Natural Killer Cells Are Prominent Factors in Control of HIV

This blog entry is the third in a series of reports on a few of the scientific abstracts submitted for presentation 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 -- to the XVIII International AIDS Conference in Vienna.

I was designated an "elite controller" of HIV in 2004, when few of us were identified and information on our spontaneous and mysterious control of the virus was hard to find. I had just passed the 12th anniversary of my diagnosis by then, and was extremely curious to know what was going on -- was I going to get sick, was I going to die? My own doctor, a specialist in HIV, could not give me an explanation, and Google searches on HCs or LTNPs were not productive either, because I tried.

It's truly remarkable, then, to learn how our mysteries are being solved by researchers around the globe, and it's in this light that I share with you a few of the most intriguing abstracts (posted here in abbreviated form). I have also posted brief comments on why I believe they are important, not only to members of the HC/LTNP community, but to the entire PLWHA population.

The conference has posted full copies of all abstracts as of today, Tuesday. You may access them via this link: http://pag.aids2010.org, giving the page a bit of time to upload.

Wednesday, July 21

WEAA0104: Specific Phenotypic and Functional Features of Natural Killer Cells From HIV-Infected Long-Term Non-Progressors and HIV-Controllers
Presented by Patrice Debré (France) V. Vieillard¹, H. Fausther-Bovendo¹, A. Samri², P. Debré¹, French Asymptomatic á Long Terme (ALT) ANRS-CO15

¹INSERM UMR-S 945, Paris, France, ²IFR113, Paris, France

Background: "Recent evidence suggests that natural killer (NK) cells play a crucial role in the HIV pathogenesis. Long-term non-progressor (LTNP) and HIV-controllers are rare HIV-infected patients who control viral replication and show delayed disease progression. They represent fascinating models of natural protection against disease progression, and for studying the immunological response to the virus."

Methods: "We have conducted an extensive analysis of the phenotypic and functional properties of CD56dim, CD56bright and CD56-/CD16+ NK cell subsets from LTNP and HIV-controllers, and compared them to HIV-progressors and healthy donors."

Results: "Hierarchical clustering analysis of NK phenotypic markers revealed that LTNP and HIV-controllers, exhibit peculiar phenotypic features, associated with high levels of interferon-gamma, activation markers, and cytolytic activity in CD3-CD56+ NK cells against K562 target cells. More importantly, cytolytic activity against autologous CD4+ T cells is abrogated after treatment with anti-NKp44L mAb in LTNP and HIV-progressors, suggesting a key role of NKp44L. In contrast, in HIV-controllers and healthy donors, NKp44L expression on CD4+ T cells and autologous NK lysis were both poorly detected."

Conclusions: "These results show that NK cells from LTNP and HIV-controllers display phenotypic and functional features, which suggest a consistent continuous involvement of the innate immune response in the control of AIDS pathogenesis."

Glossary: Cytotoxic, Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom (e.g. from the puff adder or brown recluse spider). Natural Killer cells (NK) are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses. They kill cells by releasing small cytoplasmic granules of proteins called perforin and granzyme that cause the target cell to die by apoptosis. [Source: Wikipedia.org].

My Comments: Despite the lack of patient information involved in this cohort, I believe these findings are extremely interesting, as they contribute to the ever-expanding body of knowledge about the innate immune responses, specifically NK cells, in the HC/LTNP population. A similar study, conducted four years ago by investigators at Johns Hopkins University School of Medicine, was the first of its kind to conduct a comparison between the "magnitude of NK cell effect and CD8+ T-cell effect in elite suppressors (ES)" (another term used to describe "elite controllers"). The study team stated that NK cells were "a ... less well studied cytotoxic cell" that "may play a role in the control of HIV-1." In a cohort of 9 ES [7 women, 2 men; CD4 range 383-1125; <50 copies/mL], 7 chronic progressors [3 women, 4 men; CD4 range 200-1261; VL range 22,898-61,000 copies/mL] and 9 individuals on therapy [3 women, 6 men; CD4 range 223-1174; <50 copies/ml], the study concluded that CD8+ T-cells from ES were capable of "controlling viral replication in autologous CD4+ T-cells significantly better than CD8+ T-cells from progressors." [Source: O'Connell, et al "Role of Natural Killer Cells in a Cohort of Elite Suppressors: Low Frequency of the Protective KIR3DS1 Allele and Limited Inhibition of Human Immunodeficiency Virus Type 1 Replication In Vitro"; Journal of Virology, May 2009, p. 5028-5034, doi:10.1128/JVI.02551-08].

