; No current pregnancy; HIV-1 asymptomatic seropositivity for ≥1 year; ART-naive for at least 6 months prior to enrollment; Hemoglobin ≥10 g/dL and platelets ≥100,000 | naive | 554 ± 174 | 3 | Biweekly | subcutaneous injection | left and right axillary and inguinal areas | Increase in the size of peripheral lymph nodes |
[9] | Spain, Barcelona, 2005 | Asymptomatic HIV-1 infection; Baseline and nadir CD4+ T cell counts >500 cells/mL; Baseline pre-ART PVL >5000 copies/mL; PVL <20 copies/mL for at least 104 weeks while on ART | experienced | 754 ± 36 | 5 | Every six weeks | subcutaneous injection | NR | Flu-like reactions |
[5] | Japan, Tokyo, 2006 | Undetectable viral loads (PVL <50 copies/mL) for 1 year on ART | experienced | 396 (337–504) | 6 | Biweekly | subcutaneous injection | axillary areas | Subcutaneous bleeding or erythema at injection site General malaise |
[10] | USA, Boston and New York, 2009 | PVL ≤400 copies/mL and CD4+ T cell counts ≥400/mm3 for at least 3 months prior recruitment; PVL <50 copies/mL at screening | experienced | 664 (NR) | 3 | Weeks 3, 7 and 15 | subcutaneous injection | inner aspect of the arm, 6–12 cm from the axilla | Episodes of thrombocytopenia in a patient and neutropenia in another |
[13] | Denmark, Copenhagen and Hvidovre, 2009 | Asymptomatic HIV-1 infection; CD4+ T cell counts ≥300/mm3; Absence of other chronic diseases; 1000 < PVL < 100,000 copies/mL; Presence of HLA-A * 0201 allele | experienced | 565 (355–982) | 4 | Biweekly, last dose after four weeks | subcutaneous injection | left and right axillary areas | None reported |
[11] | Spain, Barcelona, 2011 | Asymptomatic HIV-1 infection; ART-naive for at least two years before enrollment; Baseline CD4+ T cell counts >450 cells/mm3; Nadir CD4+ T cell counts >350 cells/mm3; PVL >10,000 HIV-1 copies/mL | naive | 647 (532–776) | 3 | Biweekly | subcutaneous injection | NR | Asymptomatic enlargement of local lymph nodes Flu-like symptoms |
[15] | Belgium, Brussel and Netherlands, Rotterdam, 2012 | Patients on ART; PVL ≤50 copies/ml and CD4+ T cell counts ≥500/mm3 for a period of at least 3 months prior to enrollment; Nadir CD4+ T-cell count >300/mm3 | experienced | 610 (500–960) | 4 | Monthly | subcutaneous and intradermal injection | antero-median side of an arm or a thigh | Tonsillitis episode |
[12] | Spain, Barcelona, 2013 | Asymptomatic chronic HIV-1 infection; Baseline CD4+ T cell count >450 cells/mm3; Nadir CD4+ T cell count >350 cells/mm3; Undetectable PVL(<50 copies/mL) on ART | experienced | 702 (568–900) | 3 | Biweekly | subcutaneous or intradermal injection | upper-inner part of both arms | Lymph node enlargement, erythema and flu-like symptoms |
[14] | USA, Dallas, 2014 | Asymptomatic HIV-1 infection; Baseline CD4+ T cell count >500 cells/mm3; Baseline PVL <50 copies/mL and within the previous 3 months while on ART; Nadir CD4+ T cells count ≥300 cells/mm3 | experienced | 670 (553–832) | 4 | Every 4 weeks | subcutaneous injection | upper and lower extremities | None reported |
