Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ TEMRA Cells in Early Infection Are Linked to Control of HIV-1 Viremia and Predict the Subsequent Viral Load Set Point

ABSTRACT CD8+ T cells are believed to play an important role in the control of human immunodeficiency virus type 1 (HIV-1) infection. However, despite intensive efforts, it has not been possible to consistently link the overall magnitude of the CD8+ T-cell response with control of HIV-1. Here, we have investigated the association of different CD8+ memory T-cell subsets responding to HIV-1 in early infection with future control of HIV-1 viremia. Our results demonstrate that both a larger proportion and an absolute number of HIV-1-specific CD8+ CCR7− CD45RA+ effector memory T cells (TEMRA cells) were associated with a lower future viral load set point. In contrast, a larger absolute number of HIV-1-specific CD8+ CCR7− CD45RA− effector memory T cells (TEM) was not related to the viral load set point. Overall, the findings suggest that CD8+ TEMRA cells have superior antiviral activity and indicate that both qualitative and quantitative aspects of the CD8+ T-cell response need to be considered when defining the characteristics of protective immunity to HIV-1.

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Long-Term Control of HIV-1 in Hemophiliacs Carrying Slow-Progressing Allele HLA-B*5101

Journal of Virology ◽

10.1128/jvi.00171-10 ◽

2010 ◽

Vol 84 (14) ◽

pp. 7151-7160 ◽

Cited By ~ 38

Author(s):

Yuka Kawashima ◽

Nozomi Kuse ◽

Hiroyuki Gatanaga ◽

Takuya Naruto ◽

Mamoru Fujiwara ◽

...

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Cytotoxic T Lymphocyte ◽

T Cell Response ◽

Slow Progression ◽

Lack Of Control ◽

Escape Mutants ◽

Hiv 1

ABSTRACT HLA-B*51 alleles are reported to be associated with slow disease progression to AIDS, but the mechanism underlying this association is still unclear. In the present study, we analyzed the effect of HLA-B*5101 on clinical outcome for Japanese hemophiliacs who had been infected with HIV-1 before 1985 and had been recruited in 1998 for this study. HLA-B*5101+ hemophiliacs exhibited significantly slow progression. The analysis of HLA-B*5101-restricted HIV-1-specific cytotoxic T-lymphocyte (CTL) responses to 4 HLA-B*-restricted epitopes in 10 antiretroviral-therapy (ART)-free HLA-B*5101+ hemophiliacs showed that the frequency of Pol283-8-specific CD8+ T cells was inversely correlated with the viral load, whereas the frequencies of CD8+ T cells specific for 3 other epitopes were positively correlated with the viral load. The HLA-B*5101+ hemophiliacs whose HIV-1 replication had been controlled for approximately 25 years had HIV-1 possessing the wild-type Pol283-8 sequence or the Pol283-8V mutant, which does not critically affect T-cell recognition, whereas other HLA-B*5101+ hemophiliacs had HIV-1 with escape mutations in this epitope. The results suggest that the control of HIV-1 over approximately 25 years in HLA-B*5101-positive hemophiliacs is associated with a Pol283-8-specific CD8+ T-cell response and that lack of control of HIV-1 is associated with the appearance of Pol283-8-specific escape mutants.

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HLA-B*44 Is Associated with a Lower Viral Set Point and Slow CD4 Decline in a Cohort of Chinese Homosexual Men Acutely Infected with HIV-1

Clinical and Vaccine Immunology ◽

10.1128/cvi.00015-13 ◽

2013 ◽

Vol 20 (7) ◽

pp. 1048-1054 ◽

Cited By ~ 7

Author(s):

Xin Zhang ◽

XiaoJie Huang ◽

Wei Xia ◽

WeiHua Li ◽

Tong Zhang ◽

...

Keyword(s):

Viral Load ◽

T Cell ◽

T Cell Responses ◽

Hla Class I ◽

T Cell Response ◽

Class I ◽

Set Point ◽

Cell Responses ◽

Lower Magnitude ◽

Hiv 1

ABSTRACTHLA class I alleles have been shown to have differential impacts on the viral load and the outcome of HIV-1 disease progression. In this study, HLA class I types from residents of China with acute HIV-1 infection, diagnosed between 2006 and 2011, were identified and the association between expression of individual HLA alleles and the level of the set point viral load was analyzed. A lower level of set point viral load was found to be associated with the Bw4 homozygote on HLA-B alleles. B*44 and B*57 alleles have also been found to be associated with lower set point viral load. The set point viral load of B*44-positive individuals homozygous for Bw4 was significantly lower than that of B*44-negative individuals homozygous for Bw4 (P= 0.030). The CD4 count declined to <350 in fewer B*44-positive individuals than B*44-negative individuals (X2= 7.295,P= 0.026). B*44-positive individuals had a lower magnitude of p24 pool-specific T cell responses than B*44-negative individuals homozygous for Bw4, though this was not statistically significant. The p24 pool-specific T cell responses were also inversely correlated with lower viral load (rs= −0.88,P= 0.033). Six peptides within p24 were recognized to induce the specific-T cell response in B*44-positive individuals, and the peptide breadth of response was same as that in B*44-negative individuals homozygous for Bw4, but the median magnitude of specific-T cell responses to the recognized peptides in B*44-positive individuals was lower than that in B*44-negative individuals homozygous for Bw4 (P= 0.049). These findings imply that weak p24-specific CD8+T cell responses might play an important role in the control of HIV viremia in B*44 allele-positive individuals. Such studies might contribute to the development of future therapeutic strategies that take into account the genetic background of the patients.

