A 38 years-old moderate hemophiliac A male patient was diagnosed to be co-infected with HIV (Subtype B, CCR5+) and HCV (Subtype 4), both transmitted by a blood transfusion received in 1982 during hip surgery for a fracture. Diagnoses of these infections were respectively ascertained in 1988 and 1998.
Since 1989, he received different lines of anti-retroviral treatment (ART) then HAART (Highly Active Anti-Retroviral Therapy) with poor compliance, voluntary interruption until 2008, and correct compliance since then. A 215S mutation of the HIV virus reverse transcriptase, which induces resistance to the anti-retroviral drug azidothymidine was consequently identified. His HCV infection (Metavir score A0A1-F1F2 determined by biopsy and checked regularly by noninvasive markers of hepatitis inflammation/fibrosis) was never treated. Moreover his hepatic assessment, as observed with L-aspartate aminotransferase (ASAT), L-alanine aminotransferase (ALAT) and gammaGT gamma-glutamyltransferase markers is not so much disrupted (Figure 1A).
The patient received prosthesis of the left eye in 1996 after a paintball accident and a hip replacement in 2011 for osteo-necrosis known since 1982. None of these surgeries were accompanied by infectious side effects. Indeed, over these 30 years and despite an extremely low number of T lymphocytes, the patient displayed neither opportunistic infections, nor HIV-related cancer, nor HCV-hepatitis damages. In 1989 his initial CD4+ T-cells count was 196/mm3 and since 1995 remains between 5 and 59/mm3 (Figure 1B). HIV viral loads have been mostly undetectable (below 40 copies/mL) or very low (matching deliberate HAART interruptions) since 2008 (Figure 1B).
Over the past two years, the immunophenotypic and functional status of his CD3-CD56+ NK-cells were explored by multi-parameter flow cytometry (reagents from Becton Dickinson, MountainView, CA, Figures 2A-D). Surprisingly, an abnormally high percentage of NK-cells has been steadily observed, representing approximatively 40% of peripheral lymphocytes and characterized by an expansion of the CD56bright subset (~30 to 50% of NK-cells) (Figures 2A and 2B). The percentage of CD56bright cells seems to increase when the number of CD4 decreases moreover HIV viral load is below 40 copies/ml when % of CD56bright cells is the more important (Figure 2B). These cells display high levels of natural cytotoxicity receptors NCR1 (NKp46), NCR3 (NKp30) and NKG2D compared to CD56dim cells, and have a low expression of NCR2 (NKp44) and CD69, with no labeling for CD57 nor CD25 (data not shown). The inhibitory CD94/NKG2A receptor is expressed by all CD56bright cells and a majority of CD56dim NK-cells while there is a low expression of CD158b on CD56dim and CD56bright NK-cells and a faint labeling with CD158a (Figure 2C).
Surprisingly, the NK degranulation potential (% of CD107a) that correlates with target cytolysis, usually exerted by the CD56dim NK subset, is here mainly performed by CD56bright NK-cells. Strikingly, these cells did not produce IFN-gamma following NK activation by K562 (Figure 2D).
In addition, no Th1/Th2 cytokines (TNF-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-10) have been detected in the patient's serum (data not shown).