WEAA0105: CD4 Slope in HIV Elite and Viremic Controllers -- Data From the German NoVi Cohort
Presented by Eva Wolf, Germany
E. Wolf¹, J. Eger², A. Balogh¹, J. Goelz³, J. Brust⁴, J. Rockstroh⁵, S. Koeppe⁶, M. Mueller⁷, F. Mosthaf⁸, C. Mayr⁹, E. Gersbacher¹, H. Jaeger², and the NoVi Study Group

¹MUC Research, Munich, Germany, ²MVZ Karlsplatz-HIV Research and Clinical Care Centre, Munich, Germany, ³HIV Outpatient Practice Kaiserdamm, Berlin, Germany, ⁴Private Practice for Internal Medicine, Hematology and Oncology, Mannheim, Germany, ⁵University Hospital of Bonn, Bonn, Germany, ⁶Private Practice, Berlin, Germany, ⁷Outpatient Practice, Stuttgart, Germany, ⁸Private Practice for Hematology, Oncology and Infectious Diseases, Karlsruhe, Germany, ⁹MVZ -- Aerzteforum Seestrasse, Berlin, Germany

Background: "There is few and inconclusive data on the long-term clinical outcomes in HIV-patients controlling viral replication in the absence of ART (HIV-controllers)." [sic] This team investigated "the evolution of CD4 counts in HCs with undetectable or low viremia in a multi-center cohort study." The cohort was comprised of 82 patients (35 female) with median diagnosis at 29 years of age (range 14-67 years). All patients registered persistent VLs of <500 copies/mL without ART (with a 20% blip allowed) and all registered <350 CD4 counts. Observed for 1.5 years, 94% of patients had >350 CD4 at 10 years diagnosis, with 3 patients in the cohort registering >1000 copies/mL viral loads."

Results: "82 patients were included (35 females). Median age at HIV-diagnosis was 29y (range 14-67). Baseline (BL) was defined as the beginning of the 1.5y-period necessary for eligibility. At BL, median time since HIV-diagnosis was 1.5y (IQR 1.1-8.8). Median absolute and relative CD4 were 665/µl (IQR 570-976) and 34% (IQR 25-41); CD4/CD8-ratio was 0.82 (IQR 0.6-1.1); 42% had a VL<50 copies/ml. Median follow-up was 5.3 y (IQR 3.2-9.2)."

"GEE-estimate of annual CD4-slope is based on 59 patients (who do not differ significantly in BL-characteristics from patients not included) with a median follow-up of 5.3 y (IQR 3.2-8.7). Mean CD4-slope was -7.1/l (95% CI -22.8 - +8.5); in elite controllers with VL ≤50 copies/ml in >50% of measurements, CD4-slope was -6.2/l (95% CI -24.6 - +12.3) compared to -7.9/l (95% CI -33.5 - +17.8) in viremic controllers with VL>50 copies/ml in ≥90% of measurements."

Conclusions: "In this untreated cohort of HCs, CD4 counts remained relatively stable with an annual CD4 slope of -7.1/up. Ten years post diagnosis, in 10% (8) of patients, CD4 was <350. We did not identify significant differences in CD4 slopes between EC and VCs."

