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1.
Samantha J. Westrop Nadeem A. Qazi Jeffrey Pido-Lopez Mark R. Nelson Brian Gazzard Frances M. Gotch Nesrina Imami 《PloS one》2009,4(5)
Background
HIV-1+ individuals who, without therapy, conserve cellular anti-HIV-1 responses, present with high, stable CD4+ T-cell numbers, and control viral replication, facilitate analysis of atypical viro-immunopathology. In the absence of universal definition, immune function in such HIV controllers remains an indication of non-progression.Methodology/Principal Findings
CD4 T-cell responses to a number of HIV-1 proteins and peptide pools were assessed by IFN-γ ELISpot and lymphoproliferative assays in HIV controllers and chronic progressors. Thymic output was assessed by sjTRECs levels. Follow-up of 41 HIV-1+ individuals originally identified as “Long-term non-progressors” in 1996 according to clinical criteria, and longitudinal analysis of two HIV controllers over 22 years, was also performed. HIV controllers exhibited substantial IFN-γ producing and proliferative HIV-1-specific CD4 T-cell responses to both recombinant proteins and peptide pools of Tat, Rev, Nef, Gag and Env, demonstrating functional processing and presentation. Conversely, HIV-specific T-cell responses were limited to IFN-γ production in chronic progressors. Additionally, thymic output was approximately 19 fold higher in HIV controllers than in age-matched chronic progressors. Follow-up of 41 HIV-1+ patients identified as LTNP in 1996 revealed the transitory characteristics of this status. IFN-γ production and proliferative T-cell function also declines in 2 HIV controllers over 22 years.Conclusions
Although increased thymic output and anti-HIV-1 T-cell responses are observed in HIV controllers compared to chronic progressors, the nature of nonprogressor/controller status appears to be transitory. 相似文献2.
Rafael Ribeiro Almeida Daniela Santoro Rosa Susan Pereira Ribeiro Vinicius Canato Santana Esper Georges Kallás John Sidney Alessandro Sette Jorge Kalil Edecio Cunha-Neto 《PloS one》2012,7(9)
T-cell based vaccine approaches have emerged to counteract HIV-1/AIDS. Broad, polyfunctional and cytotoxic CD4+ T-cell responses have been associated with control of HIV-1 replication, which supports the inclusion of CD4+ T-cell epitopes in vaccines. A successful HIV-1 vaccine should also be designed to overcome viral genetic diversity and be able to confer immunity in a high proportion of immunized individuals from a diverse HLA-bearing population. In this study, we rationally designed a multiepitopic DNA vaccine in order to elicit broad and cross-clade CD4+ T-cell responses against highly conserved and promiscuous peptides from the HIV-1 M-group consensus sequence. We identified 27 conserved, multiple HLA-DR-binding peptides in the HIV-1 M-group consensus sequences of Gag, Pol, Nef, Vif, Vpr, Rev and Vpu using the TEPITOPE algorithm. The peptides bound in vitro to an average of 12 out of the 17 tested HLA-DR molecules and also to several molecules such as HLA-DP, -DQ and murine IAb and IAd. Sixteen out of the 27 peptides were recognized by PBMC from patients infected with different HIV-1 variants and 72% of such patients recognized at least 1 peptide. Immunization with a DNA vaccine (HIVBr27) encoding the identified peptides elicited IFN-γ secretion against 11 out of the 27 peptides in BALB/c mice; CD4+ and CD8+ T-cell proliferation was observed against 8 and 6 peptides, respectively. HIVBr27 immunization elicited cross-clade T-cell responses against several HIV-1 peptide variants. Polyfunctional CD4+ and CD8+ T cells, able to simultaneously proliferate and produce IFN-γ and TNF-α, were also observed. This vaccine concept may cope with HIV-1 genetic diversity as well as provide increased population coverage, which are desirable features for an efficacious strategy against HIV-1/AIDS. 相似文献
3.
