Background:  HIV-1 infection leads to severe immunodeficiency in most infected subjects in an average of 10 years; however, there are marked departures from this estimate. The study of extreme phenotypes of HIV-1 infection course, such as elite controllers or rapid progressors, provides significant information in terms of the interactions between the viral variants and the host during primary HIV infection and the subsequent clinical evolution. Another interesting but still unexplored group are the extreme viremic non-progressors (VNP), which present a profile of tolerance of viral replication, reminiscent of the pattern of SIV infection in the natural host. Here, we compare the cytokine profiles in the plasma of VNP and subjects with HIV-1 standard progression (SP).

Methods:  A multiplex assay was used to assess the concentration of 27 cytokines in plasma of 5 well-defined VNP and 39 SP. In addition, sCD14 levels were assessed by ELISA. Two-tailed Mann-Whitney test was used for comparison of concentrations in each group, before and after viral load stratification.

Results:  Despite the low number of VNP, nominal significant differences were found when compared to the SP group. Tumor necrosis factor α (TNF-α) (p = 0.002) or interleukin-8 (IL-8) (p = 0.019), classically associated to high viremia, showed higher concentrations in VNP. In contrast, sCD14 was similar in both groups, demonstrating the limited immune activation, which might have been expected to be high due to the elevated virus levels in VNP. Of note, we found that a number of hematopoietic growth factors and cytokines playing a role in differentiation, proliferation, and/or survival of different immune cells subsets, showed higher concentrations in VNP, in comparison to individuals with a typical disease course. Specifically, 4 cytokines achieved nominal statistical significance: IL-7 (p = 0.036), IL-9 (p = 0.005), eotaxin (p = 0.010), and IL-4 (p = 0.043), which seem to be associated to natural control of HIV-1 infection despite high viremia.

Conclusions:  VNP represent a clearly distinct phenotype that has not been comprehensively studied. Its characterization should complement HIV immune-pathogenesis obtained from other extreme phenotypes. The present study shows that, despite having high levels of viremia, HIV-1-infected individuals can be able of naturally controlling the disease by potentiating specific mechanisms of immune homeostasis, differentiation, proliferation, and cell survival, avoiding general immune activation and massive T cell loss.