[6] | USA, Pittsburgh, 2015 | CD4+ T cell count ≥300 cells/mm3; 3000 < PVL < 100,000 copies/mL | naive | 486 (377–881) | 4 (3 doses while on ART, 1 dose after ATI) | Biweekly | subcutaneous injection | upper medial area of the arm (bilaterally) | Mild-to-moderate inflammation at the injection site; Two individuals experienced severe pruritus and pain at the injection site |
[16] | USA, Philadelphia and Canada, Montreal, 2016 | PVL ≤200 copies/mL for at least 3 months prior to enrollment; PVL <50 copies/mL at screening; CD4+ T cell count ≥450 cells/mm3; Nadir CD4+ T cell count ≥200 cells/mm3; Pre-ART (within 3 months) plasma for virus isolation availability | experienced | 632 (513–765) | 4 | Every 4 weeks | intradermal injection | axillary lymph node | Mild local injection site reactions |
Ref. | Country, City, Year | Vaccine Response Criterion | Enrolled | Placebo Arm | Comparator Arm | Vaccine Arm | Removed from Analysis n | Responders n | Non-Responders n | Study Follow-Up Length |
---|---|---|---|---|---|---|---|---|---|---|
[7] | USA, Stanford, 1998 | Any PVL decrease | 6 | 0 | 0 | 6 | 0 | 0 | 6 | 40 weeks |
[8] | Brazil, Recife, 2004 | >90% PVL decrease by 1 year | 20 | 0 | 0 | 18 | 2 | 8 | 10 | 1 year |
[9] | Spain, Barcelona, 2005 | PVL decrease of 0.5 log10 copies/mL 24 weeks after vaccination | 18 | 6 | 0 | 12 | 0 | 4 | 8 | 24 weeks |
[5] | Japan, Tokyo, 2006 | PVL decrease of 0.5 log10 copies/mL | 4 | 0 | 0 | 4 | 0 | 0 | 4 | 12 weeks |
[10] | USA, Boston and New York, 2009 | Average of the last two scheduled PVL evaluations during weeks 10–13 of ATI ≤5000 copies/mL | 29 | 0 | 15 | 14 | 1 | 4 | 9 | 12 weeks |
[13] | Denmark, Copenhagen and Hvidovre, 2009 | A PVL decrease of 1.08 log10 copies/mL was the most pronounced change among responders | 12 | 0 | 0 | 12 | 0 | 5 | 7 | 40 weeks |
[11] | Spain, Barcelona, 2011 | PVL decrease of 0.5 log10 copies/mL 24 weeks after vaccination | 24 | 12 | 0 | 12 | 4 | 4 | 4 | 48 weeks |
[15] | Belgium, Brussel and Netherlands, Rotterdam, 2012 | Remaining off ART at 96 weeks following ATI | 17 | 0 | 0 | 17 | 0 | 6 | 11 | 110 weeks |
[12] | Spain, Barcelona, 2013 | Post-vaccination PVL decrease ≥1 log | 36 | 12 | 0 | 24 | 2 | 12 | 10 | 48 weeks |
[14] | USA, Dallas, 2014 | ATI maximum PVL <5 log10 copies/mL | 19 | 0 | 0 | 19 | 1 | 9 | 9 | 48 weeks |
[6] | USA, Pittsburgh, 2015 | ATI PVL decrease >0.4 log10 copies/mL | 11 | 0 | 0 | 11 | 1 | 3 | 7 | 48 weeks |
[16] | USA, Philadelphia and Canada, Montreal, 2016 | PVL in the vaccine arm is reduced by at least 1.1 log10 copies/mL | 54 | 17 | 0 | 37 | 2 | 0 | 35 | 2 years |
Ref. | Loaded Molecules | Loaded Molecules (Summarized) | Dendritic Cell Number | Culture Medium | Days in Culture |
---|---|---|---|---|---|
[7] | Gag (residues 77 to 85, SLYNTVATL motif), Env (residues 120 to 128, KLTPLCVTL motif and residues 814 to 823, SLLNATDIAV motif) and Pol (residues 956 to 964, LLWKGEGAV motif; residues 464 to 472, ILKEPVHGV motif and residues 267 to 277, VLDVGDAYFSV motif) peptides from recombinant HIV-1 MN gp160 polypeptide | peptides | 2–8 × 106 (immature DCs) | RPMI-1640 | 2 |
[8] | AT2 (chemically)-inactivated autologous virus | whole virus | 6 × 107 | CellGro® DC Medium | 7 |
[9] | Heat-inactivated autologous virus | whole virus | 2 × 106 | MCM | 8 |
