Several studies have reported that in HIV infection, and even more in HIV/HCV co-infection, NK cells most often lack CD56 expression and have impaired functions [10–12], opposite to what was observed in the patient reported here. However, at least one study  reported a similar quantitative imbalance of CD56bright and CD56dim NK-cells in HIV or HCV patients as shown here. Two possibilities could explain this profile. The first is an alteration in the tissue localization of NK-subsets in tissues as there could be selective trapping in the liver in HCV infection or in lymph nodes (LN) in HIV infection . Secondary lymphoid tissues, and particularly LN, are important sites for HIV replication and NK development. In HIV patients, the disruption of LN architecture could interfere with the numbers of CD56bright cells reaching the circulation , and the increase of circulating CD56bright NKG2A+ cells could thus be caused by NK activation and release from LN [15, 16].
The other hypothesis is that impairment in NK-cell homeostasis, in HIV and HCV infections, could result from different behaviors of NK-subsets. An imbalance between CD56+ NK-subsets could indeed result from an enhanced production, expansion or survival of the CD56bright pool accompanied by a decreased generation or survival of CD56dim NK-cells .
When altered CD56dim/bright NK-cell ratios have been reported in asymptomatic HIV or HCV patients with low CD4+ counts, viral loads remained detectable [10, 13]. Ironson et al.  indeed described a rare group of HIV patients with very low CD4+ T-cells counts who displayed prolonged asymptomatic periods. These patients presented higher NK-cell numbers and cytotoxic potential than HIV patients with high CD4+ counts. However, unlike the patient we report upon, they retained an elevated viral load .
The particular immunophenotype observed here, characterized by high CD56bright numbers, recalls that of NK-cells from low viremic HIV patients with high numbers of CD4+ T-cells , yet our patient never recovered normal CD4+ counts.
The cytokine microenvironment may also alter the immunophenotype of NK-cells. Since IL15 and/or IL21 [13, 18] regulate NK homeostasis and effector functions, the absence of IL-15 production could favor CD56bright NK-cells and thus induce a change in CD56bright/dim proportions. Indeed, no IL-15 could be detected in the patient’s serum.
NKp44, usually induced on activated NK-cells, has been shown to be overexpressed by HIV patients with low CD4+ T-cells  and to be involved in CD4+ T-cell lysis [20, 21]. However, in the present case, NKp44 is faintly expressed by CD56bright NK-cells, thus likely not involved in CD4+ depletion through this pathway. High NKG2A expression, as observed here, has conversely been associated with the escape of HIV infected CD4+ T-cells from NK-cell killing . We cannot however exclude a lysis of CD4 cells by NK-cells, since the patient’s CD56bright cells were clearly efficiently activated by the K562 cell line [7, 8].
The replacement of CD56+ NK-cells by functionally defective CD56- NK-cells is one of the mechanisms underlying the impaired NK response commonly observed in HIV and HIV/HCV patients [23, 24]. However, in the present case, CD56-CD16+ cell numbers are low and CD56bright cells are functional, suggesting that an unusual scenario is involved to contain HIV and possibly HCV  infection.
As a whole, the functional status of this patient’s NK-cells is different from that observed in HIV or HCV infected patients for whom NK cytotoxicity relies on the CD56dim compartment [10, 13].
It is finally of interest to note that hemophiliac patients with HCV or HCV/HIV infections have been shown to be at risk of developing cancers . The special NK responses observed here could therefore also be involved in the protection of this patient towards the development of secondary complications linked to HIV/HCV infections.