My Comments: Important finding! A full 94% of HCs in this cohort retained stable CD4 counts >350 at 10 years duration of infection (although I wish the data was more clear on the results between the elite and viremic controller categories). As for the 8 individuals who experienced drops below 350 (10%), (and an increase in viral loads to >1000 copies/mL), I would have liked to see specific measurements on just how high those VLs went. This commentary would not be complete without my giving major kudos to the investigators for including such a high percentage of women -- 43% -- in this study! Hopefully this becomes a trend, instead of an exception to the rule.

WEAA04: Host Restriction and Innate Immunity to HIV Infection
Oral Abstract Session
Time: Wednesday 21 July, 16:30-18:00
Co-Chairs: Jean-François Delfraissy, France and Frank Kirchhoff, Germany

WEAA0402: Analysis of TRIM5α mRNA Polymorphisms and Characterization of a Novel TRIM5α Variant Found in HIV-1 Long-Term Non-Progressors
P. Hartjen, N. Jensen, S. Frerk, J. Schulze zur Wiesch, J. Hauber, J. van Lunzen Germany

University Medical Centre Hamburg-Eppendorf, HIV Research Laboratory, Hamburg, Germany, Heinrich-Pette-Institute, Dept. for Cell Biology and Virology, Hamburg, Germany

Background: "The tripartite motif protein TRIM5α from rhesus monkeys is a cytoplasmic restriction factor against HIV-1. Although unmodified human TRIM5α is not active against HIV-1, its restriction potential can be significantly increased by modifications. Thus, TRIM5α may be more than a species barrier and TRIM5α-variants may play a role in the delayed disease progression of Long-Term-Non-Progressors (LTNP)."

Methods: "TRIM5α cDNA from 10 subjects of either of the following groups was isolated and sequenced: a) LTNP or "slow progressors", who maintain a viral load <2000 copies/ml and CD4 counts of >500 cells/µl without any treatment for up to 10 years; b) patients in various stages of progressive disease and c) HIV-1 negative individuals as normal controls. Selected TRIM5α sequences were subcloned into a retroviral vector for functional studies in mammalian cells."

Results: "8 mutations were found in TRIM5α-cDNAs from the study group, of which 3 have previously been described by other authors. Interestingly, sequencing of huTRIM5α mRNA revealed a novel 100 bp (767-867) deletion-variant in the LTNP group, occurring in 3 of the 10 LTNP individuals but only in one seronegative control and in none of the individuals with progressive disease. Interestingly, this TRIM5α mutant (δ767-867), which is unrelated to known mutations in the SPRY region, has not been described in studies investigating genomic DNA samples. In an infection assay employing stably transfected canine Cf1Th cells and VSV-G-pseudotyped HIV-1-GFP particles, the TRIM5α(δ767-867) variant clearly reduced the rate of HIV-1 infection."

Conclusions: "TRIM5α (δ767-867) may confer protective effect against HIV-1 infection potentially representing a cellular factor that effects the delayed progression in LTNP patients."

My Comments: Novel is good. This German team finds a novel deletion-variant, TRIM5α (δ767-867) in 30% of the LTNPs (3 of 10) that may confer a protective effect against HIV-1 infection, and state that it may represent a cellular factor that contributes to delayed progression in LTNPs. Hopefully soon, geneticists working on genome-wide association scans (GWAS) can elucidate this novel finding, and, with the current explosion of innovative approaches to immune-based and stem-cell therapies, the modification of this "mutant" TRIM5α-variant could be achieved to aid in halting progression in the general PLWHA population.

By now, dear reader, you may realize that we are witnessing one of the finest moments in the research field, as the dedicated scientists hone in on the remarkable miracle that is spontaneous control of HIV. When you consider that the killer T-cell was discovered in 1989 (thank you, Dr. Bruce Walker), you might agree that huge strides are being made in regard to our immune response to HIV infection. I'll be back tomorrow with highlights of abstracts that focus on memory B-cells, genes that confer protection against progression of disease, and, last but not least, a new discovery on how elite controllers resist, that's right, resist, HIV.

In solidarity,
Loreen

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