Role of human immunodeficiency virus (HIV)-specific T-cell immunity in control of dual HIV-1 and HIV-2 infection 总被引:2,自引:0,他引:2 下载免费PDF全文
Zheng NN McElrath MJ Sow PS Hawes SE Diallo-Agne H Stern JE Li F Mesher AL Robinson AD Gottlieb GS Huang Y Kiviat NB 《Journal of virology》2007,81(17):9061-9071
Progressive immune dysfunction and AIDS develop in most cases of human immunodeficiency virus type 1 (HIV-1) infection but in only 25 to 30% of persons with HIV-2 infection. However, the natural history and immunologic responses of individuals with dual HIV-1 and HIV-2 infection are largely undefined. Based on our previous findings, we hypothesized that among patients with dual infection the control of HIV-1 is associated with the ability to respond to HIV-2 Gag epitopes and to maintain HIV-specific CD4+ T-cell responses. To test this, we compared the HIV-specific ex vivo IFN-γ enzyme-linked immunospot (ELISPOT) assay responses of 19 dually infected individuals to those of persons infected with HIV-1 or HIV-2 only. Further, we assessed the functional profile of HIV Gag-specific CD4+ and CD8+ T cells from nine HIV dually infected patients by using a multicolor intracellular cytokine staining assay. As determined by ELISPOT assay, the magnitude and frequency of IFN-γ-secreting T-cell responses to gene products of HIV-1 were higher than those to gene products of HIV-2 (2.64 versus 1.53 log10 IFN-γ spot-forming cells/106 cells [90% versus 63%, respectively].) Further, HIV-1 Env-, Gag-, and Nef- and HIV-2 Gag-specific responses were common; HIV-2 Nef-specific responses were rare. HIV-specific CD4+ T helper responses were detected in nine of nine dually infected subjects, with the majority of these T cells producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) and, to a lesser extent, interleukin-2. The HIV-1 plasma viral load was inversely correlated with HIV-2 Gag-specific IFN-γ-/TNF-α-secreting CD4+ and HIV-2 Gag-specific IFN-γ-secreting CD8+ T cells. In conclusion, the T-cell memory responses associated with containment of single HIV-1 and HIV-2 infection play a similar significant role in the immune control of dual HIV-1 and HIV-2 infection. 相似文献
4.
Gregory G. Simon Yongli Hu Asif M. Khan Jingshi Zhou Jerome Salmon Priya R. Chikhlikar Keun-Ok Jung Ernesto T. A. Marques J. Thomas August 《PloS one》2010,5(1)
This report describes the identification and bioinformatics analysis of HLA-DR4-restricted HIV-1 Gag epitope peptides, and the application of dendritic cell mediated immunization of DNA plasmid constructs. BALB/c (H-2d) and HLA-DR4 (DRA1*0101, DRB1*0401) transgenic mice were immunized with immature dendritic cells transfected by a recombinant DNA plasmid encoding the lysosome-associated membrane protein-1/HIV-1 Gag (pLAMP/gag) chimera antigen. Three immunization protocols were compared: 1) primary subcutaneous immunization with 1×105 immature dendritic cells transfected by electroporation with the pLAMP/gag DNA plasmid, and a second subcutaneous immunization with the naked pLAMP/gag DNA plasmid; 2) primary immunization as above, and a second subcutaneous immunization with a pool of overlapping peptides spanning the HIV-1 Gag sequence; and 3) immunization twice by subcutaneous injection of the pLAMP/gag DNA plasmid. Primary immunization with pLAMP/gag-transfected dendritic cells elicited the greatest number of peptide specific T-cell responses, as measured by ex vivo IFN-γ ELISpot assay, both in BALB/c and HLA-DR4 transgenic mice. The pLAMP/gag-transfected dendritic cells prime and naked DNA boost immunization protocol also resulted in an increased apparent avidity of peptide in the ELISpot assay. Strikingly, 20 of 25 peptide-specific T-cell responses in the HLA-DR4 transgenic mice contained sequences that corresponded, entirely or partially to 18 of the 19 human HLA-DR4 epitopes listed in the HIV molecular immunology database. Selection of the most conserved epitope peptides as vaccine targets was facilitated by analysis of their representation and variability in all reported sequences. These data provide a model system that demonstrates a) the superiority of immunization with dendritic cells transfected with LAMP/gag plasmid DNA, as compared to naked DNA, b) the value of HLA transgenic mice as a model system for the identification and evaluation of epitope-based vaccine strategies, and c) the application of variability analysis across reported sequences in public databases for selection of historically conserved HIV epitopes as vaccine targets. 相似文献
5.
Vinicius Canato Santana Rafael Ribeiro Almeida Susan Pereira Ribeiro Luís Carlos de Souza Ferreira Jorge Kalil Daniela Santoro Rosa Edecio Cunha-Neto 《Memórias do Instituto Oswaldo Cruz》2015,110(8):1010-1016
T-cell based vaccines against human immunodeficiency virus (HIV) generate specific
responses that may limit both transmission and disease progression by controlling
viral load. Broad, polyfunctional, and cytotoxic CD4+T-cell responses have
been associated with control of simian immunodeficiency virus/HIV-1 replication,
supporting the inclusion of CD4+ T-cell epitopes in vaccine formulations.
Plasmid-encoded granulocyte-macrophage colony-stimulating factor (pGM-CSF)
co-administration has been shown to induce potent CD4+ T-cell responses
and to promote accelerated priming and increased migration of antigen-specific
CD4+ T-cells. However, no study has shown whether co-immunisation with
pGM-CSF enhances the number of vaccine-induced polyfunctional CD4+
T-cells. Our group has previously developed a DNA vaccine encoding conserved,
multiple human leukocyte antigen (HLA)-DR binding HIV-1 subtype B peptides, which
elicited broad, polyfunctional and long-lived CD4+ T-cell responses. Here,
we show that pGM-CSF co-immunisation improved both magnitude and quality of
vaccine-induced T-cell responses, particularly by increasing proliferating
CD4+ T-cells that produce simultaneously interferon-γ, tumour necrosis
factor-α and interleukin-2. Thus, we believe that the use of pGM-CSF may be helpful
for vaccine strategies focused on the activation of anti-HIV CD4+ T-cell
immunity. 相似文献
6.
