scholarly journals Dynamics of T-Cell Responses and Memory T Cells during Primary Simian Immunodeficiency Virus Infection in Cynomolgus Macaques

2007 ◽  
Vol 81 (24) ◽  
pp. 13456-13468 ◽  
Author(s):  
Ingrid Karlsson ◽  
Benoît Malleret ◽  
Patricia Brochard ◽  
Benoît Delache ◽  
Julien Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Peripheral Blood ◽  
Primary Infection ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Cynomolgus Macaques ◽  
Cellular Immune

ABSTRACT Cellular immune responses make an important contribution to both the control of human immunodeficiency virus (HIV) replication and disease progression. We used a pathogenic model of SIVmac251 infection of cynomolgus macaques to longitudinally evaluate cellular immune responses in association with various rates of disease progression. We found an inverse relationship between plasma viral load and the simian immunodeficiency virus (SIV)-specific T cells responses in peripheral blood and lymph nodes. SIV-specific T-cell responses in peripheral blood were transient during primary infection, with the highest responses detected around 3 months after infection. There was also a transient increase of central memory CD8+ T cells in peripheral blood during primary infection, and effector memory T-cell counts in peripheral lymph nodes were increased. This study emphasizes the importance of the early virus-specific immune responses in the outcome of HIV/SIV disease and provides details about the changes of virus-specific immune responses over time.

scholarly journals Baseline Levels of Influenza-Specific B Cells and T Cell Responses Modulate Human Immune Responses to Swine Variant Influenza A/H3N2 Vaccine

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 126
Author(s):  
Lilin Lai ◽  
Nadine Rouphael ◽  
Yongxian Xu ◽  
Amy C. Sherman ◽  
Srilatha Edupuganti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza A ◽  
Vaccine Dose ◽  
T Cell Responses ◽  
Post Vaccination ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune

The cellular immune responses elicited by an investigational vaccine against an emergent variant of influenza (H3N2v) are not fully understood. Twenty-five subjects, enrolled in an investigational influenza A/H3N2v vaccine study, who received two doses of vaccine 21 days apart, were included in a sub-study of cellular immune responses. H3N2v-specific plasmablasts were determined by ELISpot 8 days after each vaccine dose and H3N2v specific CD4+ T cells were quantified by intracellular cytokine and CD154 (CD40 ligand) staining before vaccination, 8 and 21 days after each vaccine dose. Results: 95% (19/20) and 96% (24/25) subjects had pre-existing H3N2v specific memory B, and T cell responses, respectively. Plasmablast responses at Day 8 after the first vaccine administration were detected against contemporary H3N2 strains and correlated with hemagglutination inhibition HAI (IgG: p = 0.018; IgA: p < 0.001) and Neut (IgG: p = 0.038; IgA: p = 0.021) titers and with memory B cell frequency at baseline (IgA: r = 0.76, p < 0.001; IgG: r = 0.74, p = 0.0001). The CD4+ T cells at Days 8 and 21 expanded after prime vaccination and this expansion correlated strongly with early post-vaccination HAI and Neut titers (p ≤ 0.002). In an adult population, the rapid serological response observed after initial H3N2v vaccination correlates with post-vaccination plasmablasts and CD4+ T cell responses.

scholarly journals A Soluble Version of Nipah Virus Glycoprotein G Delivered by Vaccinia Virus MVA Activates Specific CD8 and CD4 T Cells in Mice

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 26 ◽  
Author(s):  
Georgia Kalodimou ◽  
Svenja Veit ◽  
Sylvia Jany ◽  
Ulrich Kalinke ◽  
Christopher C. Broder ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
G Protein ◽  
Nipah Virus ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Glycoprotein G ◽  
Cellular Immune

Nipah virus (NiV) is an emerging zoonotic virus that is transmitted by bats to humans and to pigs, causing severe respiratory disease and often fatal encephalitis. Antibodies directed against the NiV-glycoprotein (G) protein are known to play a major role in clearing NiV infection and in providing vaccine-induced protective immunity. More recently, T cells have been also shown to be involved in recovery from NiV infection. So far, relatively little is known about the role of T cell responses and the antigenic targets of NiV-G that are recognized by CD8 T cells. In this study, NiV-G protein served as the target immunogen to activate NiV-specific cellular immune responses. Modified Vaccinia virus Ankara (MVA), a safety-tested strain of vaccinia virus for preclinical and clinical vaccine research, was used for the generation of MVA–NiV-G candidate vaccines expressing different versions of recombinant NiV-G. Overlapping peptides covering the entire NiV-G protein were used to identify major histocompatibility complex class I/II-restricted T cell responses in type I interferon receptor-deficient (IFNAR−/−) mice after vaccination with the MVA–NiV-G candidate vaccines. We have identified an H2-b-restricted nonamer peptide epitope with CD8 T cell antigenicity and a H2-b 15mer with CD4 T cell antigenicity in the NiV-G protein. The identification of this epitope and the availability of the MVA–NiV-G candidate vaccines will help to evaluate NiV-G-specific immune responses and the potential immune correlates of vaccine-mediated protection in the appropriate murine models of NiV-G infection. Of note, a soluble version of NiV-G was advantageous in activating NiV-G-specific cellular immune responses using these peptides.