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Clonal expansion and TCR-independent differentiation shape the HIV-specific CD8+ effector-memory T-cell repertoire in vivo

Blood ◽

10.1182/blood-2009-11-254136 ◽

2010 ◽

Vol 116 (3) ◽

pp. 396-405 ◽

Cited By ~ 17

Author(s):

Dirk Meyer-Olson ◽

Brenna C. Simons ◽

Joseph A. Conrad ◽

Rita M. Smith ◽

Louise Barnett ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

Significant Proportion ◽

Clonal Expansion ◽

Effector Memory ◽

Structural Constraints ◽

Effector Memory T Cells ◽

Hiv 1

AbstractFlexibility of the HIV-specific T-cell receptor repertoire is a hallmark of HIV-1 infection. Altered differentiation of HIV-specific CD45RO+/CCR7− (TemRO) CD8+ effector-memory T cells into CD45RA+/CCR7− (TemRA) CD8+ effector-memory T cells as well as increased expression of the senescence marker CD57 has been frequently observed HIV-1 infection, but the structural relationship between clonal expansion and T-cell differentiation has not been defined. In this study, we demonstrate that HIV-specific clonotypes have differing degrees of TemRA differentiation but always maintain a significant proportion of TemRO-phenotype cells. These data indicate that structural constraints of the TCR/peptide major histocompatibility complex interaction play a central role in the TemRA differentiation of HIV-specific CD8+ T cells in chronic HIV-1 infection. Clonotypes with a predominantly TemRA phenotype had a substantial fraction of cells without expression of CD57; and in contrast to the high clonotypic variability of TemRA differentiation, expression of CD57 was highly correlated among T-cell clonotypes within epitope-specific responses, indicating TCR-independent expression of CD57 in vivo. Our data highlight the importance of the structural composition of the TCR repertoire for the effector-memory differentiation of the immune response in chronic viral infections and suggest that TCR-dependent and -independent homeostasis shapes the pathogen-specific effector-memory repertoire in vivo.

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IL-8 responsiveness defines a subset of CD8 T cells poised to kill

Blood ◽

10.1182/blood-2004-03-1067 ◽

2004 ◽

Vol 104 (12) ◽

pp. 3463-3471 ◽

Cited By ~ 56

Author(s):

Christoph Hess ◽

Terry K. Means ◽

Patrick Autissier ◽

Tonia Woodberry ◽

Marcus Altfeld ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Chemokine Receptor ◽

Cd8 T Cells ◽

Molecular Mechanisms ◽

Cell Subset ◽

Cd8 T Cell ◽

Effector Memory ◽

Immune System Activation ◽

Hiv 1

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)–responsive CD8 T-cell subset that was enriched in perforin, granzyme B, and interferon-γ (IFNγ), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1–specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation.

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Dynamics and Correlates of CD8 T-Cell Counts in Africans with Primary Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.01467-16 ◽

2016 ◽

Vol 90 (22) ◽

pp. 10423-10430 ◽

Cited By ~ 1

Author(s):

Heather A. Prentice ◽

Hailin Lu ◽

Matthew A. Price ◽

Anatoli Kamali ◽

Etienne Karita ◽

...

