Research Abstracts

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1   Link   Multiple‐Cohort Genetic Association Study Reveals CXCR6 as a New Chemokine Receptor Involved in Long‐Term Nonprogression to AIDS
The Journal of Infectious Diseases 2010;202:908–915
0022-1899/2010/20206-0014$15.00
DOI: 10.1086/655782
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2   Link   HIV Controllers HLA-DRB1*13 and HLA-DQB1*06 Have Strong, Polyfunctional Mucosal CD4+ T-cell Responses
JVI Accepts, published online ahead of print on 18 August 2010
J. Virol. doi:10.1128/JVI.00980-10
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3   Link   Immunodominant HIV-Specific CD8+ T-cell Responses are Common to Blood and Gastrointestinal Mucosa, and Gag-specific Responses Dominate in Rectal Mucosa of HIV Controllers.
J Virol. 2010 Jul 28. [Epub ahead of print]
PMID: 20668079 [PubMed - as supplied by publisher]
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4   Link   High Levels of CD57+CD28- T-Cells, Low T-Cell Proliferation and Preferential Expansion of Terminally Differentiated CD4+ T-Cells in HIV-Elite Controllers
Curr HIV Res. 2010 Jul 19. [Epub ahead of print]
PMID: 20636274 [PubMed - as supplied by publisher]
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5   Link   How Do HIV Elite Controllers Do What They Do?
15 July, 2010
Clinical Infectious Diseases 2010;51:239–241
1058-4838/2010/5102-0017$15.00
DOI: 10.1086/653678
2398
6   Link   Long-term Nonprogressive Disease Among Untreated HIV-Infected Individuals / Clinical Implications of Understanding Immune Control of HIV
JAMA Vol. 304 No. 2, July 14, 2010
JAMA. 2010;304(2):194-201. doi:10.1001/jama.2010.925
1994
7   Link   Correlates of spontaneous viral control among long-term survivors of perinatal HIV-1 infection expressing human leukocyte antigen-B57.
AIDS. 2010 Jun 19;24(10):1425-35.
PMID: 20539088 [PubMed - in process]PMCID: PMC2903552 [Available on 2011/6/19]
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8   Link   Infrequent Recovery of HIV from but Robust Exogenous Infection of Activated CD4+ T Cells in HIV Elite Controllers
15 July 2010 Volume 51, Number 2
Clinical Infectious Diseases 2010;51:233–238
1058-4838/2010/5102-0016$15.00
DOI: 10.1086/653677
2287
9   Link   Host and Viral Genetic Correlates of Clinical Definitions of HIV-1 Disease Progression
Received: March 30, 2010; Accepted: May 21, 2010; Published: June 11, 2010
Casado C, Colombo S, Rauch A, Martínez R, Günthard HF, et al. (2010) Host and Viral Genetic Correlates of Clinical Definitions of HIV-1 Disease Progression. PLoS ONE 5(6): e11079. doi:10.1371/journal.pone.0011079
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10   Link   Perforin Expression Directly Ex Vivo by HIV-Specific CD8+ T-Cells Is a Correlate of HIV Elite Control
Received: December 23, 2009; Accepted: April 22, 2010; Published: May 27, 2010
Citation: Hersperger AR, Pereyra F, Nason M, Demers K, Sheth P, et al. (2010) Perforin Expression Directly Ex Vivo by HIV-Specific CD8+ T-Cells Is a Correlate of HIV Elite Control. PLoS Pathog 6(5): e1000917. doi:10.1371/journal.ppat.1000917

Editor: Joel Blankson, Johns Hopkins School of Medicine, United States of America

