scholarly journals Expansion of Inefficient HIV-Specific CD8 T Cells during Acute Infection

2016 ◽  
Vol 90 (8) ◽  
pp. 4005-4016 ◽  
Author(s):  
Michael A. Eller ◽  
Nilu Goonetilleke ◽  
Boonrat Tassaneetrithep ◽  
Leigh Anne Eller ◽  
Margaret C. Costanzo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Population ◽  
Acute Infection ◽  
T Cell Responses ◽  
Hiv Replication ◽  
Acute Hiv Infection ◽  
Cell Responses ◽  
Acute Hiv

ABSTRACTAttrition within the CD4+T cell compartment, high viremia, and a cytokine storm characterize the early days after HIV infection. When the first emerging HIV-specific CD8+T cell responses gain control over viral replication it is incomplete, and clearance of HIV infection is not achieved even in the rare cases of individuals who spontaneously control viral replication to nearly immeasurably low levels. Thus, despite their partial ability to control viremia, HIV-specific CD8+T cell responses are insufficient to clear HIV infection. Studying individuals in the first few days of acute HIV infection, we detected the emergence of a unique population of CD38+CD27−CD8+T cells characterized by the low expression of the CD8 receptor (CD8dim). Interestingly, while high frequencies of HIV-specific CD8+T cell responses occur within the CD38+CD27−CD8dimT cell population, the minority populations of CD8brightT cells are significantly more effective in inhibiting HIV replication. Furthermore, the frequency of CD8dimT cells directly correlates with viral load and clinical predictors of more rapid disease progression. We found that a canonical burst of proliferative cytokines coincides with the emergence of CD8dimT cells, and the size of this population inversely correlates with the acute loss of CD4+T cells. These data indicate, for the first time, that early CD4+T cell loss coincides with the expansion of a functionally impaired HIV-specific CD8dimT cell population less efficient in controlling HIV viremia.IMPORTANCEA distinct population of activated CD8+T cells appears during acute HIV infection with diminished capacity to inhibit HIV replication and is predictive of viral set point, offering the first immunologic evidence of CD8+T cell dysfunction during acute infection.

scholarly journals HIV-Specific Cytolytic CD4 T Cell Responses During Acute HIV Infection Predict Disease Outcome

2012 ◽  
Vol 4 (123) ◽  
pp. 123ra25-123ra25 ◽  
Author(s):  
D. Z. Soghoian ◽  
H. Jessen ◽  
M. Flanders ◽  
K. Sierra-Davidson ◽  
S. Cutler ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Disease Outcome ◽  
Acute Hiv Infection ◽  
Cell Responses ◽  
Acute Hiv

scholarly journals Induction of Gag-Specific CD4 T Cell Responses during Acute HIV Infection Is Associated with Improved Viral Control

2014 ◽  
Vol 88 (13) ◽  
pp. 7357-7366 ◽  
Author(s):  
M. Schieffer ◽  
H. K. Jessen ◽  
A. F. Oster ◽  
F. Pissani ◽  
D. Z. Soghoian ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Viral Control ◽  
Acute Hiv Infection ◽  
Cell Responses ◽  
Acute Hiv

scholarly journals CD4+CD8+T Cells Represent a Significant Portion of the Anti-HIV T Cell Response to Acute HIV Infection

2012 ◽  
Vol 188 (9) ◽  
pp. 4289-4296 ◽  
Author(s):  
Marc A. Frahm ◽  
Ralph A. Picking ◽  
JoAnn D. Kuruc ◽  
Kara S. McGee ◽  
Cynthia L. Gay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Cell Response ◽  
T Cell Response ◽  
Acute Hiv Infection ◽  
Acute Hiv ◽  
Anti Hiv

scholarly journals MHC Class I Presented T Cell Epitopes as Potential Antigens for Therapeutic Vaccine against HBV Chronic Infection

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Joseph D. Comber ◽  
Aykan Karabudak ◽  
Vivekananda Shetty ◽  
James S. Testa ◽  
Xiaofang Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Infection ◽  
Acute Infection ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Hbv Infection ◽  
Mhc I ◽  
Cell Responses ◽  
Cell Immunity

Approximately 370 million people worldwide are chronically infected with hepatitis B virus (HBV). Despite the success of the prophylactic HBV vaccine, no therapeutic vaccine or other immunotherapy modality is available for treatment of chronically infected individuals. Clearance of HBV depends on robust, sustained CD8+ T activity; however, the limited numbers of therapeutic vaccines tested have not induced such a response. Most of these vaccines have relied on peptide prediction algorithms to identify MHC-I epitopes or characterization of T cell responses during acute infection. Here, we took an immunoproteomic approach to characterize MHC-I restricted epitopes from cells chronically infected with HBV and therefore more likely to represent the true targets of CD8+ T cells during chronic infection. In this study, we identified eight novel MHC-I restricted epitopes derived from a broad range of HBV proteins that were capable of activating CD8+ T cells. Furthermore, five of the eight epitopes were able to bind HLA-A2 and A24 alleles and activated HBV specific T cell responses. These epitopes also have potential as new tools to characterize T cell immunity in chronic HBV infection and may serve as candidate antigens for a therapeutic vaccine against HBV infection.

scholarly journals HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4+T Cell Responses

2015 ◽  
Vol 90 (5) ◽  
pp. 2208-2220 ◽  
Author(s):  
Srinika Ranasinghe ◽  
Damien Z. Soghoian ◽  
Madelene Lindqvist ◽  
Musie Ghebremichael ◽  
Faith Donaghey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Hiv Infection ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Antibody Activity ◽  
Cell Responses

