scholarly journals Viral Evolution and Cytotoxic T Cell Restricted Selection in Acute Infant HIV-1 Infection

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Miguel A. Garcia-Knight ◽  
Jennifer Slyker ◽  
Barbara Lohman Payne ◽  
Sergei L. Kosakovsky Pond ◽  
Thushan I. de Silva ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Evolution ◽  
Cytotoxic T Cell ◽  
Restricted Selection ◽  
Hiv 1

scholarly journals Fitness-Balanced Escape Determines Resolution of Dynamic Founder Virus Escape Processes in HIV-1 Infection

2015 ◽  
Vol 89 (20) ◽  
pp. 10303-10318 ◽  
Author(s):  
Justine E. Sunshine ◽  
Brendan B. Larsen ◽  
Brandon Maust ◽  
Ellie Casey ◽  
Wenje Deng ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Evolution ◽  
T Cell Responses ◽  
Fitness Cost ◽  
Viral Population ◽  
Cell Responses ◽  
Founder Virus ◽  
Ctl Escape ◽  
The Impact ◽  
Hiv 1

ABSTRACTTo understand the interplay between host cytotoxic T-lymphocyte (CTL) responses and the mechanisms by which HIV-1 evades them, we studied viral evolutionary patterns associated with host CTL responses in six linked transmission pairs. HIV-1 sequences corresponding to full-length p17 and p24gagwere generated by 454 pyrosequencing for all pairs near the time of transmission, and seroconverting partners were followed for a median of 847 days postinfection. T-cell responses were screened by gamma interferon/interleukin-2 (IFN-γ/IL-2) FluoroSpot using autologous peptide sets reflecting any Gag variant present in at least 5% of sequence reads in the individual's viral population. While we found little evidence for the occurrence of CTL reversions, CTL escape processes were found to be highly dynamic, with multiple epitope variants emerging simultaneously. We found a correlation between epitope entropy and the number of epitope variants per response (r= 0.43;P= 0.05). In cases in which multiple escape mutations developed within a targeted epitope, a variant with no fitness cost became fixed in the viral population. When multiple mutations within an epitope achieved fitness-balanced escape, these escape mutants were each maintained in the viral population. Additional mutations found to confer escape but undetected in viral populations incurred high fitness costs, suggesting that functional constraints limit the available sites tolerable to escape mutations. These results further our understanding of the impact of CTL escape and reversion from the founder virus in HIV infection and contribute to the identification of immunogenic Gag regions most vulnerable to a targeted T-cell attack.IMPORTANCERapid diversification of the viral population is a hallmark of HIV-1 infection, and understanding the selective forces driving the emergence of viral variants can provide critical insight into the interplay between host immune responses and viral evolution. We used deep sequencing to comprehensively follow viral evolution over time in six linked HIV transmission pairs. We then mapped T-cell responses to explore if mutations arose due to adaption to the host and found that escape processes were often highly dynamic, with multiple mutations arising within targeted epitopes. When we explored the impact of these mutations on replicative capacity, we found that dynamic escape processes only resolve with the selection of mutations that conferred escape with no fitness cost to the virus. These results provide further understanding of the complicated viral-host interactions that occur during early HIV-1 infection and may help inform the design of future vaccine immunogens.

scholarly journals HIV-1 Epitope Variability Is Associated with T Cell Receptor Repertoire Instability and Breadth

2017 ◽  
Vol 91 (16) ◽  
Author(s):  
Arumugam Balamurugan ◽  
Deon Claiborne ◽  
Hwee L. Ng ◽  
Otto O. Yang
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Viral Evolution ◽  
Inverse Correlation ◽  
Cell Receptor ◽  
Immune Control ◽  
Major Barrier ◽  
Receptor Repertoire ◽  
Hiv 1

