July 20, 2010
As many of you may know, I am a publicly visible member of a small minority of HIV-positive people who control the virus in as-of-yet unexplained ways; we are called "HIV controllers" (HCs) and/or "long-term nonprogressors" (LTNPs). In addition to participation in 13 separate clinical research studies in the United States, I have established the Zephyr L.T.N.P. Foundation to link members of this community to studies, provide support services and to maintain the topic of HCs/LTNPs in the public view. As of today, only 1,725 of us have been identified worldwide, and each of us contributes valuable clues toward a better understanding of the human immune response to HIV. It is our collective hope that, through our contributions to science, we may help to advance the development of a therapeutic vaccine for HIV/AIDS, as well.
I'm pleased to report there are over 30 abstract submissions to this year's conference from research teams located in 10 different countries -- Bulgaria and the Russian Federation have chimed in, too -- about their findings on HCs/LTNPs. A few of these have literally knocked me off my chair, so profound are their conclusions, but all of them herald a time of discovery and a huge leap toward the reasons for our "mechanisms of control." I will be highlighting a few of the most promising abstracts (in abbreviated form) with brief comments on why I (humbly) believe the findings are important to achieving the goal.
A symposium session on "Innate Immunity -- Key to Control?" took place on Monday. As these sessions are not available on Webcasts, I am not able to report on the presentations given. However, the paragraph describing the symposia content is interesting, and gives us a view on what was discussed:
MOSY05: Innate Immunity -- Key to Control?
Time: Monday, 19 July, 14:30-16:00
Co-Chairs: Richard Koup, United States, and Christine Rouzioux, France
This session highlights and summarizes recent findings on innate defense mechanisms against HIV infection. The first two presentations will focus on recently defined host restriction factors, their mechanism of action against HIV and how the virus overcomes their interference. The third and fourth presentation will focus on innate cellular defense by discussing the role of natural killer cells and dendritic cells in HIV infection. In sum, this session will provide the participants with an overview of the most prominent innate defense mechanisms and will provide insights into the interplay of HIV and host factors.
MOSY0502: Innate Control of HIV
F. Kirchhoff, Germany
MOSY0503: Innate Sensing and Restriction of HIV-Infected Lymphocytes
O. Schwartz, France
MOSY0504: Multifaceted Interactions of Retroviruses With the Complement System
H. Stoiber, Austria
TUPDA1: Role of Dendritic Cells in HIV Infection
Oral Poster Discussion
Time: Tuesday, 20 July, 13:00-14:00
Chair: Heribert Stoiber, Austria
Presented by Mathias Lichterfeld, United States
H. Chen1, T. Cung1, K. Seiss1, J. Beamon1, J. Huang1, P. Burke1, B. Ryan1, L. Porter1, R. Weiss2, A. Brass1, E. Rosenberg3, B. Walker1, X. Yu1, M. Lichterfeld3
1Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, United States, 2University of California at Davis, Davis, United States, 3Infectious Disease Division, Massachusetts General Hospital, Boston, United States
Background: "Elite" controllers are a small population of HIV-1 infected persons with undetectable viremia in the absence of antiretroviral therapy, but correlates of immune protection in this patient population are ill defined. Here, we investigated the susceptibility of CD4 T cells from elite controllers to HIV-1 infection, and tested how p21, a host protein that can inhibit HIV-1 replication in hematopoietic stem cells, modulates HIV-1 replication steps in these cells. The identification of unique immunological characteristics of ECs is a premier opportunity for determining components of immune protection against HIV-1. ECs have significantly better antigen-presenting properties, compared to HIV-1 progressors and "preferentially" induced memory-cell like allostimulatory responses with upregulation of CD62L, CD127, and down-regulation of CD57, plus weaker abilities (TNF-a, IL-6 and IL12p70) in comparison to HIV progressors and HIV negative controls.
Conclusions: HIV-1 "elite" controllers have myeloid dendritic cells with a unique combination of increased antigen presenting and decreased cytokine-section properties. This extraordinary functional profile is mediated and maintained by upregulation of the immunomodulatory receptors ILT2 and ILT5. Manipulation of ILT-mediated dendritic cell function might thus represent a promising strategy for immunological approaches to treatment and prevention of HIV-1 infection. These data indicate that the selective upregulation of p21 represents a natural barrier against HIV-1 reverse transcription and mRNA transcription in CD4 T cells from elite controllers, and significantly contributes to the ability of elite controllers to maintain undetectable viral replication. Manipulation of p21 may provide novel opportunities to increase hosts resistance to HIV-1 infection.
Glossary: A dendritic cell (DC) is an immune cell with highly branched extensions that occurs in lymphoid tissues, engulfs microbes, and stimulates T cells by displaying the foreign antigens of the microbes on their surfaces. [Source: NIAID Science Education brochure; NIH Publication No. 07-5423; Sept. 2007].
My Comments: A major discovery, this protein (p21) is expressed at 10- to 20-fold higher levels in the CD4 T-cells of elite controllers (n = 15) when compared to the other participants in the study -- HIV-1 progressors (n = 16) and HIV-1-negative persons (n = 14). It makes the process by which the virus changes its genetic material (RNA) into our own (DNA), called "reverse transcriptase," less effective and translates into a lower rate of replication of HIV within the host. I'm excited to read that this finding may represent a "promising strategy for immunological approaches to treatment and prevention of HIV-1 infection" (in another version of the abstract).
Poster Exhibition (PE)
TRACK A -- Basic Sciences
PE0001-PE0034: Viral Persistence and Latency
TUPE0011: HIV-Controllers With a Known Date of Seroconversion -- What Happens Before and During HIV-Control, Results From CASCADE
Y. Madec1, F. Boufassa1, M. Prins2, C. Sabin3, A. d'Arminio Monforte4, P. Amornkul5, A. Venet1, O. Lambotte1, K. Porter3, L. Meyer1, CASCADE Collaboration
1France, 2Netherlands, 3United Kingdom, 4Italy, 5United States
Background: This team created a data-set from 19,615 HIV-positive participants involved in 24 separate studies in Europe, Australia and the US. They identified 125 controllers (0.064%) with a known date of seroconversion. 60 controllers (48% of cohort) had a first VL registered within 24 months of infection (range was 6 months to 3.9 years). In general, the mean average of duration of infection for all participants was 14.8 years. End of control, defined as 2 consecutive VL >2000 copies/mL, occurred in 20 controllers (16%).
Conclusions: HIV control may occur late after seroconversion. HIV control lasted more than 15 years in 50% of the HIV Controllers.
My Comments: First, this study reflects the most quoted range of percentiles used (0.05% to 15%) for the HC/LTNP sub-group within the general PLWHA (people living with HIV/AIDS) population. For individuals who find themselves designated as "slow progressors" (SLPs) or "viremic controllers" with concerns about progression, the results of this study may be encouraging. By my math, I show that 84% of HCs did not lose viral control after 14.8 years of infection: [n = 125] - [n = 20] = 105 controllers (84%). Though, I need to study the full paper to know for sure. I am, however, delighted to see the collaboration here between France, the Netherlands, Italy, the United Kingdom and the United States!
Stay tuned for my report on Wednesday's presentations -- I'll be reviewing four very important abstracts that will advance the dialogue on the markers associated with T-cell activation, genes that confer protection against disease progression, and those productive little devils known as "natural killer" (NK) cells!