Received: December 23, 2009; Accepted: April 22, 2010; Published: May 27, 2010
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11   Link   Impaired Replication Capacity of Acute/Early Viruses in Persons Who Become HIV Controllers
Journal of Virology, August 2010, p. 7581-7591, Vol. 84, No. 15
0022-538X/10/$012.00+0 doi:10.1128/JVI.00286-10
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12   Link   Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection
Nature 465, 350-354 (20 May 2010) | doi:10.1038/nature08997; Received 13 October 2009; Accepted 11 March 2010; Published online 5 May 2010
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13   Link   Control of HIV-1 in Elite Suppressors despite Ongoing Replication and Evolution in Plasma Virus
Journal of Virology, July 2010, p. 7018-7028, Vol. 84, No. 14
0022-538X/10/$012.00+0 doi:10.1128/JVI.00548-10
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14   Link   AIDS Vaccine Conference, Paris, October 19-22, 2009: Rapid perforin upregulation by CD8 T cells in elite controllers as a correlate of immune-mediated control of HIV replication
AR Hersperger, et al
Background:
Evidence suggests that CD8 T cells are important to the control of HIV replication in elite controllers. However, the mechanism behind the enhanced suppressive capacity of CD8 T cells in these subjects remains unclear.
Methods:
We have recently discovered the novel ability of human CD8 T cells to rapidly upregulate perforin following antigen-specific stimulation. Using polychromatic flow cytometry and standard intracellular cytokine staining assays, we measured perforin expression, cytokine production, and degranulation by CD8 T cells following stimulation using overlapping peptide pools encompassing the entire HIV proteome. We studied several HIV-infected groups that differentially control viral replication off therapy: elite controllers (n = 34), viremic controllers (n = 29), chronic progressors (n = 24), and viremic nonprogressors (n = 6).
Results:
We observe that on average 40% of the total CD8 T cell response in elite controllers is perforin-positive following HIV-specific stimulation compared to 20% in the other cohorts. However, the proportion of the HIV-specific CD8 T cell response that produces IFN-gamma does not vary widely between the groups. Elite controllers have a significantly larger proportion of responding CD8 T cells that degranulate yet remain perforin-positive following 6 hours of stimulation, suggesting that CD8 T cells in these individuals have an increased capacity to upregulate new perforin production. The cells that express perforin, which are enriched in elite controllers, display almost entirely an effector phenotype (CD27negCD45ROnegCD57+/-). Overall, there is a strong negative correlation (p
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15   Link   9/4/09 Effector mechanisms in HIV-1 infected Elite Controllers: Highly Active Immune Responses?
J. Blankson.
Elite controllers (EC) are HIV-1 infected patients control viral replication to a level of controllers,
and they differ from traditional long-term non-progressors (LTNPs) who maintain stable CD4 counts and
are asymptomatic without antiretroviral therapy. Recent studies suggest that many EC are infected with
replication-competent virus. Thus it appears that host factors such as innate immunity, the humoral
immune response, and the cellular immune response are involved in the suppression of viral replication
in EC. This article will review the effector mechanisms that are thought to play a role in the remarkable
control of viral replication seen in these patients.
This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretro-
viral drug discovery and development, Vol 85, issue 1, 2010.
2009 Elsevier B.V. All rights reserved.
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16   Link   9/2009 Elucidating the elite: mechanisms of control in HIV-1 infection K. O'Connell, et al.
Trends Pharmacol Sci. 2009 Dec;30(12):631-7.

Elucidating the elite: mechanisms of control in HIV-1 infection.

O'Connell KA, Bailey JR, Blankson JN.

Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

Abstract
In patients with progressive disease, untreated HIV-1 infection is characterized by high viral loads and decreasing CD4(+)T cell counts which lead to opportunistic infection and other AIDS-defining illness. A rare subset of patients termed 'elite controllers' (ECs) maintain control over viremia and often retain normal CD4(+)T cell levels without treatment with antiretroviral drugs. For the most part these patients are infected with replication-competent, fit virus. Factors such as strong, polyfunctional cytotoxic T lymphocyte (CTL) responses and retention of T cell proliferative ability appear to be important in control of HIV-1. Defining what enables ECs to control viral replication will aid in the development of effective vaccine and treatment regimens. This review will discuss differences between ECs and progressors while emphasizing recent findings on the immunological response of ECs to HIV-1.
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17   Link   Human Immunodeficiency Virus Type 1 Elite Neutralizers: Individuals with Broad and Potent Neutralizing Activity Identified by Using a High-Throughput Neutralization Assay together with an Analytical Selection Algorithm (Abstract)
The development of a rapid and efficient system to identify human immunodeficiency virus type 1 (HIV-1)-infected individuals with broad and potent HIV-1-specific neutralizing antibody responses is an important step toward the discovery of critical neutralization targets for rational AIDS vaccine design. In this study, samples from HIV-1-infected volunteers from diverse epidemiological regions were screened for neutralization responses using pseudovirus panels composed of clades A, B, C, and D and circulating recombinant forms (CRFs).
Initially, 463 serum and plasma samples from Australia, Rwanda, Uganda, the United Kingdom, and Zambia were screened to explore neutralization patterns and selection ranking algorithms. Samples were identified that neutralized representative isolates from at least four clade/CRF groups with titers above prespecified thresholds and ranked based on a weighted average of their log-transformed neutralization titers. Linear regression methods selected a five-pseudovirus subset, representing clades A, B, and C and one CRF01_AE, that could identify top-ranking samples with 50% inhibitory concentration (IC50) neutralization titers of 100 to multiple isolates within at least four clade groups. This reduced panel was then used to screen 1,234 new samples from the Ivory Coast, Kenya, South Africa, Thailand, and the United States, and 1% were identified as elite neutralizers. Elite activity is defined as the ability to neutralize, on average, more than one pseudovirus at an IC50 titer of 300 within a clade group and across at least four clade groups. These elite neutralizers provide promising starting material for the isolation of broadly neutralizing monoclonal antibodies to assist in HIV-1 vaccine design.

