scholarly journals Effect of Intranodally Administered Dendritic Cell-Based HIV Vaccine in Combination With Pegylated Interferon α-2a on Viral Control Following ART Discontinuation: A Phase 2A Randomized Clinical Trial

2021 ◽  
Vol 12 ◽  
Author(s):  
Lorna Leal ◽  
Elvira Couto ◽  
Sonsoles Sánchez-Palomino ◽  
Núria Climent ◽  
Irene Fernández ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Pegylated Interferon ◽  
Vaccine Group ◽  
Viral Dynamics ◽  
Set Point ◽  
Cell Responses ◽  
Hiv 1

IntroductionFunctional cure has been proposed as an alternative to lifelong antiretroviral therapy and therapeutic vaccines represent one of the most promising approaches.Materials and MethodsWe conducted a double-blind randomized placebo-controlled clinical trial to evaluate the safety, immunogenicity, and effect on viral dynamics of a therapeutic vaccine produced with monocyte-derived dendritic cells (MD-DC) loaded with a high dose of heat-inactivated autologous (HIA) HIV-1 in combination with pegylated interferon alpha 2a (IFNα-2a) in people with chronic HIV-1.ResultsTwenty-nine male individuals on successful ART and with CD4+ ≥450 cells/mm3 were randomized 1:1:1:1 to receive three ultrasound-guided inguinal intranodal immunizations, one every 2 weeks: (1) vaccine ~107 MD-DC pulsed with HIA-HIV-1 (1010 HIV RNA copies) (n = 8); (2) vaccine plus three doses of 180 mcg IFNα-2a at weeks 4–6 (n = 6); (3) placebo = saline (n = 7); and (4) placebo plus three doses of 180 mcg IFNα-2a (n = 8). Thereafter, treatment was interrupted (ATI). Vaccines, IFNα-2a, and the administration procedures were safe and well tolerated. All patients’ viral load rebounded during the 12-week ATI period. According to groups, changes in viral set-point between pre-ART and during ATI were not significant. When comparing all groups, there was a tendency in changes in viral set-point between the vaccine group vs. vaccine + IFNα-2a group (>0.5log10p = 0.05). HIV-1-specific T-cell responses (IFN-ƴ Elispot) were higher at baseline in placebo than in the vaccine group (2,259 ± 535 vs. 900 ± 200 SFC/106 PBMC, p = 0.028). A significant difference in the change of specific T-cell responses was only observed at week 4 between vaccine and placebo groups (694 ± 327 vs. 1,718 ± 282 SFC/106 PBMC, p = 0.04). No effect on T-cell responses or changes in viral reservoir were observed after INFα-2a administration.DiscussionResults from this study show that intranodally administered DC therapeutic vaccine in combination with IFNα-2a was safe and well-tolerated but had a minimal impact on viral dynamics in HIV-1 chronic infected participants.Clinical Trial Registration(www.ClinicalTrials.gov), identifier NCT02767193

scholarly journals HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

2015 ◽  
Vol 89 (18) ◽  
pp. 9189-9199 ◽  
Author(s):  
Cristina Andrés ◽  
Montserrat Plana ◽  
Alberto C. Guardo ◽  
Carmen Alvarez-Fernández ◽  
Nuria Climent ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Therapeutic Vaccines ◽  
Cell Responses ◽  
Hiv 1

ABSTRACTHIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n= 24) (DC-HIV-1) or nonpulsed DCs (n= 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log10to 1.9 copies/106CD4 T cells,P= 0.22) and did increase in controls (mean of 1.8 log10to 2.1 copies/106CD4 T cells,P= 0.02) (P= 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r[Pearson's correlation coefficient] = −0.69,P= 0.002, andr= −0.82,P< 0.0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.)IMPORTANCEThere is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection.

scholarly journals HLA-B*44 Is Associated with a Lower Viral Set Point and Slow CD4 Decline in a Cohort of Chinese Homosexual Men Acutely Infected with HIV-1

2013 ◽  
Vol 20 (7) ◽  
pp. 1048-1054 ◽  
Author(s):  
Xin Zhang ◽  
XiaoJie Huang ◽  
Wei Xia ◽  
WeiHua Li ◽  
Tong Zhang ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
T Cell Responses ◽  
Hla Class I ◽  
T Cell Response ◽  
Class I ◽  
Set Point ◽  
Cell Responses ◽  
Lower Magnitude ◽  
Hiv 1

