Induction of a Striking Systemic Cytokine Cascade prior to Peak Viremia in Acute Human Immunodeficiency Virus Type 1 Infection, in Contrast to More Modest and Delayed Responses in Acute Hepatitis B and C Virus Infections

Recent studies have highlighted the impact of events in acute human immunodeficiency virus type 1 (HIV-1) infection on subsequent disease pathogenesis (10). Following HIV transmission, there is an eclipse phase of approximately 10 days (18) during which virus is initially amplified at the transmission site and in local lymphoid tissues, and then systemic dissemination begins (23). Exponential virus expansion is associated with a massive depletion of memory CD4+ T cells, particularly from gut-associated lymphoid tissues (30, 32). Plasma viral titers subsequently decline, but immune activation and viral replication continue and are associated with a further T-cell loss (24, 33), eventually leading to the development of AIDS. Appreciation of the role of acute-phase events in HIV pathogenesis emphasizes the need to understand the immune responses activated in the earliest stages of infection and the roles that they may be playing in the containment of viral replication or in fueling immune activation and viral spread (6). A previously reported study of simian immunodeficiency virus (SIV)-infected macaques suggested that the earliest immune response in the genital tract was dominated by the induction of proinflammatory cytokines, which may have helped to promote viral spread, with the induction of antiviral cytokines such as alpha interferon (IFN-α) and IFN-β occurring too late to prevent virus replication and dissemination (1). Further support for an immunopathological role for components of the immune response activated in the early stages of infection is provided by comparisons of pathogenic versus nonpathogenic SIV infections of nonhuman primates, where an immunosuppressive cytokine profile associated with low levels of immune activation has been identified as being a key correlate of good disease prognosis (27). This suggests that prophylactic HIV vaccines must induce immune responses that block transmission or blunt viral replication so that immunopathological cytokine production is reduced or down-modulate the cytokine response stimulated in the context of early viral replication. To inform vaccine design and identify the window of time that a vaccine has to induce salutary secondary responses after transmission, it is critical to define the nature and timing of the early cytokine response in HIV-infected individuals. Several groups have attempted to characterize the cytokine response induced in acute HIV infection by analysis of plasma cytokine levels or cytokine mRNA expression levels in peripheral blood leukocytes. These studies have yielded somewhat conflicting results, with some reporting the upregulation of cytokines and chemokines including IFN-α (17, 47), tumor necrosis factor alpha (TNF-α) (3, 20, 36, 39, 47), IFN-γ (5, 20, 36, 42), interleukin-1β (IL-1β) (42), IL-10 (20, 36), inducible protein 10 (IP-10) (40), and regulated on activation, normal T-expressed and -secreted (RANTES) (31) and no change or a decrease in levels of cytokines including IL-2, IL-4, and IL-6 (5, 20, 42), while others have not observed these changes or have reported opposing findings, e.g., reduced TNF-α levels (5). The discrepancies may be due in part to differences in the assays used to measure cytokine responses in different studies but likely also reflect the dynamic nature of acute HIV infection and the variation between studies in the timing of sample collection. Many studies were cross-sectional, while others focused on time points relatively late in acute infection. In the current study, we constructed a comprehensive picture of the dynamics of systemic innate and initial adaptive immune activation in the earliest stages of HIV-1 infection by performing a kinetic analysis of 30 plasma cytokines and chemokines during the eclipse and viral expansion phases using sequential samples, typically collected 2 to 5 days apart, from plasma donors acquiring HIV-1 infection. For comparison, we studied similar plasma panels from donors who acquired either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. We found that in contrast to HBV and HCV, acute-phase HIV replication is associated with the activation of a dramatic cytokine cascade, with plasma levels of some of the most rapidly induced innate cytokines peaking 7 days after the first detection of plasma viremia and multiple other cytokines being upregulated as viral titers increase to their peak.