scholarly journals Magnitude and Quality of Vaccine-Elicited T-Cell Responses in the Control of Immunodeficiency Virus Replication in Rhesus Monkeys

2008 ◽  
Vol 82 (17) ◽  
pp. 8812-8819 ◽  
Author(s):  
Yue Sun ◽  
Sampa Santra ◽  
Jörn E. Schmitz ◽  
Mario Roederer ◽  
Norman L. Letvin
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Rhesus Monkeys ◽  
T Cell Responses ◽  
Viral Control ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Cellular Immune ◽  
Functional Profiles

ABSTRACT While a diversity of immunogens that elicit qualitatively different cellular immune responses are being assessed in clinical human immunodeficiency virus vaccine trials, the consequences of those varied responses for viral control remain poorly understood. In the present study, we evaluated the induction of virus-specific T-cell responses in rhesus monkeys using a series of diverse vaccine vectors. We assessed both the magnitude and the functional profile of the virus-specific CD8+ T cells by measuring gamma interferon, interleukin-2, and tumor necrosis factor alpha production. We found that the different vectors generated virus-specific T-cell responses of different magnitudes and with different functional profiles. Heterologous prime-boost vaccine regimens induced particularly high-frequency virus-specific T-cell responses with polyfunctional repertoires. Yet, immediately after a pathogenic simian-human immunodeficiency virus (SHIV) challenge, no significant differences were observed between these cohorts of vaccinated monkeys in the magnitudes or the functional profiles of their virus-specific CD8+ T cells. This finding suggests that the high viral load shapes the functional repertoire of the cellular immune response during primary infection. Nevertheless, in all vaccination regimens, higher frequency and more polyfunctional vaccine-elicited virus-specific CD8+ T-cell responses were associated with better viral control after SHIV challenge. These observations highlight the contributions of both the quality and the magnitude of vaccine-elicited cellular immune responses in the control of immunodeficiency virus replication.

scholarly journals Transmitted/Founder Viruses Rapidly Escape from CD8+T Cell Responses in Acute Hepatitis C Virus Infection

2015 ◽  
Vol 89 (10) ◽  
pp. 5478-5490 ◽  
Author(s):  
Rowena A. Bull ◽  
Preston Leung ◽  
Silvana Gaudieri ◽  
Pooja Deshpande ◽  
Barbara Cameron ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Immune Responses ◽  
Primary Infection ◽  
T Cell Responses ◽  
Viral Population ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune

ABSTRACTThe interaction between hepatitis C virus (HCV) and cellular immune responses during very early infection is critical for disease outcome. To date, the impact of antigen-specific cellular immune responses on the evolution of the viral population establishing infection and on potential escape has not been studied. Understanding these early host-virus dynamics is important for the development of a preventative vaccine. Three subjects who were followed longitudinally from the detection of viremia preseroconversion until disease outcome were analyzed. The evolution of transmitted/founder (T/F) viruses was undertaken using deep sequencing. CD8+T cell responses were measured via enzyme-linked immunosorbent spot (ELISpot) assay using HLA class I-restricted T/F epitopes. T/F viruses were rapidly extinguished in all subjects associated with either viral clearance (n= 1) or replacement with viral variants leading to establishment of chronic infection (n= 2). CD8+T cell responses against 11 T/F epitopes were detectable by 33 to 44 days postinfection, and 5 of these epitopes had not previously been reported. These responses declined rapidly in those who became chronically infected and were maintained in the subject who cleared infection. Higher-magnitude CD8+T cell responses were associated with rapid development of immune escape variants at a rate of up to 0.1 per day. Rapid escape from CD8+T cell responses has been quantified for the first time in the early phase of primary HCV infection. These rapid escape dynamics were associated with higher-magnitude CD8+T cell responses. These findings raise questions regarding optimal selection of immunogens for HCV vaccine development and suggest that detailed analysis of individual epitopes may be required.IMPORTANCEA major limitation in our detailed understanding of the role of immune response in HCV clearance has been the lack of data on very early primary infection when the transmitted viral variants successfully establish the acute infection. This study was made possible through the availability of specimens from a unique cohort of asymptomatic primary infection cases in whom the first available viremic samples were collected approximately 3 weeks postinfection and at regular intervals thereafter. The study included detailed examination of both the evolution of the viral population and the host cellular immune responses against the T/F viruses. The findings here provide the first evidence of host cellular responses targeting T/F variants and imposing a strong selective force toward viral escape. The results of this study provide useful insight on how virus escapes the host response and consequently on future analysis of vaccine-induced immunity.