Rajesh Thippeshappa Hongmei Ruan Weiming Wang Paul Zhou Jason T. Kimata 《Journal of virology》2013,87(12):6678-6692
Human immunodeficiency virus type 1 (HIV-1) antagonizes innate restriction factors in order to infect and persistently replicate in a host. In a previous study, we demonstrated that HIV-1 NL4-3 with a simian immunodeficiency virus mne (SIVmne) vif gene substitution (HSIV-vif-NL4-3) could infect and replicate in pig-tailed macaques (PTM), indicating that APOBEC3 proteins are primary barriers to transmission. Because viral replication was persistent but low, we hypothesized that HSIV-vif-NL4-3 may be suppressed by type I interferons (IFN-I), which are known to upregulate the expression of innate restriction factors. Here, we demonstrate that IFN-α more potently suppresses HSIV-vif-NL4-3 in PTM CD4+ T cells than it does pathogenic SIVmne027. Importantly, we identify a variant (HSIV-vif-Yu2) that is resistant to IFN-α, indicating that the IFN-α-induced barrier can be overcome by HSIV-vif chimeras in PTM CD4+ T cells. Interestingly, HSIV-vif-Yu2 and HSIV-vif-NL4-3 are similarly restricted by PTM BST2/Tetherin, and neither virus downregulates it from the surface of infected PTM CD4+ T cells. Resistance to IFN-α-induced restriction appears to be conferred by a determinant in HSIV-vif-Yu2 that includes env su. Finally, we show that the Yu-2 env su allele may overcome an IFN-α-induced barrier to entry. Together, our data demonstrate that the prototype macaque-tropic HIV-1 clones based on NL4-3 may not sufficiently antagonize innate restriction in PTM cells. However, variants with resistance to IFN-α-induced restriction factors in PTM CD4+ T cells may enhance viral replication by overcoming a barrier early in the viral replication cycle. 相似文献
7.
Mahdis Monajemi Claire F. Woodworth Katrin Zipperlen Maureen Gallant Michael D. Grant Mani Larijani 《PloS one》2014,9(4)
Due to constitutive expression in cells targeted by human immunodeficiency virus (HIV), and immediate mode of viral restriction upon HIV entry into the host cell, APOBEC3G (A3G) and APOBEC3F (A3F) have been considered primarily as agents of innate immunity. Recent bioinformatic and mouse model studies hint at the possibility that mutation of the HIV genome by these enzymes may also affect adaptive immunity but whether this occurs in HIV-infected individuals has not been examined. We evaluated whether APOBEC-mediated mutations within common HIV CD8+ T cell epitopes can potentially enhance or diminish activation of HIV-specific CD8+ T cells from infected individuals. We compared ex vivo activation of CD8+ T lymphocytes from HIV-infected individuals by wild type HIV peptide epitopes and synthetic variants bearing simulated A3G/F-induced mutations by measuring interferon-γ (IFN-γ) production. We found that A3G/F-induced mutations consistently diminished HIV-specific CD8+ T cell responses against the common epitopes we tested. If this reflects a significant trend in vivo, then adaptation by HIV to enrich sequences that are favored for mutation by A3G/F (A3G/F hotspots) in portions of its genome that encode immunogenic CD8+ T cell epitopes would favor CTL escape. Indeed, we found the most frequently mutated A3G motif (CCC) is enriched up to 6-fold within viral genomic sequences encoding immunodominant CD8+ T cell epitopes in Gag, Pol and Nef. Within each gene, A3G/F hotspots are more abundant in sequences encoding epitopes that are commonly recognized due to their HLA restriction. Thus, in our system, mutations of the HIV genome, mimicking A3G/F activity, appeared to abrogate or severely reduce CTL recognition. We suggest that the physiological significance of this potential effect in facilitating CTL escape is echoed in the adaptation of the HIV genome to enrich A3G/F hotspots in sequences encoding CTL epitopes that are more immunogenic at the population level. 相似文献
8.
