scholarly journals HIV/AIDS Vaccine Candidates Based on Replication-Competent Recombinant Poxvirus NYVAC-C-KC Expressing Trimeric gp140 and Gag-Derived Virus-Like Particles or Lacking the Viral Molecule B19 That Inhibits Type I Interferon Activate Relevant HIV-1-Specific B and T Cell Immune Functions in Nonhuman Primates

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
Juan García-Arriaza ◽  
Beatriz Perdiguero ◽  
Jonathan L. Heeney ◽  
Michael S. Seaman ◽  
David C. Montefiori ◽  
...  
Keyword(s):  
T Cell ◽  
Nonhuman Primates ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Vaccine Candidates ◽  
Aids Vaccine ◽  
Clade C ◽  
Hiv 1 ◽  
Hiv Aids

ABSTRACT The nonreplicating attenuated poxvirus vector NYVAC expressing clade C(CN54) HIV-1 Env(gp120) and Gag-Pol-Nef antigens (NYVAC-C) showed limited immunogenicity in phase I clinical trials. To enhance the capacity of the NYVAC vector to trigger broad humoral responses and a more balanced activation of CD4+ and CD8+ T cells, here we compared the HIV-1-specific immunogenicity elicited in nonhuman primates immunized with two replicating NYVAC vectors that have been modified by the insertion of the K1L and C7L vaccinia virus host range genes and express the clade C(ZM96) trimeric HIV-1 gp140 protein or a Gag(ZM96)-Pol-Nef(CN54) polyprotein as Gag-derived virus-like particles (termed NYVAC-C-KC). Additionally, one NYVAC-C-KC vector was generated by deleting the viral gene B19R, an inhibitor of the type I interferon response (NYVAC-C-KC-ΔB19R). An immunization protocol mimicking that of the RV144 phase III clinical trial was used. Two groups of macaques received two doses of the corresponding NYVAC-C-KC vectors (weeks 0 and 4) and booster doses with NYVAC-C-KC vectors plus the clade C HIV-1 gp120 protein (weeks 12 and 24). The two replicating NYVAC-C-KC vectors induced enhanced and similar HIV-1-specific CD4+ and CD8+ T cell responses, similar levels of binding IgG antibodies, low levels of IgA antibodies, and high levels of antibody-dependent cellular cytotoxicity responses and HIV-1-neutralizing antibodies. Small differences within the NYVAC-C-KC-ΔB19R group were seen in the magnitude of CD4+ and CD8+ T cells, the induction of some cytokines, and the neutralization of some HIV-1 isolates. Thus, replication-competent NYVAC-C-KC vectors acquired relevant immunological properties as vaccine candidates against HIV/AIDS, and the viral B19 molecule exerts some control of immune functions. IMPORTANCE It is of special importance to find a safe and effective HIV/AIDS vaccine that can induce strong and broad T cell and humoral immune responses correlating with HIV-1 protection. Here we developed novel replicating poxvirus NYVAC-based HIV/AIDS vaccine candidates expressing clade C HIV-1 antigens, with one of them lacking the vaccinia virus B19 protein, an inhibitor of the type I interferon response. Immunization of nonhuman primates with these novel NYVAC-C-KC vectors and the protein component gp120 elicited high levels of T cell and humoral immune responses, with the vector containing a deletion in B19R inducing a trend toward a higher magnitude of CD4+ and CD8+ T cell responses and neutralization of some HIV-1 strains. These poxvirus vectors could be considered HIV/AIDS vaccine candidates based on their activation of potential immune correlates of protection.

scholarly journals Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates

2015 ◽  
Vol 89 (16) ◽  
pp. 8525-8539 ◽  
Author(s):  
Juan García-Arriaza ◽  
Beatriz Perdiguero ◽  
Jonathan Heeney ◽  
Michael Seaman ◽  
David C. Montefiori ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Nonhuman Primates ◽  
Humoral Immune ◽  
Aids Vaccine ◽  
Humoral Immune Responses ◽  
Gp120 Protein ◽  
Clade C ◽  
Hiv 1 ◽  
Hiv Aids