ABSTRACT Mutational escape of HIV-1 from HIV-1-specific CD8+ T lymphocytes (CTLs) is a major barrier for effective immune control. Each epitope typically is targeted by multiple clones with distinct T cell receptors (TCRs). While the clonal repertoire may be important for containing epitope variation, determinants of its composition are poorly understood. We investigate the clonal repertoire of 29 CTL responses against 23 HIV-1 epitopes longitudinally in nine chronically infected untreated subjects with plasma viremia of <3,000 RNA copies/ml over 17 to 179 weeks. The composition of TCRs targeting each epitope varied considerably in stability over time, although clonal stability (Sorensen index) was not significantly time dependent within this interval. However, TCR stability inversely correlated with epitope variability in the Los Alamos HIV-1 Sequence Database, consistent with TCR evolution being driven by epitope variation. Finally, a robust inverse correlation of TCR breadth against each epitope versus epitope variability further suggested that this variability drives TCR repertoire diversification. In the context of studies demonstrating rapidly shifting HIV-1 sequences in vivo, our findings support a variably dynamic process of shifting CTL clonality lagging in tandem with viral evolution and suggest that preventing escape of HIV-1 may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways. IMPORTANCE Mutational escape of HIV-1 from HIV-1-specific CD8+ T lymphocytes (CTLs) is a major barrier to effective immune control. The number of distinct CTL clones targeting each epitope is proposed to be an important factor, but the determinants are poorly understood. Here, we demonstrate that the clonal stability and number of clones for the CTL response against an epitope are inversely associated with the general variability of the epitope. These results show that CTLs constantly lag epitope mutation, suggesting that preventing HIV-1 escape may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways.

scholarly journals Dendritic cells transduced by multiply deleted HIV-1 vectors exhibit normal phenotypes and functions and elicit an HIV-specific cytotoxic T-lymphocyte response in vitro

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1327-1333 ◽  
Author(s):  
Andreas Gruber ◽  
June Kan-Mitchell ◽  
Kelli L. Kuhen ◽  
Tetsu Mukai ◽  
Flossie Wong-Staal
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Ex Vivo ◽  
T Cell Response ◽  
Adoptive T Cell Therapy ◽  
Cytotoxic T Cell ◽  
T Cell Therapy ◽  
Hiv 1

Abstract Dendritic cells (DCs) genetically modified to continually express and present antigens may be potent physiologic adjuvants for induction of prophylactic or therapeutic immunity. We have previously shown that an env and nef deleted HIV-1 vector (HIV-1ΔEN) pseudotyped with VSV-G transduced monocyte-derived macrophages as well as CD34+ precursors of DCs. Here we extended these findings with HIV-1ΔEN to highly differentiated human DCs derived in culture from circulating monocytes (DCs). In addition, a new vector derived from HIV-1ΔEN but further deleted in its remaining accessory genes vif, vpr, and vpu(HIV-1ΔEN V3) was also tested. Both vectors efficiently transduced DCs. Transduction of DCs did not significantly alter their viability or their immunophenotype when compared with untransduced DCs. Furthermore, the phagocytic potential of immature DCs, as well as their ability to differentiate into mature DCs capable of stimulating T-cell proliferation, was not affected. Finally, DCs transduced by the HIV-1ΔEN vector were able to elicit a primary antiviral cytotoxic T-cell response in autologous CD8 T cells. These results suggest that HIV-1–based vectors expressing viral antigens may be useful for in vivo active immunization as well as ex vivo priming of cytotoxic T cells for adoptive T-cell therapy.

Quantitating the HIV-1-Specific Cytotoxic T Cell Response

2015 ◽  
pp. 30-39
Author(s):  
Andrew Carmichael ◽  
Nicholas Alp ◽  
Leszek Borysiewicz
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Hiv 1

The CD160+ CD8high cytotoxic T cell subset correlates with response to HAART in HIV-1+ patients

2005 ◽  
Vol 237 (2) ◽  
pp. 96-105 ◽  
Author(s):  
Maria H. Nikolova ◽  
Maria N. Muhtarova ◽  
Hristo B. Taskov ◽  
Kostadin Kostov ◽  
Ljubomir Vezenkov ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Subset ◽  
Cytotoxic T Cell ◽  
T Cell Subset ◽  
Hiv 1

Multiple transmissions of a stable human leucocyte antigen-B27 cytotoxic T-cell-escape strain of HIV-1 in The Netherlands

AIDS ◽  
2009 ◽  
Vol 23 (12) ◽  
pp. 1495-1500 ◽  
Author(s):  
Marion Cornelissen ◽  
Frederik M Hoogland ◽  
Nicole KT Back ◽  
Suzanne Jurriaans ◽  
Fokla Zorgdrager ◽  
...  
Keyword(s):  
T Cell ◽  
The Netherlands ◽  
Human Leucocyte Antigen ◽  
Cytotoxic T Cell ◽  
Hiv 1