Lingyun Shao Xinyun Zhang Yan Gao Yunya Xu Shu Zhang Shenglei Yu Xinhua Weng Hongbo Shen Zheng W. Chen Weimin Jiang Wenhong Zhang 《PloS one》2016,11(3)
Objective
Detailed studies of correlation between HIV-M.tb co-infection and hierarchy declines of CD8+/CD4+ T-cell counts and IFN-γ responses have not been done. We conducted case-control studies to address this issue.Methods
164 HIV-1-infected individuals comprised of HIV-1+ATB, HIV-1+LTB and HIV-1+TB- groups were evaluated. Immune phenotyping and complete blood count (CBC) were employed to measure CD4+ and CD8+ T-cell counts; T.SPOT.TB and intracellular cytokine staining (ICS) were utilized to detect ESAT6, CFP10 or PPD-specific IFN-γ responses.Results
There were significant differences in median CD4+ T-cell counts between HIV-1+ATB (164/μL), HIV-1+LTB (447/μL) and HIV-1+TB- (329/μL) groups. Hierarchy low CD4+ T-cell counts (<200/μL, 200-500/μL, >500/μL) were correlated significantly with active TB but not M.tb co-infection. Interestingly, hierarchy low CD8+ T-cell counts were not only associated significantly with active TB but also with M.tb co-infection (P<0.001). Immunologically, HIV-1+ATB group showed significantly lower numbers of ESAT-6-/CFP-10-specific IFN-γ+ T cells than HIV-1+LTB group. Consistently, PPD-specific IFN-γ+CD4+/CD8+ T effector cells in HIV-1+ATB group were significantly lower than those in HIV-1+LTB group (P<0.001).Conclusions
Hierarchy low CD8+ T-cell counts and effector function in HIV-1-infected individuals are correlated with both M.tb co-infection and active TB. Hierarchy low CD4+ T-cell counts and Th1 effector function in HIV-1+ individuals are associated with increased frequencies of active TB, but not M.tb co-infection. 相似文献9.
Yue Peng Fan-ching Lin Paulo H. Verardi Leslie A. Jones Tilahun D. Yilma 《Journal of virology》2009,83(4):1592-1601
A vaccine for human immunodeficiency virus (HIV) infection is desperately needed to control the AIDS pandemic. To address this problem, we constructed single-cycle simian immunodeficiency viruses (SIVs) pseudotyped with the glycoprotein of vesicular stomatitis virus and expressing different levels of gamma interferon (IFN-γ) as a potential vaccine strategy. We previously showed that IFN-γ expression by pseudotyped SIVs does not alter viral single-cycle infectivity. T cells primed with dendritic cells transduced by pseudotyped SIVs expressing high levels of IFN-γ had stronger T-cell responses than those primed with dendritic cells transduced by constructs lacking IFN-γ. In the present study, we tested the immunogenicities of these pseudotyped SIVs in a rat model. The construct expressing low levels of rat IFN-γ (dSIVLRγ) induced higher levels of cell-mediated and humoral immune responses than the construct lacking IFN-γ (dSIVR). Rats vaccinated with dSIVLRγ also had lower viral loads than those vaccinated with dSIVR when inoculated with a recombinant vaccinia virus expressing SIV Gag-Pol as a surrogate challenge. The construct expressing high levels of IFN-γ (dSIVHRγ) did not further enhance immunity and was less protective than dSIVLRγ. In conclusion, the data indicated that IFN-γ functioned as an adjuvant to augment antigen-specific immune responses in a dose- and cell type-related manner in vivo. Thus, fine-tuning of the cytokine expression appears to be essential in designing vaccine vectors expressing adjuvant genes such as the gene for IFN-γ. Furthermore, we provide evidence of the utility of the rat model to evaluate the immunogenicities of single-cycle HIV/SIV recombinant vaccines before initiating studies with nonhuman primate models. 相似文献
10.
Bosco Christiano Maciel da Silva Maria Fernanda Rios Grassi Raimundo Coutinho Rita Elizabeth Moreira Mascarenhas Viviana Nilla Olavarria Adriana Coutinho-Borgo Jorge Kalil Edecio Cunha Neto Simone Gon?alves Fonseca 《Memórias do Instituto Oswaldo Cruz》2014,109(8):999-1004
The interferon (IFN)-γ response to peptides can be a useful diagnostic marker of
Mycobacterium tuberculosis (MTB) latent infection. We identified promiscuous and
potentially protective CD4+ T-cell epitopes from the most conserved
regions of MTB antigenic proteins by scanning the MTB antigenic proteins GroEL2,
phosphate-binding protein 1 precursor and 19 kDa antigen with the TEPITOPE algorithm.
Seven peptide sequences predicted to bind to multiple human leukocyte antigen
(HLA)-DR molecules were synthesised and tested with IFN-γ enzyme-linked immunospot
(ELISPOT) assays using peripheral blood mononuclear cells (PBMCs) from 16 Mantoux
tuberculin skin test (TST)-positive and 16 TST-negative healthy donors. Eighty-eight
percent of TST-positive donors responded to at least one of the peptides, compared to
25% of TST-negative donors. Each individual peptide induced IFN-γ production by PBMCs
from at least 31% of the TST-positive donors. The magnitude of the response against
all peptides was 182 ± 230 x 106 IFN-γ spot forming cells (SFC) among
TST-positive donors and 36 ± 62 x 106 SFC among TST-negative donors (p =
0.007). The response to GroEL2 (463-477) was only observed in the TST-positive group.
