Ssed by Spearman correlation. BFA biological activity compared with HIV-negative MSM, XAV-939 web HIV-infected individuals had significantly increased multiple plasma cytokines, including GM-CSF, IFN-2, IL-12p70, IP-10 and VEGF, during both acute and chronic stages of infection. Furthermore, rapid disease progressors (RDPs) had earlier and more robust cytokine storms, compared with slow disease progressors (SDPs) (49.6 days vs. 74.9 days, respectively; 6.7-fold vs. 3.7-fold change of cytokines, respectively), suggesting the faster and stronger cytokine storm during AHI could promote disease progression. On the other hand, HIV-1 infection induced more interlocked cytokines network, establishing new strong correlations and imposing a higher rigidity. There were, respectively, 146 (44.9 ) statistically significant correlations of cytokines in RDPs and 241 (74.2 ) in SDPs (p < 0.001). This study suggests that immunomodulatory interventions aimed at controlling cytokine storm in AHI may be beneficial to slow eventual disease progression. When the immune system is fighting pathogens, cytokines activate immune cells such as T cells and macrophages, stimulating them to produce more cytokines resulting in so-called cytokine storms or cascades1,2. There is growing evidence that the immune responses initiated during acute HIV infection can play critical roles in modulating of disease progression. Several studies investigated the cascade of cytokine production in the periphery and show an initial rapid production of IFN-, followed by tumor necrosis factor (TNF)-, inducible protein (IP)-10, and interleukin (IL)-18, IL-10 and IFN- production, while others have not observed these changes or have reported opposing findings3?. The discrepancies likely reflect the diversity and unity of dynamics during AHI but also could be due in part to the variation in the timing of sample collection among studies. Some studies were cross-sectional, while others focused on time points relatively late in AHI9,10. The cytokine storms during AHI can act as a double-edged sword, as they have the potential to cause significant damage to virus-specific immunity but also inhibit infection by reducing T cell recruitment and activation11. Some studies show that type I-IFN plays a role in slowing disease progression by inducing multiple antiviral genes and limiting initial viral replication, while others have reported that type I-IFN signaling is linked to immune activation and viral persistence and blocking of type I-IFN during LCMV infection enhances viral clearance12?4. These contradictory reports suggest that there is a need to investigate the dynamic of cytokines in natural HIV-1 infection. HIV-1 infection does not only increase cytokine levels, but also reorganizes cytokine networks, establishes new strong correlations between various cytokines and thus imposes a high rigidity to the cytokine network15,16.Center for Infectious Diseases, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China. 2Infectious Diseases Department, Peking Union Medical College Hospital, Beijing, 100730, China. 3The Aaron Diamond AIDS Research Center, New York, NY 10016, United States. 4School of Biomedical Engineering, Capital Medical University, Beijing 100069, China. *These authors contributed equally to this work. Correspondence and requests for materials should be addressed to H.C. (email: [email protected]) or H.L. (email: [email protected]) or H.W. (email: [email protected])Scientific RepoRts | 6:36234 | D.Ssed by Spearman correlation. Compared with HIV-negative MSM, HIV-infected individuals had significantly increased multiple plasma cytokines, including GM-CSF, IFN-2, IL-12p70, IP-10 and VEGF, during both acute and chronic stages of infection. Furthermore, rapid disease progressors (RDPs) had earlier and more robust cytokine storms, compared with slow disease progressors (SDPs) (49.6 days vs. 74.9 days, respectively; 6.7-fold vs. 3.7-fold change of cytokines, respectively), suggesting the faster and stronger cytokine storm during AHI could promote disease progression. On the other hand, HIV-1 infection induced more interlocked cytokines network, establishing new strong correlations and imposing a higher rigidity. There were, respectively, 146 (44.9 ) statistically significant correlations of cytokines in RDPs and 241 (74.2 ) in SDPs (p < 0.001). This study suggests that immunomodulatory interventions aimed at controlling cytokine storm in AHI may be beneficial to slow eventual disease progression. When the immune system is fighting pathogens, cytokines activate immune cells such as T cells and macrophages, stimulating them to produce more cytokines resulting in so-called cytokine storms or cascades1,2. There is growing evidence that the immune responses initiated during acute HIV infection can play critical roles in modulating of disease progression. Several studies investigated the cascade of cytokine production in the periphery and show an initial rapid production of IFN-, followed by tumor necrosis factor (TNF)-, inducible protein (IP)-10, and interleukin (IL)-18, IL-10 and IFN- production, while others have not observed these changes or have reported opposing findings3?. The discrepancies likely reflect the diversity and unity of dynamics during AHI but also could be due in part to the variation in the timing of sample collection among studies. Some studies were cross-sectional, while others focused on time points relatively late in AHI9,10. The cytokine storms during AHI can act as a double-edged sword, as they have the potential to cause significant damage to virus-specific immunity but also inhibit infection by reducing T cell recruitment and activation11. Some studies show that type I-IFN plays a role in slowing disease progression by inducing multiple antiviral genes and limiting initial viral replication, while others have reported that type I-IFN signaling is linked to immune activation and viral persistence and blocking of type I-IFN during LCMV infection enhances viral clearance12?4. These contradictory reports suggest that there is a need to investigate the dynamic of cytokines in natural HIV-1 infection. HIV-1 infection does not only increase cytokine levels, but also reorganizes cytokine networks, establishes new strong correlations between various cytokines and thus imposes a high rigidity to the cytokine network15,16.Center for Infectious Diseases, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China. 2Infectious Diseases Department, Peking Union Medical College Hospital, Beijing, 100730, China. 3The Aaron Diamond AIDS Research Center, New York, NY 10016, United States. 4School of Biomedical Engineering, Capital Medical University, Beijing 100069, China. *These authors contributed equally to this work. Correspondence and requests for materials should be addressed to H.C. (email: [email protected]) or H.L. (email: [email protected]) or H.W. (email: [email protected])Scientific RepoRts | 6:36234 | D.