scholarly journals Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8 + T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques

2016 ◽  
Vol 90 (21) ◽  
pp. 9942-9952 ◽  
Author(s):  
Victor I. Ayala ◽  
Matthew T. Trivett ◽  
Eugene V. Barsov ◽  
Sumiti Jain ◽  
Michael Piatak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Rhesus Macaques ◽  
High Dose ◽  
Cell Responses ◽  
Large Numbers ◽  
Immunodeficiency Virus ◽  
Virus Exposure ◽  
Cellular Immune

ABSTRACT AIDS virus infections are rarely controlled by cell-mediated immunity, in part due to viral immune evasion and immunodeficiency resulting from CD4 + T-cell infection. One likely aspect of this failure is that antiviral cellular immune responses are either absent or present at low levels during the initial establishment of infection. To test whether an extensive, timely, and effective response could reduce the establishment of infection from a high-dose inoculum, we adoptively transferred large numbers of T cells that were molecularly engineered with anti-simian immunodeficiency virus (anti-SIV) activity into rhesus macaques 3 days following an intrarectal SIV inoculation. To measure in vivo antiviral activity, we assessed the number of viruses transmitted using SIVmac239X, a molecularly tagged viral stock containing 10 genotypic variants, at a dose calculated to transmit 12 founder viruses. Single-genome sequencing of plasma virus revealed that the two animals receiving T cells expressing SIV-specific T-cell receptors (TCRs) had significantly fewer viral genotypes than the two control animals receiving non-SIV-specific T cells (means of 4.0 versus 7.5 transmitted viral genotypes; P = 0.044). Accounting for the likelihood of transmission of multiple viruses of a particular genotype, the calculated means of the total number of founder viruses transmitted were 4.5 and 14.5 in the experimental and control groups, respectively ( P = 0.021). Thus, a large antiviral T-cell response timed with virus exposure can limit viral transmission. The presence of strong, preexisting T-cell responses, including those induced by vaccines, might help prevent the establishment of infection at the lower-exposure doses in humans that typically transmit only a single virus. IMPORTANCE The establishment of AIDS virus infection in an individual is essentially a race between the spreading virus and host immune defenses. Cell-mediated immune responses induced by infection or vaccination are important contributors in limiting viral replication. However, in human immunodeficiency virus (HIV)/SIV infection, the virus usually wins the race, irreversibly crippling the immune system before an effective cellular immune response is developed and active. We found that providing an accelerated response by adoptively transferring large numbers of antiviral T cells shortly after a high-dose mucosal inoculation, while not preventing infection altogether, limited the number of individual viruses transmitted. Thus, the presence of strong, preexisting T-cell responses, including those induced by vaccines, might prevent infection in humans, where the virus exposure is considerably lower.

scholarly journals Loss of virus-specific CD4+ T cells with increases in viral loads in the chronic phase after vaccine-based partial control of primary simian immunodeficiency virus replication in macaques

2004 ◽  
Vol 85 (7) ◽  
pp. 1955-1963 ◽  
Author(s):  
Wen-Hui Lun ◽  
Akiko Takeda ◽  
Hiromi Nakamura ◽  
Munehide Kano ◽  
Kazuyasu Mori ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Virus Replication ◽  
Chronic Phase ◽  
Partial Control ◽  
Viral Loads ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Cellular Immune

Virus-specific cellular immune responses play an important role in the control of immunodeficiency virus replication. However, preclinical trials of vaccines that induce virus-specific cellular immune responses have failed to contain simian immunodeficiency virus (SIV) replication in macaques. A defective provirus DNA vaccine system that efficiently induces virus-specific CD8+ T-cell responses has previously been developed. The vaccinated macaques showed reduced viral loads, but failed to contain SIVmac239 replication. In this study, macaques that showed partial control of SIV replication were followed up to see if or how they lost this control in the chronic phase. Two of them showed increased viral loads about 4 or 8 months after challenge and finally developed AIDS. Analysis of SIV-specific T-cell levels by detection of SIV-specific gamma interferon (IFN-γ) production revealed that these two macaques maintained SIV-specific CD8+ T cells, even after loss of control, but lost SIV-specific CD4+ T cells when plasma viral loads increased. The remaining macaque kept viral loads at low levels and maintained SIV-specific CD4+ T cells, as well as CD8+ T cells, for more than 3 years. Additional analysis using macaques vaccinated with a Gag-expressing Sendai virus vector also found loss of viraemia control, with loss of SIV-specific CD4+ T cells in the chronic phase of SIV infection. Thus, SIV-specific CD4+ T cells that were able to produce IFN-γ in response to SIV antigens were preserved by the vaccine-based partial control of primary SIV replication, but were lost with abrogation of control in the chronic phase.