Journal: Journal of Virology
Citation: Journal of Virology, July 2009, p. 7337-7348, Vol. 83, No. 14
0022-538X/09/$08.00+0 doi:10.1128/JVI.00110-09
Received: January 16, 2009; Accepted: April 22, 2009; Published: July 2009
Copyright: © 2009, American Society for Microbiology. All Rights Reserved.
Abstract Link: Journal of Virology
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18   Link   AIDS Vaccine Conference, Paris, October 19-22,2009: High Avidity CD4+ T cell response directed to an immunodominant Gag epitope in HIV controllers: an ANRS EP36 study
B. Vingert, et al
Background:
Evidence suggests that CD8 T cells are important to the control of HIV replication in elite controllers. However, the mechanism behind the enhanced suppressive capacity of CD8 T cells in these subjects remains unclear.
Methods:
CD4+ T cell lines were derived from patients who spontaneously controlled HIV replication (HIV controller group, n = 17) and patients who achieved viral control following successful antiretroviral therapy (HAART group, n = 20). Cell lines were compared for growth kinetics, Vβ repertoire, and sensitivity to antigen.
Results:
Specific cell lines were obtained at high rate for both HIV controllers (16/17) and efficiently treated patients (19/20) in response to the immunodominant Gag293 peptide. However, lines from controllers showed faster growth kinetics than those of treated patients. After normalizing for growth rates, IFN-γ responses directed against the immunodominant Gag293 peptide showed higher functional avidity in HIV controllers, while responses to Gag161, Gag263, or CMV peptides did not differ between groups. Characterization of Gag293-specific CD4+ T cells through MHC class II tetramer labeling revealed a diverse Vβ repertoire, suggesting that multiple clones contributed to the high avidity CD4+ T cell population in HIV controllers. The high functional avidity of the Gag293-specific response could be explained, at least in part, by a high avidity interaction between the TCR and the peptide-MHC complex, as demonstrated by class II tetramer binding.
Conclusion:
This study provides evidence that HIV controllers harbor a pool of high avidity memory CD4+ T cell precursors directed against an immunodominant Gag peptide. The capacity to mount a rapid CD4 response in the presence of minimal amounts of Gag antigen helps explain how HIV controllers maintain an active antiviral response in the face of very low viremia.

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19   Link   Transient Nature of Long-Term Nonprogression and Broad Virus-Specific Proliferative T-Cell Responses with Sustained Thymic Output in HIV-1 Controllers (Abstract)
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.

Journal: PLoS ONE
Citation: Westrop SJ, Qazi NA, Pido-Lopez J, Nelson MR, Gazzard B, et al. (2009) Transient Nature of Long-Term Nonprogression and Broad Virus-Specific Proliferative T-Cell Responses with Sustained Thymic Output in HIV-1 Controllers. PLoS ONE 4(5): e5474. doi:10.1371/journal.pone.0005474
Editor: Rupert Kaul, University of Toronto, Canada
Received: February 10, 2009; Accepted: March 30, 2009; Published: May 12, 2009
Copyright: © 2009 Westrop et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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20   Link   Elite Controllers May Experience Higher Immune Activation Levels Than Other HIV-Infected Patients, Spurring Concerns of CD4+ Decline
BY:
Gerald Pierone Jr., M.D.

DATE:
6 February 2008

PUBLISHED BY:
The Body

SUMMARY:
An Interview With Peter Hunt, M.D.

There's nothing like hearing the results of studies directly from those who actually conducted the research. It is these women and men who are transforming HIV treatment and care. In this interview, you'll meet one of these impressive HIV researchers and read an explanation of the study he presented at CROI 2008. The interview was conducted by Gerald Pierone, M.D., an HIV clinician/researcher and the founder and executive director of the AIDS Research and Treatment Center of the Treasure Coast in Fort Pierce, Fla.
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21   Link   HIV Controllers: Mechanisms of Durable Virus Control in the Absence of Antiretroviral Therapy
BY:
Steven G. Deeks and Bruce D. Walker

DATE:
30 Septmber 2007

PUBLISHED BY:
Immunity

SUMMARY:
Chronic viral infections can appear in two very different forms: those that are typically immunologically contained after acute symptomatic infection, such as Epstein-Barr virus (EBV), and those that predictably lead to persistent viremia and progressive clinical disease. Human immunodeficiency virus (HIV) infection is typical of the latter and has resulted in more than 20 million deaths worldwide. Here we review a remarkable subset of persons infected with HIV who are able to achieve long-term control of viremia and avoid immunodeficiency without the need for antiviral therapy. We review the contributing role of host genetic factors, innate and adaptive immune responses, and viral factors that may contribute to this phenotype. These individuals indicate that as with other potentially pathogenic chronic viral infections, the human immune system is able to fully control HIV and prevent HIV-associated disease, at least in some individuals. Further understanding of the mechanisms whereby this occurs should yield critical insights for prophylactic and therapeutic antiviral interventions.
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CROI 2011

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    There is increasing evidence of the transmission of HIV strains with resistance to anti-HIV drugs in low- and middle-income countries. Research in eleven sub-Saharan African countries showed that the chances of detecting transmitted resistance increased by over a third each year that a country had been scaling up HIV treatment. A separate study involving people recently diagnosed
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Controllers in Study

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86%

Our Goal:
2000
Currently:
1725
Updated:
December 30, 2009

Current Breakdown: 505 Elite Controllers 1009 Viremic Controllers 211 Other