ABSTRACTHLA class I alleles have been shown to have differential impacts on the viral load and the outcome of HIV-1 disease progression. In this study, HLA class I types from residents of China with acute HIV-1 infection, diagnosed between 2006 and 2011, were identified and the association between expression of individual HLA alleles and the level of the set point viral load was analyzed. A lower level of set point viral load was found to be associated with the Bw4 homozygote on HLA-B alleles. B*44 and B*57 alleles have also been found to be associated with lower set point viral load. The set point viral load of B*44-positive individuals homozygous for Bw4 was significantly lower than that of B*44-negative individuals homozygous for Bw4 (P= 0.030). The CD4 count declined to <350 in fewer B*44-positive individuals than B*44-negative individuals (X2= 7.295,P= 0.026). B*44-positive individuals had a lower magnitude of p24 pool-specific T cell responses than B*44-negative individuals homozygous for Bw4, though this was not statistically significant. The p24 pool-specific T cell responses were also inversely correlated with lower viral load (rs= −0.88,P= 0.033). Six peptides within p24 were recognized to induce the specific-T cell response in B*44-positive individuals, and the peptide breadth of response was same as that in B*44-negative individuals homozygous for Bw4, but the median magnitude of specific-T cell responses to the recognized peptides in B*44-positive individuals was lower than that in B*44-negative individuals homozygous for Bw4 (P= 0.049). These findings imply that weak p24-specific CD8+T cell responses might play an important role in the control of HIV viremia in B*44 allele-positive individuals. Such studies might contribute to the development of future therapeutic strategies that take into account the genetic background of the patients.

scholarly journals Human Immunodeficiency Virus-Specific Gamma Interferon Enzyme-Linked Immunospot Assay Responses Targeting Specific Regions of the Proteome during Primary Subtype C Infection Are Poor Predictors of the Course of Viremia and Set Point

2008 ◽  
Vol 83 (1) ◽  
pp. 470-478 ◽  
Author(s):  
Clive M. Gray ◽  
Mandla Mlotshwa ◽  
Catherine Riou ◽  
Tiyani Mathebula ◽  
Debra de Assis Rosa ◽  
...  
Keyword(s):  
T Cell ◽  
Elispot Assay ◽  
T Cell Responses ◽  
Subtype C ◽  
Course Of Disease ◽  
Set Point ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Hiv 1

ABSTRACT It is unknown whether patterns of human immunodeficiency virus (HIV)-specific T-cell responses during acute infection may influence the viral set point and the course of disease. We wished to establish whether the magnitude and breadth of HIV type 1 (HIV-1)-specific T-cell responses at 3 months postinfection were correlated with the viral-load set point at 12 months and hypothesized that the magnitude and breadth of HIV-specific T-cell responses during primary infection would predict the set point. Gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses across the complete proteome were measured in 47 subtype C HIV-1-infected participants at a median of 12 weeks postinfection. When corrected for amino acid length and individuals responding to each region, the order of recognition was as follows: Nef > Gag > Pol > Rev > Vpr > Env > Vpu > Vif > Tat. Nef responses were significantly (P < 0.05) dominant, targeted six epitopic regions, and were unrelated to the course of viremia. There was no significant difference in the magnitude and breadth of responses for each protein region with disease progression, although there was a trend of increased breadth (mean, four to seven pools) in rapid progressors. Correlation of the magnitude and breadth of IFN-γ responses with the viral set point at 12 months revealed almost zero association for each protein region. Taken together, these data demonstrate that the magnitude and breadth of IFN-γ ELISPOT assay responses at 3 months postinfection are unrelated to the course of disease in the first year of infection and are not associated with, and have low predictive power for, the viral set point at 12 months.

Analysis of PSA-Specific T-Cell Responses of Prostate Cancer Patients Given a PSA-Based Vaccine on a Clinical Trial

2003 ◽  
Author(s):  
James Gulley ◽  
William Dahut ◽  
Philip M. Arlen ◽  
Kwong Tsang ◽  
Jeffrey Schlom
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cell ◽  
Cancer Patients ◽  
T Cell Responses ◽  
Cell Responses
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