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Protective Genes Play Crucial Role in Defense Against HIV
Profound Discoveries From Around the World on HIV Controllers/Long-Term Nonprogressors, Part Two

By Loreen Willenberg

July 21, 2010

This blog entry is the second in a series of reports on a few of the scientific abstracts submitted on the subject of "HIV Controllers (HCs)" and "Long Term Nonprogressors (LTNPs) -- a small minority of HIV-positive people who control the virus in as-of-yet unexplained ways, without antiretroviral therapy.

This year marks two milestones for 1) the number of abstracts submitted for presentation on this subject, and 2) the number of international collaborating clinical research teams -- such as the "CASCADE Collaboration": team members from France, Italy, the Netherlands, the United Kingdom and the United States. The abstracts are representative of eight groups working together across many disciplines and institutions to unlock the mysteries of viral control. In fact, in the many years I've been following developments on this field, I've never seen as many abstracts or so many countries contribute -- last count was 16 -- to the body of knowledge being accumulated on the HC/LTNP group. It's tremendous!

I am grateful for the invitation from the fabulous editorial staff at The Body to highlight a few of the most intriguing abstracts (posted here in abbreviated form) with brief comments on why I believe they are important, not only to members of the HC/LTNP community, but to the entire PLWHA population.

Wednesday, July 21

WEAA01: Correlates of Immune Protection
Oral Abstract Session
Time: 11:00 - 12:30
Chairs: Manuel Romaris, Spain and Rafick-Pierre Sékaly, Canada

WEAA0101: Early Immunological Correlates of Subsequent HIV Progression
Presented by Mario Roederer, United States
P. Chattopadhyay1, Y. Mahnke1, M. Sauer2, T. Brodie1, J. Mascola3, N. Michael4, E. Kallas2, A. Ganesan4, M. Roederer1, and the IDCRP working group

1Vaccine Research Center, NIH, ImmunoTechnology Section, Bethesda, United States, 2Universidade Federal de São Paulo, São Paulo, Brazil, 3Vaccine Research Center, NIH, Bethesda, United States, 4Walter Reed Army Medical Center, Rockville, United States

Background: "SIV (Simian Immunodeficiency Virus) studies reveal dramatic systemic destruction of CD4+ memory T cells during acute disease; this, and early levels of central memory (TCM) subsets predicted survival. In chronic HIV, activated T-cells are powerful predictors of clinical outcome. However, in early HIV, large studies that define predictors are lacking." This study was comprised of 466 treatment naive individuals (enrolled in the US National HIV History Study begun in 1990) and 51 treatment naive individuals (enrolled in an ongoing prospective study) in Brazil. Samples were from the earliest possible time points post- infection (median 225 days after seroconversion); clinical follow-up was substantial (median 4 years).

This team studied the following parameters: 1) T-cell differentiation, proliferation and activation; 2) phenotype and quality of HIV-specific T-cells; 3) cell-associated viral load (CAVL). They found that central memory (TCM) T-cell levels at the earliest HIV+ visit did not predict long-term outcome. However, the following were associated with slower progression: high levels of long-lived cells (naive or CD127 + memory CD8), low Ki-67 expression, and low CAVL during the first 7.5 months. The study team also focused on the markers associated with T-cell activation -- CD38, CCR5, Granzyme B, CD57 -- and noted dramatic differences in the cytokine response profiles to HIV Gag + Env within individuals."

Conclusions: "The results suggest 1) early depletion of precursor cells, mediated by proliferation/differentiation, is a poor prognostic factor independent of antigen load; 2) Ki-67 measurements can inform early treatment decisions; and 3) the quality of the T-cell response to HIV early in disease impacts on progression. Our data define measurements that may identify benefical immunogen-elicited protection in individuals with breakthrough infections in vaccine efficacy trials."