scholarly journals 326 SARS-CoV-2 specific T-cells in TIL from patients with epithelial cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A352-A352
Author(s):  
Pedro Noronha ◽  
Georgia Paraschoudi ◽  
Eric Sousa ◽  
Jéssica Kamiki ◽  
Patrícia António ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Ifn Gamma ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune

BackgroundSARS-CoV-2 primarily infects the upper and lower airway system, yet also endothelial cells and multiple tissues/organ systems. Anti-SARS-CoV-2 directed cellular immune responses may be deleterious or may confer immune protection – more research is needed in order to link epitope-specific T-cell responses with clinically relevant endpoints.1 Analysis of epitope reactivity in blood from healthy individuals showed pre-existing (CD4+) reactivity most likely due to previous exposure to the common old coronavirus species HCoV-OC43, HCoV-229E, - NL63 or HKU1, or – not mutually exclusive - cross-reactive T-cell responses that would recognize SARS-CoV-2, yet also other non-SARS-CoV-2 targets.2,3 Detailed single cell analysis in PBMCs from patients with COVID-19 showed strong T-cell activation and expansion of TCR gamma – delta T-cells in patients with fast recovery or mild clinical symptoms.4 Previous studies examining antigen-specific T-cell responses in tumor-infiltrating T-cells (TIL) showed that EBV or CMV-specific cellular immune responses in TIL from patients with melanoma or pancreatic cancer. Such virus -specific T-cells may represent ‘bystander’ T-cell activation, yet they may also impact on the quality and quantity of anti-tumor directed immune responses. We tested therefore TIL expanded from 5 patients with gastrointestinal cancer, who underwent elective tumor surgery during the COVID-19 pandemic for recognition of a comprehensive panel of SARS-CoV-2 T-cell epitopes and compared the reactivity, defined by IFN-gamma production to TIL reactivity in TIL harvested from patients in 2018, prior to the pandemic.MethodsA set of 187 individual T-cell epitopes were tested for TIL recognition using 100IU IL-2 and 100 IU IL-15. Different peptide epitopes were selected: i) all epitopes were not shared with the 4 common old coronavirus species, ii) some peptides were unique for SARS-CoV-2, and iii) others were shared with SARS-CoV-1. Antigen targets were either 15 mers or 9mers for MHC class II or class I epitopes, respectively, derived from the nucleocapsid, membrane, spike protein, ORF8 or the ORF3a. The amount of IFN-gamma production was reported as pg/10e4 cells/epitope/5 days. Controls included CMV and EBV peptides.ResultsWe detected strong IFN-gamma production directed against antigenic ‘hotspots’ including the ORF3a, epitopes from the SARS-CoV-2 nucleocapsid and spike protein with a range of 12 up to 30 targets being recognized/TIL.ConclusionsSARS-CoV-2 epitope recognition, defined by IFN production, can be readily detected in TIL from patients who underwent surgery during the pandemic, which is not the case for TIL harvested prior to the circulating SARS-CoV-2. This suggests a broader exposure of individuals to SARS-CoV-2 and shows that SARS-CoV-2 responses may shape the quality and quantity of anti-cancer directed cellular immune responses in patients with solid epithelial malignancies.AcknowledgementsWe thank the Surgery, Pathology and Vivarium Units of Champalimaud Clinical Center (N. Figueiredo, A. Brandl, A. Beltran, M. Castillo, C. Silva ).Ethics ApprovalThis study was approved by the Champalimaud Foundation Ethics Committee.ConsentAll donors provided written consent and the study was approved by the local ethics committee. The study is in compliance with the Declaration of Helsinki.ReferencesGrifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., Rawlings, S. A., Sutherland, A., Premkumar, L., Jadi, R. S., Marrama, D., de Silva, A. M., Frazier, A., Carlin, A. F., Greenbaum, J. A., Peters, B., Krammer, F., Smith, D. M., Crotty, S., & Sette, A. ( 2020). Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell, 181(7), 1489–1501.e15. https://doi.org/10.1016/j.cell.2020.05.015Mateus, J., Grifoni, A., Tarke, A., Sidney, J., Ramirez, S. I., Dan, J. M., Burger, Z. C., Rawlings, S. A., Smith, D. M., Phillips, E., Mallal, S., Lammers, M., Rubiro, P., Quiambao, L., Sutherland, A., Yu, E. D., da Silva Antunes, R., Greenbaum, J., Frazier, A., … Weiskopf, D. ( 2020). Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science, eabd3871. https://doi.org/10.1126/science.abd3871Le Bert, N., Tan, A. T., Kunasegaran, K., Tham, C. Y. L., Hafezi, M., Chia, A., Chng, M. H. Y., Lin, M., Tan, N., Linster, M., Chia, W. N., Chen, M. I.-C., Wang, L.-F., Ooi, E. E., Kalimuddin, S., Tambyah, P. A., Low, J. G.-H., Tan, Y.-J., & Bertoletti, A. ( 2020). SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature, 584(7821), 457–462. https://doi.org/10.1038/s41586-020-2550-zZhang, J., Wang, X., Xing, X. et al. Single-cell landscape of immunological responses in patients with COVID-19. Nat Immunol 2020;21:1107–1118. https://doi.org/10.1038/s41590-020-0762-x