ABSTRACTWe compared the HIV-1-specific cellular and humoral immune responses elicited in rhesus macaques immunized with two poxvirus vectors (NYVAC and ALVAC) expressing the same HIV-1 antigens from clade C, Env gp140 as a trimeric cell-released protein and a Gag-Pol-Nef polyprotein as Gag-induced virus-like particles (VLPs) (referred to as NYVAC-C and ALVAC-C). The immunization protocol consisted of two doses of the corresponding poxvirus vector plus two doses of a combination of the poxvirus vector and a purified HIV-1 gp120 protein from clade C. This immunogenicity profile was also compared to that elicited by vaccine regimens consisting of two doses of the ALVAC vector expressing HIV-1 antigens from clades B/E (ALVAC-vCP1521) plus two doses of a combination of ALVAC-vCP1521 and HIV-1 gp120 protein from clades B/E (similar to the RV144 trial regimen) or clade C. The results showed that immunization of macaques with NYVAC-C stimulated at different times more potent HIV-1-specific CD4+T-cell responses and induced a trend toward higher-magnitude HIV-1-specific CD8+T-cell immune responses than did ALVAC-C. Furthermore, NYVAC-C induced a trend toward higher levels of binding IgG antibodies against clade C HIV-1 gp140, gp120, or murine leukemia virus (MuLV) gp70-scaffolded V1/V2 and toward best cross-clade-binding IgG responses against HIV-1 gp140 from clades A, B, and group M consensus, than did ALVAC-C. Of the linear binding IgG responses, most were directed against the V3 loop in all immunization groups. Additionally, NYVAC-C and ALVAC-C also induced similar levels of HIV-1-neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC) responses. Interestingly, binding IgA antibody levels against HIV-1 gp120 or MuLV gp70-scaffolded V1/V2 were absent or very low in all immunization groups. Overall, these results provide a comprehensive survey of the immunogenicity of NYVAC versus ALVAC expressing HIV-1 antigens in nonhuman primates and indicate that NYVAC may represent an alternative candidate to ALVAC in the development of a future HIV-1 vaccine.IMPORTANCEThe finding of a safe and effective HIV/AIDS vaccine immunogen is one of the main research priorities. Here, we generated two poxvirus-based HIV vaccine candidates (NYVAC and ALVAC vectors) expressing the same clade C HIV-1 antigens in separate vectors, and we analyzed in nonhuman primates their immunogenicity profiles. The results showed that immunization with NYVAC-C induced a trend toward higher HIV-1-specific cellular and humoral immune responses than did ALVAC-C, indicating that this new NYVAC vector could be a novel optimized HIV/AIDS vaccine candidate for human clinical trials.

Generation and immunogenicity of novel HIV/AIDS vaccine candidates targeting HIV-1 Env/Gag-Pol-Nef antigens of clade C

Vaccine ◽  
2007 ◽  
Vol 25 (11) ◽  
pp. 1969-1992 ◽  
Author(s):  
Carmen Elena Gómez ◽  
Jose Luis Nájera ◽  
Victoria Jiménez ◽  
Kurt Bieler ◽  
Jens Wild ◽  
...  
Keyword(s):  
Vaccine Candidates ◽  
Aids Vaccine ◽  
Clade C ◽  
Hiv 1 ◽  
Hiv Aids

scholarly journals Absence of cGAS-mediated type I IFN responses in HIV-1–infected T cells

2020 ◽  
Vol 117 (32) ◽  
pp. 19475-19486
Author(s):  
Carina Elsner ◽  
Aparna Ponnurangam ◽  
Julia Kazmierski ◽  
Thomas Zillinger ◽  
Jenny Jansen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Plasmid Dna ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
T Cell Lines ◽  
Hiv 1 ◽  
Dependent Type