This combination of novel MTB CD4 T-cell epitopes should be tested in a larger cohort
of individuals with latent tuberculosis (TB) to evaluate its potential to diagnose
latent TB and it may be included in ELISPOT-based IFN-γ assays to identify
individuals with this condition. 相似文献
11.
DNA Vaccination Affords Significant Protection against Feline Immunodeficiency Virus Infection without Inducing Detectable Antiviral Antibodies 总被引:2,自引:1,他引:2 下载免费PDF全文
Margaret J. Hosie J. Norman Flynn Mark A. Rigby Celia Cannon Thomas Dunsford Nancy A. Mackay David Argyle Brian J. Willett Takayuki Miyazawa David E. Onions Oswald Jarrett James C. Neil 《Journal of virology》1998,72(9):7310-7319
To test the potential of a multigene DNA vaccine against lentivirus infection, we generated a defective mutant provirus of feline immunodeficiency virus (FIV) with an in-frame deletion in pol (FIVΔRT). In a first experiment, FIVΔRT DNA was administered intramuscularly to 10 animals, half of which also received feline gamma interferon (IFN-γ) DNA. The DNA was administered in four 100-μg doses at 0, 10, and 23 weeks. Immunization with FIVΔRT elicited cytotoxic T-cell (CTL) responses to FIV Gag and Env in the absence of a serological response. After challenge with homologous virus at week 26, all 10 of the control animals became seropositive and viremic but 4 of the 10 vaccinates remained seronegative and virus free. Furthermore, quantitative virus isolation and quantitative PCR analysis of viral DNA in peripheral blood mononuclear cells revealed significantly lower virus loads in the FIVΔRT vaccinates than in the controls. Immunization with FIVΔRT in conjunction with IFN-γ gave the highest proportion of protected cats, with only two of five vaccinates showing evidence of infection following challenge. In a second experiment involving two groups (FIVΔRT plus IFN-γ and IFN-γ alone), the immunization schedule was reduced to 0, 4, and 8 weeks. Once again, CTL responses were seen prior to challenge in the absence of detectable antibodies. Two of five cats receiving the proviral DNA vaccine were protected against infection, with an overall reduction in virus load compared to the five infected controls. These findings demonstrate that DNA vaccination can elicit protection against lentivirus infection in the absence of a serological response and suggest the need to reconsider efficacy criteria for lentivirus vaccines. 相似文献
12.
Yunda Huang Ann Duerr Nicole Frahm Lily Zhang Zoe Moodie Steve De Rosa M. Juliana McElrath Peter B. Gilbert 《PloS one》2014,9(11)
Background
Elevated risk of HIV-1 infection among recipients of an adenovirus serotype 5 (Ad5)-vectored HIV-1 vaccine was previously reported in the Step HIV-1 vaccine efficacy trial. We assessed pre-infection cellular immune responses measured at 4 weeks after the second vaccination to determine their roles in HIV-1 infection susceptibility among Step study male participants.Methods
We examined ex vivo interferon-γ (IFN-γ) secretion from peripheral blood mononuclear cells (PBMC) using an ELISpot assay in 112 HIV-infected and 962 uninfected participants. In addition, we performed flow cytometric assays to examine T-cell activation, and ex vivo IFN-γ and interleukin-2 secretion from CD4+ and CD8+ T cells. We accounted for the sub-sampling design in Cox proportional hazards models to estimate hazard ratios (HRs) of HIV-1 infection per 1-loge increase of the immune responses.Findings
We found that HIV-specific immune responses were not associated with risk of HIV-1 infection. However, each 1-loge increase of mock responses measured by the ELISpot assay (i.e., IFN-γ secretion in the absence of antigen-specific stimulation) was associated with a 62% increase of HIV-1 infection risk among vaccine recipients (HR = 1.62, 95% CI: (1.28, 2.04), p<0.001). This association remains after accounting for CD4+ or CD8+ T-cell activation. We observed a moderate correlation between ELISpot mock responses and CD4+ T-cells secreting IFN-γ (ρ = 0.33, p = 0.007). In addition, the effect of the Step vaccine on infection risk appeared to vary with ELISpot mock response levels, especially among participants who had pre-existing anti-Ad5 antibodies (interaction p = 0.04).Conclusions
The proportion of cells, likely CD4+ T-cells, producing IFN-γ without stimulation by exogenous antigen appears to carry information beyond T-cell activation and baseline characteristics that predict risk of HIV-1 infection. These results motivate additional investigation to understand the potential link between IFN-γ secretion and underlying causes of elevated HIV-1 infection risk among vaccine recipients in the Step study. 相似文献13.
14.