[5] | Gag (residues 28 to 36, KYKLKHIVW and KYRLKHIVW motifs; residues 296 to 306, RDYVDRFYKTL motif), Nef (residues 138 to 147, RYPLTFGWCF and RFPLTFGWCF motifs) and Env (residues 584 to 594, RYLRDQQLLGI and RYLQDQQLLGI motifs) peptides | peptides | 0.7–1.8 ×106 | RPMI-1640 | 7 |
[10] | Recombinant virus produced by a canarypox vector (ALVAC vCP1452) | whole virus | 1.5–6 × 106 | MCM | 6 |
[13] | HLA A*0201-binding peptides (Gag, Pol, Env, Vpu and Vif) | peptides | 1 × 107 | X-VIVO™ 15 | 8 |
[11] | Heat-inactivated autologous virus | whole virus | 8 × 106 | X-VIVO™ 15 | 7 |
[15] | Mature DCs were electroporated with mRNA derived from pGEM-sig-Tat-DC-LAMP, pGEM-sigRev-DC-LAMP, pGEM-sig-Nef-DC-LAMP and pST1-sig-Gag-DCLAMP plasmids for peptides expression | mRNA (by electroporation) | 1 × 107 | X-VIVO™ 15 | 7 |
[12] | Heat-inactivated autologous virus | whole virus | 2 × 106 | X-VIVO™ 15 | 7 |
[14] | Viral epitopes from Gag (17 to 35, and 253 to 284 residues), Nef (66 to 97 and 116 to 145 residues) and Pol (residues 325 to 355) lipopeptides | peptides | 15 × 106 | CellGro® DC Medium | 3 |
[6] | Autologous CD4+ T cells which had been superinfected with endogenous inactivated HIV-1 with psoralen and UVB irradiation | peptides (indirectly) | 1 × 107 | CellGro® DC Medium | 6 |
[16] | Mature DCs were electroporated with autologous HIV-1 Gag, Nef, Rev, and Vpr mRNA for peptides expression | mRNA (by electroporation) | 1.2 × 107 | Not reported | 7 |
Ref. | DC Maturation Procedure | ||||||||
---|---|---|---|---|---|---|---|---|---|
GM-CSF Supplementation | IFN-α Supplementation | IFN-γ Supplementation | IL-1β Supplementation | IL-4 Supplementation | IL-6 Supplementation | PGE2 Supplementation | TNF-α Supplementation | Other Molecules Supplementation | |
[7] | No | No | No | No | No | No | No | No | - |
[8] | Yes | No | No | Yes | Yes | Yes | No | Yes | - |
[9] | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | - |
[5] | Yes | No | No | No | Yes | No | No | Yes | - |
[10] | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | - |
[13] | Yes | No | No | Yes | Yes | Yes | Yes | Yes | - |
[11] | Yes | No | No | Yes | Yes | Yes | No | Yes | - |
[15] | Yes | No | No | Yes | Yes | Yes | Yes | Yes | - |
[12] | Yes | No | No | Yes | Yes | Yes | Yes | Yes | - |
[14] | Yes | Yes | No | No | No | No | No | No | LPS |
[6] | Yes | Yes | Yes | Yes | Yes | No | No | Yes | polyinosinic:polycytidylic acid |
[16] | No | No | Yes | No | No | No | Yes | Yes | CD40L |
Variable | Linear Univariate Meta-Regression Coefficient | Coefficient Standard Error | p-Value | Decision |
---|---|---|---|---|
Antigen: | ||||
whole virus | Reference | - | - | |
mRNA | −0.8419 | 0.5442 | 0.1219 | Pre-selected |
peptides | −0.2937 | 0.3993 | 0.4621 | |
Baseline (pre-vaccine) CD4+ T cell counts: | ||||
more than 700 cells/mm3 | Reference | - | - | Pre-selected |
between 600 and 700 cells/mm3 | −0.4542 | 0.4405 | 0.3025 | |
between 500 and 600 cells/mm3 | −0.0367 | 0.5174 | 0.9434 | |
less than 500 cells/mm3 | −0.9804 | 0.7178 | 0.1720 | |
Days in culture (DCs maturation) | −0.0062 | 0.1118 | 0.9558 | Not pre-selected |
DC maturation culture medium: | ||||
RPMI-1640 | Reference | - | - | |
CellGro® | 2.8743 | 0.8972 | 0.0014 | |