The DNA sensor cGAS catalyzes the production of the cyclic dinucleotide cGAMP, resulting in type I interferon responses. We addressed the functionality of cGAS-mediated DNA sensing in human and murine T cells. Activated primary CD4+T cells expressed cGAS and responded to plasmid DNA by upregulation of ISGs and release of bioactive interferon. In mouse T cells, cGAS KO ablated sensing of plasmid DNA, and TREX1 KO enabled cells to sense short immunostimulatory DNA. Expression ofIFIT1andMX2was downregulated and upregulated in cGAS KO and TREX1 KO T cell lines, respectively, compared to parental cells. Despite their intact cGAS sensing pathway, human CD4+T cells failed to mount a reverse transcriptase (RT) inhibitor-sensitive immune response following HIV-1 infection. In contrast, infection of human T cells with HSV-1 that is functionally deficient for the cGAS antagonist pUL41 (HSV-1ΔUL41N) resulted in a cGAS-dependent type I interferon response. In accordance with our results in primary CD4+T cells, plasmid challenge or HSV-1ΔUL41N inoculation of T cell lines provoked an entirely cGAS-dependent type I interferon response, including IRF3 phosphorylation and expression of ISGs. In contrast, no RT-dependent interferon response was detected following transduction of T cell lines with VSV-G-pseudotyped lentiviral or gammaretroviral particles. Together, T cells are capable to raise a cGAS-dependent cell-intrinsic response to both plasmid DNA challenge or inoculation with HSV-1ΔUL41N. However, HIV-1 infection does not appear to trigger cGAS-mediated sensing of viral DNA in T cells, possibly by revealing viral DNA of insufficient quantity, length, and/or accessibility to cGAS.

scholarly journals Alteration of type I interferon response is associated with subclinical atherosclerosis in virologically suppressed HIV‐1‐infected male patients

2021 ◽  
Author(s):  
Letizia Santinelli ◽  
Gabriella De Girolamo ◽  
Cristian Borrazzo ◽  
Paolo Vassalini ◽  
Claudia Pinacchio ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Subclinical Atherosclerosis ◽  
Interferon Response ◽  
Type I ◽  
Infected Male ◽  
Male Patients ◽  
Hiv 1

scholarly journals A compartmentalized type I interferon response in the gut during chronic HIV-1 infection is associated with immunopathogenesis

AIDS ◽  
2018 ◽  
Vol 32 (12) ◽  
pp. 1599-1611 ◽  
Author(s):  
Stephanie M. Dillon ◽  
Kejun Guo ◽  
Gregory L. Austin ◽  
Sara Gianella ◽  
Phillip A. Engen ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Hiv 1

scholarly journals Early type I Interferon response induces upregulation of human β-defensin 1 during acute HIV-1 infection

PLoS ONE ◽  
2017 ◽  
Vol 12 (3) ◽  
pp. e0173161 ◽  
Author(s):  
Björn Corleis ◽  
Antonella C. Lisanti ◽  
Christian Körner ◽  
Abigail E. Schiff ◽  
Eric S. Rosenberg ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Early Type ◽  
Acute Hiv ◽  
Hiv 1

scholarly journals Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

2018 ◽  
Author(s):  
Shaylynn Miller ◽  
Patrick Coit ◽  
Elizabeth Gensterblum-Miller ◽  
Paul Renauer ◽  
Nathan C Kilian ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide

AbstractObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from lupus patients and controls, and investigated the functional relevance of some of these changes in lupus.MethodsGenome-wide DNA methylation of lupus and age, sex, and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR.ResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared to healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. Co-incubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69, in lupus patients but not in healthy controls. This can be blocked by neutralizing antibodies targeting HLA-DR.ConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in lupus patients. A possible pathogenic role for CD8+ T cells in lupus that is dependent upon a high type-I interferon environment and epigenetic priming warrants further characterization.

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