In recent years, the prevalence of HIV-1 infection has been rapidly increasing among men who have sex with men (MSM). However, it remains unknown how the host immune system responds to the infection in this population. We assessed the quantity of HIV-specific CD8+ T-cell responses by using Elispot assay and their functionalities by measuring 5 CD8+ T-cell evaluations (IL-2, MIP-1β, CD107a, TNF-α, IFN-γ) with flow cytometry assays among 18 primarily and 37 early chronically HIV-infected MSM. Our results demonstrated that subjects at early chronic phase developed HIV-specific CD8+ T-cell responses with higher magnitudes and more diversified functionalities in comparison with those at primary infection. However, populations with IL-2+ CD107a+ or in combination with other functionality failed to develop in parallel. The multifunctional but not monofunctional HIV-specific CD8+ T cells were associated with higher CD4+ T -cell counts and lower viral loads. These data revealed that prolonged infection from primary to early chronic infection could selectively increase the functionalities of HIV-specific CD8+ T cells in HIV-infected MSM population, the failure to develop IL-2 and cytotoxic functionalities in parallel may explain why the increased HIV-specific CD8+ T cells were unable to enhance the containment of HIV-1 replication at the early chronic stage. 相似文献
15.
Mehrnoosh Doroudchi Oleg Yegorov Tom Baumgartner Anne-Elen Kernaleguen Gaelle Breton Michel L. Ndongala Mohamed-Rachid Boulassel Jean-Pierre Routy Nicole F. Bernard Rafick-Pierre Sékaly Bader Yassine-Diab 《PloS one》2012,7(11)
Objective
To determine the function and phenotype of CD8+ T-cells targeting consensus and autologous sequences of entire HIV-1 Nef protein.Methods
Multiparameter flow cytometry-based analysis was used to evaluate the responses of two treatment naïve HIV-infected individuals, during primary and the chronic phases of infection.Results
A greater breadth and magnitude of CD8 IFN-γ responses to autologous compared to clade-B consensus peptides was observed in both subjects. Cross recognition between autologous and consensus peptides decreased in both subjects during progression from primary to chronic infection. The frequencies of TEMRA and TEM CD8+ T-cells targeting autologous peptides were higher than those targeting consensus peptides and were more polyfunctional (IFN-γ+ Gr-B+ CD107a+).Conclusions
Our data indicate superior sensitivity and specificity of autologous peptides. The functional and maturational aspects of “real” versus “cross-recognized” responses were also found to differ, highlighting the importance of a sequence-specific approach towards understanding HIV immune response. 相似文献16.
Kristin G.-I. Mohn Rebecca Jane Cox Gro Tunheim Jan Erik Berdal Anna Germundsson Hauge ?sne Jul-Larsen Norwegian Pandemic Group Bjoern Peters Fredrik Oftung Christine Monceyron Jonassen Siri Mjaaland 《PloS one》2015,10(11)
Increased understanding of immune responses influencing clinical severity during pandemic influenza infection is important for improved treatment and vaccine development. In this study we recruited 46 adult patients during the 2009 influenza pandemic and characterized humoral and cellular immune responses. Those included were either acute hospitalized or convalescent patients with different disease severities (mild, moderate or severe). In general, protective antibody responses increased with enhanced disease severity. In the acute patients, we found higher levels of TNF-α single-producing CD4+T-cells in the severely ill as compared to patients with moderate disease. Stimulation of peripheral blood mononuclear cells (PBMC) from a subset of acute patients with peptide T-cell epitopes showed significantly lower frequencies of influenza specific CD8+ compared with CD4+ IFN-γ T-cells in acute patients. Both T-cell subsets were predominantly directed against the envelope antigens (HA and NA). However, in the convalescent patients we found high levels of both CD4+ and CD8+ T-cells directed against conserved core antigens (NP, PA, PB, and M). The results indicate that the antigen targets recognized by the T-cell subsets may vary according to the phase of infection. The apparent low levels of cross-reactive CD8+ T-cells recognizing internal antigens in acute hospitalized patients suggest an important role for this T-cell subset in protective immunity against influenza. 相似文献
17.
Gray CM Mlotshwa M Riou C Mathebula T de Assis Rosa D Mashishi T Seoighe C Ngandu N van Loggerenberg F Morris L Mlisana K Williamson C Karim SA;CAPRISA Acute Infection Study Team 《Journal of virology》2009,83(1):470-478
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. 相似文献
18.