ABSTRACTAntigen-specific CD4+T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4+T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4+T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4+T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4+T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4+T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4+T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4+T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4+T cells and, to a lesser extent, gp41-specific CD4+T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.IMPORTANCEOne of the earliest discoveries related to CD4+T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4+T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4+T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4+T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4+T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4+T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.

scholarly journals Analysis of Total Human Immunodeficiency Virus (HIV)-Specific CD4+ and CD8+ T-Cell Responses: Relationship to Viral Load in Untreated HIV Infection

2001 ◽  
Vol 75 (24) ◽  
pp. 11983-11991 ◽  
Author(s):  
Michael R. Betts ◽  
David R. Ambrozak ◽  
Daniel C. Douek ◽  
Sebastian Bonhoeffer ◽  
Jason M. Brenchley ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Hiv Infection ◽  
Highly Active Antiretroviral Therapy ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus (HIV)-specific T-cell responses are thought to play a key role in viral load decline during primary infection and in determining the subsequent viral load set point. The requirements for this effect are unknown, partly because comprehensive analysis of total HIV-specific CD4+ and CD8+T-cell responses to all HIV-encoded epitopes has not been accomplished. To assess these responses, we used cytokine flow cytometry and overlapping peptide pools encompassing all products of the HIV-1 genome to study total HIV-specific T-cell responses in 23 highly active antiretroviral therapy naı̈ve HIV-infected patients. HIV-specific CD8+ T-cell responses were detectable in all patients, ranging between 1.6 and 18.4% of total CD8+ T cells. HIV-specific CD4+ T-cell responses were present in 21 of 23 patients, although the responses were lower (0.2 to 2.94%). Contrary to previous reports, a positive correlation was identified between the plasma viral load and the total HIV-, Env-, and Nef-specific CD8+ T-cell frequency. No correlation was found either between viral load and total or Gag-specific CD4+ T-cell response or between the frequency of HIV-specific CD4+ and CD8+ T cells. These results suggest that overall frequencies of HIV-specific T cells are not the sole determinant of immune-mediated protection in HIV-infection.

scholarly journals Cooperativity of HIV-Specific Cytolytic CD4 T Cells and CD8 T Cells in Control of HIV Viremia

2015 ◽  
Vol 89 (15) ◽  
pp. 7494-7505 ◽  
Author(s):  
Susan Johnson ◽  
Michael Eller ◽  
Jeffrey E. Teigler ◽  
Sebastien M. Maloveste ◽  
Bruce T. Schultz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Viral Infections ◽  
Flow Cytometric Analysis ◽  
Th1 Cells ◽  
Hiv Replication ◽  
Acute Hiv Infection ◽  
Transcriptional Signature ◽  
Cell Functions

ABSTRACTCD4+T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+T cell functions beyond helper effects have been described, and a role for cytolytic CD4+T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+T cells revealed a distinct transcriptional signature compared to Th1 CD4+cells but shared similar features with HIV-specific cytolytic CD8+T cells. Furthermore, HIV-specific cytolytic CD4+T cells showed comparable killing activity relative to HIV-specific CD8+T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4+T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4+T cells as an independent subset distinct from Th1 cells that show combined activity with CD8+T cells in the long-term control of HIV infection.IMPORTANCEThe ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8+T cells to control the virus, while CD4+T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4+T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4+T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8+T cells. These findings are important for our understanding of HIV immunopathology.

scholarly journals The Breadth of Expandable Memory CD8+T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers

2015 ◽  
Vol 89 (21) ◽  
pp. 10735-10747 ◽  
Author(s):  
Zaza M. Ndhlovu ◽  
Eleni Stampouloglou ◽  
Kevin Cesa ◽  
Orestes Mavrothalassitis ◽  
Donna Marie Alvino ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
T Lymphocytes ◽  
Hiv Infection ◽  
T Cell Responses ◽  
T Cell Response ◽  
Elite Controllers ◽  
Cell Responses ◽  
Specific Memory

ABSTRACTPrevious studies have shown that elite controllers with minimal effector T cell responses harbor a low-frequency, readily expandable, highly functional, and broadly directed memory population. Here, we interrogated thein vivorelevance of this cell population by investigating whether the breadth of expandable memory responses is associated with the magnitude of residual viremia in individuals achieving durable suppression of HIV infection. HIV-specific memory CD8+T cells were expanded by using autologous epitopic and variant peptides. Viral load was measured by an ultrasensitive single-copy PCR assay. Following expansion, controllers showed a greater increase in the overall breadth of Gag responses than did untreated progressors (P= 0.01) as well as treated progressors (P= 0.0003). Nef- and Env-specific memory cells expanded poorly for all groups, and their expanded breadths were indistinguishable among groups (P= 0.9 for Nef as determined by a Kruskal-Wallis test;P= 0.6 for Env as determined by a Kruskal-Wallis test). More importantly, we show that the breadth of expandable, previously undetectable Gag-specific responses was inversely correlated with residual viral load (r= −0.6;P= 0.009). Together, these data reveal a direct link between the abundance of Gag-specific expandable memory responses and prolonged maintenance of low-level viremia. Our studies highlight a CD8+T cell feature that would be desirable in a vaccine-induced T cell response.IMPORTANCEMany studies have shown that the rare ability of some individuals to control HIV infection in the absence of antiretroviral therapy appears to be heavily dependent upon special HIV-specific killer T lymphocytes that are able to inhibit viral replication. The identification of key features of these immune cells has the potential to inform rational HIV vaccine design. This study shows that a special subset of killer lymphocytes, known as central memory CD8+T lymphocytes, is at least partially involved in the durable control of HIV replication. HIV controllers maintain a large proportion of Gag-specific expandable memory CD8+T cells involved in ongoing viral suppression. These data suggest that induction of this cell subset by future HIV vaccines may be important for narrowing possible routes of rapid escape from vaccine-induced CD8+T cell responses.

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