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Human Leukocyte ◽

Neutralizing Antibody ◽

Sensitivity Analyses ◽

Supporting Evidence ◽

Cell Counts ◽

Cellular And Humoral Immunity ◽

Hiv 1

ABSTRACT In individuals with HIV-1 infection, depletion of CD4 + T cells is often accompanied by a malfunction of CD8 + T cells that are persistently activated and/or exhausted. While the dynamics and correlates of CD4 counts have been well documented, the same does not apply to CD8 counts. Here, we examined the CD8 counts in a cohort of 497 Africans with primary HIV-1 infection evaluated in monthly to quarterly follow-up visits for up to 3 years in the absence of antiretroviral therapy. Statistical models revealed that (i) CD8 counts were relatively steady in the 3- to 36-month period of infection and similar between men and women; (ii) neither geography nor heterogeneity in the HIV-1 set-point viral load could account for the roughly 10-fold range of CD8 counts in the cohort ( P > 0.25 in all tests); and (iii) factors independently associated with relatively high CD8 counts included demographics (age ≤ 40 years, adjusted P = 0.010) and several human leukocyte antigen class I (HLA-I) alleles, including HLA-A*03:01 ( P = 0.013), B*15:10 ( P = 0.007), and B*58:02 ( P < 0.001). Multiple sensitivity analyses provided supporting evidence for these novel relationships. Overall, these findings suggest that factors associated with the CD8 count have little overlap with those previously reported for other HIV-1-related outcome measures, including viral load, CD4 count, and CD4/CD8 ratio. IMPORTANCE Longitudinal data from 497 HIV-1 seroconverters allowed us to systematically evaluate the dynamics and correlates of CD8 + T-cell counts during untreated primary HIV-1 infection in eastern and southern Africans. Our findings suggest that individuals with certain HLA-I alleles, including A*03 (exclusively A*03:01), persistently maintain relatively high CD8 counts following HIV-1 infection, a finding which may offer an intriguing explanation for the recently reported, negative association of A*03 with HIV-1-specific, broadly neutralizing antibody responses. In future studies, attention to HLA-I genotyping data may benefit in-depth understanding of both cellular and humoral immunity, as well as the intrinsic balances of these types of immunity, especially in settings where there is emerging evidence of antagonism between the two arms of adaptive immunity.

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Combination of a Sindbis-SARS-CoV-2 spike vaccine and αOX40 antibody elicits protective immunity against SARS-CoV-2 induced disease and potentiates long-term SARS-CoV-2-specific humoral and T-cell immunity

10.1101/2021.05.28.446009 ◽

2021 ◽

Author(s):

Antonella Scaglione ◽

Silvana Opp ◽

Alicia Hurtado ◽

Christine Pampeno ◽

Ziyan Lin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Protective Immunity ◽

T Cell Response ◽

Spike Protein ◽

Effector Memory ◽

World Population ◽

Vaccine Platform ◽

Vaccine Approach

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world population at record speeds. However, there is still demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (OX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T cell response in mice. Protein binding, immunohistochemical and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response that can be used as a new candidate to combat SARS-CoV-2. Given the strong T cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as, serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.

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HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4+ T Cells

Journal of Virology ◽

10.1128/jvi.00374-10 ◽

2010 ◽

Vol 84 (13) ◽

pp. 6505-6514 ◽

Cited By ~ 47

Author(s):

Jennifer M. Pfaff ◽

Craig B. Wilen ◽

Jessamina E. Harrison ◽

James F. Demarest ◽

Benhur Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virologic Failure ◽

Cell Subset ◽

Ccr5 Antagonist ◽

Effector Memory ◽

Drug Resistant ◽

Degree Of Protection ◽

Ccr5 Antagonists ◽

Hiv 1

ABSTRACT We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4+ T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N′ terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a tropism shift toward effector memory cells upon infection of primary CD4+ T cells in the presence of APL, with relative sparing of the central memory CD4+ T cell subset. If such a tropism shift proves to be a common feature of CCR5-antagonist-resistant viruses, then continued use of CCR5 antagonists even in the face of virologic failure could provide a relative degree of protection to the TCM subset of CD4+ T cells and result in improved T cell homeostasis and immune function.

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Short-Lived Effector CD8 T Cells Induced by Genetically Attenuated Malaria Parasite Vaccination Express CD11c

Infection and Immunity ◽

10.1128/iai.00871-13 ◽

2013 ◽

Vol 81 (11) ◽

pp. 4171-4181 ◽

Cited By ~ 20

Author(s):

Laura A. Cooney ◽

Megha Gupta ◽

Sunil Thomas ◽

Sebastian Mikolajczak ◽

Kimberly Y. Choi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Inflammatory Cytokines ◽

Plasmodium Yoelii ◽

T Cell Response ◽

Parasite Development ◽

Effector Memory ◽

Cell Phenotype ◽

Effector Cells ◽

Ifn Γ

ABSTRACTVaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodentPlasmodium yoeliimodel. Protection is dependent on CD8+T cells, involves perforin and gamma interferon (IFN-γ), and is correlated with the expansion of effector memory CD8+T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8+T cell phenotype and demonstrated significant upregulation of CD11c on CD3+CD8b+T cells in the liver, spleen, and peripheral blood. CD11c+CD8+T cells are predominantly CD11ahiCD44hiCD62L−, indicative of antigen-experienced effector cells. Followingin vitrorestimulation with malaria-infected hepatocytes, CD11c+CD8+T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), perforin, and CD107a. CD11c−CD8+T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8+T cells. Coculture of CD11c+, but not CD11c−, CD8+T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8+T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c+CD8+T cell response, but CD11c expression was lost as the CD8+T cells entered the memory phase. Further analyses showed that CD11c+CD8+T cells are primarily KLRG1+CD127−terminal effectors, whereas all KLRG1−CD127+memory precursor effector cells are CD11c−CD8+T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes.

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