Human Immunodeficiency Virus Type 1 Escapes from Interleukin-2-Producing CD4+ T-Cell Responses without High-Frequency Fixation of Mutations 下载免费PDF全文
R. Brad Jones Feng-Yun Yue Xiao Xiao Jenny Gu Diana V. Hunter Shariq Mujib Gabor Gyenes Rosemarie D. Mason Ruqaya Mohamed Kelly S. MacDonald Colin Kovacs Mario A. Ostrowski 《Journal of virology》2009,83(17):8722-8732
The presence of interleukin-2 (IL-2)-producing human immunodeficiency virus type 1 (HIV-1)-specific CD4+ T-cell responses has been associated with the immunological control of HIV-1 replication; however, the causal relationship between these factors remains unclear. Here we show that IL-2-producing HIV-1-specific CD4+ T cells can be cloned from acutely HIV-1-infected individuals. Despite the early presence of these cells, each of the individuals in the present study exhibited progressive disease, with one individual showing rapid progression. In this rapid progressor, three IL-2-producing HIV-1 Gag-specific CD4+ T-cell responses were identified and mapped to the following optimal epitopes: HIVWASRELER, REPRGSDIAGT, and FRDYVDRFYKT. Responses to these epitopes in peripheral blood mononuclear cells were monitored longitudinally to >1 year postinfection, and contemporaneous circulating plasma viruses were sequenced. A variant of the FRDYVDRFYKT epitope sequence, FRDYVDQFYKT, was observed in 1/21 plasma viruses sequenced at 5 months postinfection and 1/10 viruses at 7 months postinfection. This variant failed to stimulate the corresponding CD4+ T-cell clone and thus constitutes an escape mutant. Responses to each of the three Gag epitopes were rapidly lost, and this loss was accompanied by a loss of antigen-specific cells in the periphery as measured by using an FRDYVDRFYKT-presenting major histocompatibility complex class II tetramer. Highly active antiretroviral therapy was associated with the reemergence of FRDYVDRFYKT-specific cells by tetramer. Thus, our data support that IL-2-producing HIV-1-specific CD4+ T-cell responses can exert immune pressure during early HIV-1 infection but that the inability of these responses to enforce enduring control of viral replication is related to the deletion and/or dysfunction of HIV-1-specific CD4+ T cells rather than to the fixation of escape mutations at high frequencies.In the typical course of acute human immunodeficiency virus type 1 (HIV-1) infection an initial burst of high-level viremia is reduced by at least 100-fold to a set point level (11, 12). This precipitous drop in viral load is suggestive of a partially effective host immune response to primary HIV-1 infection. Several lines of evidence support an important role for CD8+ T cells in suppressing HIV-1 replication in acute infection: principally, the decline in HIV-1 viremia is temporally associated with the emergence of an HIV-1-specific CD8+ T-cell response, and the in vivo depletion of CD8+ T cells in simian immunodeficiency virus-infected macaques consistently results in elevated viral loads (7, 24, 30). Consistent with the application of effective immune pressure, it has been well established that HIV-1- and simian immunodeficiency virus-specific CD8+ T cells drive the emergence and fixation of escape mutations in the epitopes that they target (1, 3, 8, 18, 31, 33, 34). This evidence has contributed to the prioritization of vaccine candidates that elicit potent HIV-1-specific CD8+ T-cell responses.The role of CD4+ T-cell responses in the response to acute HIV-1 infection is less clear. There is compelling evidence that CD4+ T-cell help may be critical for the establishment of a qualitatively and quantitatively robust CD8+ T-cell memory pool for persistent virus infections (4, 9, 17, 37, 39). Furthermore, an important role for CD4+ help in maintaining an effective CD8+ T-cell response has been established in the lymphocytic choriomeningitis virus model of chronic viral infection (28, 45). Evidence in support of a role for the CD4+ T-cell response to HIV-1 infection in suppressing viral replication is derived from studies which demonstrated that a CD4+ T-cell response characterized by vigorous proliferation and production of interleukin-2 (IL-2) is associated with control of viremia (6, 35). It has further been demonstrated that the functional defect of CD8+ T cells observed in chronic HIV-1 infection can be induced in vitro by the depletion of CD4+ T cells or the addition of IL-2-neutralizing antibodies and can be corrected in vivo by vaccine-mediated augmentation of HIV-1-specific CD4+ T-cell responses (26). These observations have suggested that an IL-2-producing response may be necessary for controlling viremia. However, in the majority of HIV-1-infected individuals, a qualitative impairment of the HIV-1-specific CD4+ T-cell response occurs early after infection, resulting in the loss of proliferative capacity as well as the ability to produce IL-2 (43). This impairment correlates well with levels of antigen and viremia (29). The relationship between viral control and the presence of IL-2-producing HIV-specific CD4+ T-cell responses must be interpreted with caution, however, as the causal relationship between these two factors is unclear. The maintenance of an IL-2-producing HIV-1-specific CD4+ T-cell proliferative response could simply be the result of control of viremia achieved through another means, rather than causal in the association. Therapeutic