Changes in the Cytotoxic T-Cell Repertoire of HIV-1-Infected Individuals: Relationship to Disease Progression

1993 ◽  
Vol 6 (1) ◽  
pp. 85-95 ◽  
Author(s):  
MICHAEL D. GRANT ◽  
FIONA M. SMAILL ◽  
KAREN LAURIE ◽  
KENNETH L. ROSENTHAL
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
Cytotoxic T Cell ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Hiv 1

scholarly journals Single-cell immune profiling reveals the impact of antiretroviral therapy on HIV-1-induced immune dysfunction, T cell clonal expansion, and HIV-1 persistence in vivo

2021 ◽  
Author(s):  
Jack A. Collora ◽  
Delia Pinto-Santini ◽  
Siavash Pasalar ◽  
Neal Ravindra ◽  
Carmela Ganoza ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Single Cell ◽  
Cytotoxic T Cell ◽  
T Cell Clones ◽  
Cell Clones ◽  
Immune Profiling ◽  
Hiv 1

AbstractDespite antiretroviral therapy (ART), HIV-1 persists in proliferating T cell clones that increase over time. To understand whether early ART affects HIV-1 persistence in vivo, we performed single-cell ECCITE-seq and profiled 89,279 CD4+ T cells in paired samples during viremia and after immediate versus delayed ART in six people in the randomized interventional Sabes study. We found that immediate ART partially reverted TNF responses while delayed ART did not. Antigen and TNF responses persisted despite immediate ART and shaped the transcriptional landscape of CD4+ T cells, HIV-1 RNA+ cells, and T cell clones harboring them (cloneHIV-1). Some HIV-1 RNA+ cells reside in the most clonally expanded cytotoxic T cell populations (GZMB and GZMK Th1 cells). CloneHIV-1+ were larger in clone size, persisted despite ART, and exhibited transcriptional signatures of antigen, cytotoxic effector, and cytokine responses. Using machine-learning algorithms, we identified markers for HIV-1 RNA+ cells and cloneHIV-1+ as potential therapeutic targets. Overall, by combining single-cell immune profiling and T cell expansion dynamics tracking, we identified drivers of HIV-1 persistence in vivo.

scholarly journals Dendritic cells transduced by multiply deleted HIV-1 vectors exhibit normal phenotypes and functions and elicit an HIV-specific cytotoxic T-lymphocyte response in vitro

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1327-1333 ◽  
Author(s):  
Andreas Gruber ◽  
June Kan-Mitchell ◽  
Kelli L. Kuhen ◽  
Tetsu Mukai ◽  
Flossie Wong-Staal
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Ex Vivo ◽  
T Cell Response ◽  
Adoptive T Cell Therapy ◽  
Cytotoxic T Cell ◽  
T Cell Therapy ◽  
Hiv 1

Dendritic cells (DCs) genetically modified to continually express and present antigens may be potent physiologic adjuvants for induction of prophylactic or therapeutic immunity. We have previously shown that an env and nef deleted HIV-1 vector (HIV-1ΔEN) pseudotyped with VSV-G transduced monocyte-derived macrophages as well as CD34+ precursors of DCs. Here we extended these findings with HIV-1ΔEN to highly differentiated human DCs derived in culture from circulating monocytes (DCs). In addition, a new vector derived from HIV-1ΔEN but further deleted in its remaining accessory genes vif, vpr, and vpu(HIV-1ΔEN V3) was also tested. Both vectors efficiently transduced DCs. Transduction of DCs did not significantly alter their viability or their immunophenotype when compared with untransduced DCs. Furthermore, the phagocytic potential of immature DCs, as well as their ability to differentiate into mature DCs capable of stimulating T-cell proliferation, was not affected. Finally, DCs transduced by the HIV-1ΔEN vector were able to elicit a primary antiviral cytotoxic T-cell response in autologous CD8 T cells. These results suggest that HIV-1–based vectors expressing viral antigens may be useful for in vivo active immunization as well as ex vivo priming of cytotoxic T cells for adoptive T-cell therapy.

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