MCM | 2.2890 | 0.9458 | 0.0155 | Pre-selected |
X-VIVO™ 15 | 2.8780 | 0.8836 | 0.0011 | |
GM-CSF supplementation (yes or no) | 3.1400 | 1.0378 | 0.0025 | Pre-selected |
IFN-α supplementation (yes or no) | −0.1512 | 0.3660 | 0.6795 | Not pre-selected |
IFN-γ supplementation (yes or no) | −1.2007 | 0.6481 | 0.0639 | Pre-selected; removed due to collinearity |
IL-1β supplementation (yes or no) | 0.5968 | 0.5336 | 0.2633 | Pre-selected |
IL-4 supplementation (yes or no) | 0.3529 | 0.5235 | 0.5002 | Not pre-selected |
IL-6 supplementation (yes or no) | 0.5672 | 0.4479 | 0.2053 | Pre-selected; removed due to collinearity |
Number of DCs per vaccine dose | −0.0032 | 0.0408 | 0.9369 | Not pre-selected |
Number of vaccine doses | −0.5006 | 0.2386 | 0.0359 | Pre-selected; removed due to collinearity |
Periodicity of vaccine doses (biweekly or every four weeks or more) | 0.4793 | 0.3577 | 0.1802 | Pre-selected; removed due to collinearity |
PGE2 supplementation (yes or no) | −0.1765 | 0.3592 | 0.6231 | Not pre-selected |
TNF-α supplementation (yes or no) | −0.1830 | 0.4887 | 0.7081 | Not pre-selected |
Variable | Linear Multivariate Meta-Regression Coefficient | 95% Confidence Interval | p-Value |
---|---|---|---|
(Model Intercept) | −3.4826 | (−6.5475)–(−0.4176) | 0.0259 |
Antigen: | |||
whole virus | Reference | - | - |
mRNA | −0.6289 | (−2.1234)–0.8657 | 0.4095 |
peptides | 1.0689 | (−3.2088)–5.3466 | 0.6243 |
Baseline (pre-vaccine) CD4+ T cell counts: | |||
more than 700 cells/mm3 | Reference | - | - |
between 600 and 700 cells/mm3 | −0.1513 | (−1.318)–1.0155 | 0.7994 |
between 500 and 600 cells/mm3 | −1.5793 | (−6.0215)–2.8629 | 0.4859 |
less than 500 cells/mm3 | −3.4955 | (−12.266)–5.2751 | 0.4347 |
GM-CSF supplementation (yes or no) | 3.712 | (−3.8567)–11.2806 | 0.3364 |
DC maturation culture medium: | |||
RPMI-1640 | Reference | - | - |
CellGro® | −1.147 | (−10.2552)–7.9612 | 0.805 |
MCM | −3.4024 | (−16.7094)–9.9046 | 0.6163 |
X-VIVO™ 15 | −2.5523 | (−15.9238)–10.8191 | 0.7083 |
IL-1β supplementation (yes or no) | 2.4969 | (−6.0232)–11.01 | 0.5657 |
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Coelho, A.V.C.; De Moura, R.R.; Kamada, A.J.; Da Silva, R.C.; Guimarães, R.L.; Brandão, L.A.C.; De Alencar, L.C.A.; Crovella, S. Dendritic Cell-Based Immunotherapies to Fight HIV: How Far from a Success Story? A Systematic Review and Meta-Analysis. Int. J. Mol. Sci. 2016, 17, 1985. https://doi.org/10.3390/ijms17121985
Coelho AVC, De Moura RR, Kamada AJ, Da Silva RC, Guimarães RL, Brandão LAC, De Alencar LCA, Crovella S. Dendritic Cell-Based Immunotherapies to Fight HIV: How Far from a Success Story? A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences. 2016; 17(12):1985. https://doi.org/10.3390/ijms17121985
Chicago/Turabian StyleCoelho, Antonio Victor Campos, Ronald Rodrigues De Moura, Anselmo Jiro Kamada, Ronaldo Celerino Da Silva, Rafael Lima Guimarães, Lucas André Cavalcanti Brandão, Luiz Cláudio Arraes De Alencar, and Sergio Crovella. 2016. "Dendritic Cell-Based Immunotherapies to Fight HIV: How Far from a Success Story? A Systematic Review and Meta-Analysis" International Journal of Molecular Sciences 17, no. 12: 1985. https://doi.org/10.3390/ijms17121985