administration of IL-2 to chronically infected individuals failed to reveal any clinical benefit, perhaps supporting that IL-2 is a marker, rather than a driver, of immunological control (25). However, it is unclear whether the systemic administration of IL-2 effectively substitutes for the targeted production of IL-2 by HIV-1-specific CD4+ T cells.The fixation of escape mutations in CD4+ T-cell epitopes during acute infection would provide direct evidence that CD4+ T cells apply immunological pressure against HIV-1. Harcourt et al. identified epitopes targeted by proliferative CD4+ T-cell responses in chronically infected individuals and sequenced these epitopes from proviral DNA at multiple time points (16). Variations in these epitope sequences were observed over time, and a minority of these variants failed to stimulate CD4+ T-cell lines raised against the index peptide. This study indicated the potential for HIV-1 virus to escape within proviral populations. However, the observation that the majority of emergent variants were still able to stimulate CD4+ T-cell responses argues against potent selective pressure for escape mutants (16). A second study examined gamma interferon (IFN-γ)-producing CD4+ T-cell responses and contemporaneous circulating virus epitopes in a cohort of chronically infected, untreated, HIV-1-infected individuals. A lack of intrapatient variability within CD4+ T-cell epitopes was observed in this study, and while two of four subjects exhibited epitope sequences that differed from the consensus HIV-1 sequence, there was a trend to greater sequence variability outside of epitopic regions, arguing against potent immune pressure (23). These studies support that HIV-1-specific CD4+ T-cell responses fail to exert potent selective pressure against cognate epitopes in chronic infection; however, it is difficult to determine whether or not the observed epitopic variations are indicative of relatively weak selective pressures. Since the overall cellular immune response to HIV-1 infection is particularly robust and effective during the acute phase of infection, we examined the kinetics of the HIV-1-specific IL-2-secreting CD4+ T-cell-mediated immune response during acute/early HIV-1 infection and studied the effects of this response on circulating plasma viruses. 相似文献
19.
Mohamed Abdel-Mohsen Xutao Deng Teri Liegler John C. Guatelli Mohamed S. Salama Hussam El-din A. Ghanem Andri Rauch Bruno Ledergerber Steven G. Deeks Huldrych F. Günthard Joseph K. Wong Satish K. Pillai 《Journal of virology》2014,88(1):763-767
Alpha interferon (IFN-α) suppresses human immunodeficiency virus type 1 (HIV-1) replication in vitro by inducing cell-intrinsic retroviral restriction mechanisms. We investigated the effects of IFN-α/ribavirin (IFN-α/riba) treatment on 34 anti-HIV-1 restriction factors in vivo. Expression of several anti-HIV-1 restriction factors was significantly induced by IFN-α/riba in HIV/hepatitis C virus (HCV)-coinfected individuals. Fold induction of cumulative restriction factor expression in CD4+ T cells was significantly correlated with viral load reduction during IFN-α/riba treatment (r2 = 0.649; P < 0.016). Exogenous IFN-α induces supraphysiologic restriction factor expression associated with a pronounced decrease in HIV-1 viremia. 相似文献
20.
Gastrointestinal T Lymphocytes Retain High Potential for Cytokine Responses but Have Severe CD4+ T-Cell Depletion at All Stages of Simian Immunodeficiency Virus Infection Compared to Peripheral Lymphocytes 下载免费PDF全文
Zeljka Smit-McBride Joseph J. Mattapallil Michael McChesney David Ferrick Satya Dandekar 《Journal of virology》1998,72(8):6646-6656
Gastrointestinal complications in human immunodeficiency virus (HIV) infection are indicative of impaired intestinal mucosal immune system. We used simian immunodeficiency virus (SIV)-infected rhesus macaques as an animal model for HIV to determine pathogenic effects of SIV on intestinal T lymphocytes. Intestinal CD4+ T-cell depletion and the potential for cytokine responses were examined during SIV infection and compared with results for lymphocytes from lymph nodes and blood. Flow cytometric analysis demonstrated severe depletion of CD4+CD8− single-positive T cells and CD4+CD8+ double-positive T cells in intestinal lamina propria lymphocytes (LPL) and intraepithelial lymphocytes (IEL) during primary SIV infection which persisted through the entire course of SIV infection. In contrast, CD4+ T-cell depletion was gradual in peripheral lymph nodes and blood. Flow cytometric analysis of intracellular gamma interferon (IFN-γ) and interleukin-4 (IL-4) production following short-term mitogenic activation revealed that LPL retained same or higher capacity for IFN-γ production in all stages of SIV infection compared to uninfected controls, whereas peripheral blood mononuclear cells displayed a gradual decline. The CD8+ T cells were the major producers of IFN-γ. There was no detectable change in the frequency of IL-4-producing cells in both LPL and peripheral blood mononuclear cells. Thus, severe depletion of CD4+ LPL and IEL in primary SIV infection accompanied by altered cytokine responses may reflect altered T-cell homeostasis in intestinal mucosa. This could be a mechanism of SIV-associated enteropathy and viral pathogenesis. Dynamic changes in intestinal T lymphocytes were not adequately represented in peripheral lymph nodes or blood. 相似文献