scholarly journals Comprehensive Epitope Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses Directed against the Entire Expressed HIV-1 Genome Demonstrate Broadly Directed Responses, but No Correlation to Viral Load

2003 ◽  
Vol 77 (3) ◽  
pp. 2081-2092 ◽  
Author(s):  
M. M. Addo ◽  
X. G. Yu ◽  
A. Rathod ◽  
D. Cohen ◽  
R. L. Eldridge ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Protein Subunits ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Total Magnitude ◽  
Cellular Immune ◽  
Hiv 1

ABSTRACT Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/106 PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.

scholarly journals Increased Loss of CCR5+ CD45RA− CD4+ T Cells in CD8+ Lymphocyte-Depleted Simian Immunodeficiency Virus-Infected Rhesus Monkeys

2008 ◽  
Vol 82 (11) ◽  
pp. 5618-5630 ◽  
Author(s):  
Ronald S. Veazey ◽  
Paula M. Acierno ◽  
Kimberly J. McEvers ◽  
Susanne H. C. Baumeister ◽  
Gabriel J. Foster ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Simian Immunodeficiency Virus ◽  
Peripheral Blood ◽  
T Cell Responses ◽  
Lymphocyte Depletion ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT Previously we have shown that CD8+ T cells are critical for containment of simian immunodeficiency virus (SIV) viremia and that rapid and profound depletion of CD4+ T cells occurs in the intestinal tract of acutely infected macaques. To determine the impact of SIV-specific CD8+ T-cell responses on the magnitude of the CD4+ T-cell depletion, we investigated the effect of CD8+ lymphocyte depletion during primary SIV infection on CD4+ T-cell subsets and function in peripheral blood, lymph nodes, and intestinal tissues. In peripheral blood, CD8+ lymphocyte-depletion changed the dynamics of CD4+ T-cell loss, resulting in a more pronounced loss 2 weeks after infection, followed by a temporal rebound approximately 2 months after infection, when absolute numbers of CD4+ T cells were restored to baseline levels. These CD4+ T cells showed a markedly skewed phenotype, however, as there were decreased levels of memory cells in CD8+ lymphocyte-depleted macaques compared to controls. In intestinal tissues and lymph nodes, we observed a significantly higher loss of CCR5+ CD45RA− CD4+ T cells in CD8+ lymphocyte-depleted macaques than in controls, suggesting that these SIV-targeted CD4+ T cells were eliminated more efficiently in CD8+ lymphocyte-depleted animals. Also, CD8+ lymphocyte depletion significantly affected the ability to generate SIV Gag-specific CD4+ T-cell responses and neutralizing antibodies. These results reemphasize that SIV-specific CD8+ T-cell responses are absolutely critical to initiate at least partial control of SIV infection.

scholarly journals Viral Suppression and Immune Restoration in the Gastrointestinal Mucosa of Human Immunodeficiency Virus Type 1-Infected Patients Initiating Therapy during Primary or Chronic Infection

2006 ◽  
Vol 80 (16) ◽  
pp. 8236-8247 ◽  
Author(s):  
Moraima Guadalupe ◽  
Sumathi Sankaran ◽  
Michael D. George ◽  
Elizabeth Reay ◽  
David Verhoeven ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Microarray Analysis ◽  
Dna Microarray ◽  
Peripheral Blood ◽  
Viral Suppression ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11α, αEβ7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.

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