Glossary: Cytokines are powerful chemical substances secreted by cells that enable the body's cells to communicate with one another. [Source: NIAID Science Education brochure; NIH Pulication No. 07-5423; Sept. 2007]. Granzyme B is a protein that in humans is encoded by the GZMB gene. Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells share the remarkable ability to recognize specific infected target cells. They are thought to protect their host by inducing apoptosis, bearing on their surface 'nonself' antigens, usually peptides or proteins resulting from infection by intracellular pathogens. The protein encoded by this gene is crucial for the rapid induction of target cell apoptosis by CTL in cell-mediated immune response. The Ki-67 protein (also known as MKI67) is a cellular marker for proliferation. [Source:].

My Comments: In the era of the "when to start treatment" debate, it never hurts to have new tools in the tool-kit that can help to inform the decision. Measurement of Ki-67, TCM and low CAVL could be those tools. In addition, please note the team's remark about the quality of the T-cell response (activation, differentiation and proliferation) to early infection -- depending upon the results of these novel measurements, the individual being tested may eventually become an HIV Controller and/or a Long-Term Nonprogressor.

WEAA0102: Protective HLA Alleles Limit HIV Reservoir in Long-Term Non-Progressors Central Memory CD4+ T Cells
Presented by Benjamin Descours, France
B. Descours1, V. Avettand Fenoel2, C. Blanc3, A. Samri1, A. Mélard2, V. Supervie4, G. Carcelain1, C. Rouzioux2, B. Autran1, ALT ANRS CO15

1UPMC, Paris VI, umrs945, Paris, France, 2Université Paris Descartes, EA3620, Laboratoire de Virologie, Paris, France, 3UPMC, Paris VI, Plateforme de Cytométrie en Flux inter IFR, Paris, France, 4UPMC, Paris VI, umrs943, Paris, France

Background: (This study observed 18 LTNPs.) "The natural equilibrium between the immune system and HIV observed in LTNP lead us to analyze the impact of HIV reservoir size and distribution among resting CD4 T-cells of i) a strong HIV immune control conferred by the over-represented protective HLA-B*27 and/or -B*57 alleles and ii) a prolonged control of viremia in Long Term Non-progressors-Elite Controllers (LTNP-ECs). The study team observed a hierarchy in HIV distribution among resting CD4 T-cell subsets with the Transitional Memory subset (TTM) as the most infected followed by Central Memory (TCM) cells. Naive (TN) and Effector Memory (TEM) cells equally contributed to the HIV reservoir, though 10-fold less than the TTM and TCM.

Antigen mimicry induced HIV replication in all CD4 subsets except in TN from LTNP-ECs in which, however, IL-7 could rescue HIV production. Interestingly, the lower level of infection observed in TCM reflects a relative protection of TCM only in HLA B*27 and/or -B*57 patients. Lower TCM infection level and preservation of the TCM pool size were both specifically and significantly associated with the stronger HIV-specific CD8 T-cell response observed in such patients. In contrast, the natural control of viremia observed in Elite controllers translated into protection of TN, TCM and TTM without preservation of TEM.

Conclusions: "HLA and elite control impact differently on HIV reservoir distribution over the CD4 T-cell differentiation stages. Elite control implies a wide protection of long-lived cells while strong HIV-specific immunity in HLA-B*27/B*57 patients results in maintenance of a larger and healthier TCM pool, crucial for mounting robust immune responses. Lower level of infection observed in TCM reflects a relative protection of TCM only in HLA-B*27/-B*57 patients. This finding is significantly associated with stronger HIV-specific CD8 T-cell responses observed in such patients."

My Comments: Very important finding. ECs who carry the genes (alleles) HLA-B*27/-B*57 maintain a larger & healthier pool of Central Memory Cells (TCM) that are crucial for mounting robust immune responses, and protect naive cells (TN), central memory cells (TCM) and transitional memory cells (TTM) without preserving effector memory cells.

I think I'll go watch a Turner Classic Movie now! More of Wednesday's presentations tomorrow -- stay tuned.

In solidarity,

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