Innate immunity in acute HIV-1 infection

Abstract

Purpose of review: Acute HIV-1 infection (AHI) is composed of the eclipse phase, during which the transmitted virus struggles to avoid eradication and achieve amplification/spread; the expansion phase when virus disseminates and undergoes exponential replication associated with extensive CD4⁺ T-cell destruction; and the containment phase when set-point levels of viremia and immune activation are established. The importance of interactions between HIV-1 and innate responses in determining events throughout AHI is increasingly recognized, and is reviewed here.

Recent findings: During the eclipse phase, HIV-1 subverts dendritic cell functions to promote its replication at mucosal sites and employs multiple strategies to minimize control by type 1 interferons. Systemic virus dissemination is associated with widespread activation of innate responses which fuels HIV-1 replication. To minimize the protective effects of innate responses, HIV-1 resists control by natural killer cells and may impair innate regulation of adaptive responses. Innate responses remain chronically activated after HIV-1 containment which is thought to drive HIV-1 pathogenesis.

Summary: Innate responses are pivotal determinants of events at all stages of AHI. Increased understanding of mechanisms involved in innate control of HIV-1 and pathways regulating innate activation during HIV-1 infection could facilitate development of novel approaches to combating this infection.

Figure 1. Diagram illustrating the different phases of acute HIV-1 infection and the host immune responses available to counteract virus replication at each

Following mucosal HIV-1 transmission virus replication is initially confined to small foci of infection at the mucosal site. After local amplification, infection disseminates to the draining lymph node and blood; the eclipse phase ends when virus first reaches detectable levels in the plasma (the horizontal dotted line indicates the limit of sensitivity of standard HIV-1 RNA assays). An exponential burst of virus replication then ensues, associated with extensive depletion of CD4+ T cells, particularly from the gut-associated lymphoid tissues. Plasma virus titres often reach peaks of 1–100 million RNA copies/ml at the end of the viral expansion phase. HIV-1 replication is subsequently contained, and set-point levels of persisting viral replication and immune activation are established by 3–6 months post-infection. Interactions occur between HIV-1 and the innate immune system at all stages of acute infection. Adaptive responses start to be induced during the viral expansion phase and play an important role in containment of virus replication and establishment of the set-point persisting viral load.

Figure 2. Diagram illustrating the dynamics with which innate responses are activated during AHI

pDCs are recruited to mucosal sites of HIV-1 infection within hours of viral exposure, and produce pro-inflammatory cytokines and chemokines that attract CD4+ T cells to the transmission site hence facilitating viral replication, plus IFN-1 that mediate local antiviral activity. Systemic activation of innate responses is triggered as widespread virus dissemination occurs. There is rapid activation of pDCs and cDCs associated with elevations in plasma levels of multiple innate cytokines and chemokines, followed by activation and expansion of NK cells. Although innate effector mechanisms contribute to control of virus replication, the intense systemic immune activation simultaneously promotes viral replication. The initial intense activation of innate responses is not sustained after the acute viral burst, but a heightened state of activation continues to be maintained after viremia is contained. This chronic up-regulation of immune activation is thought to be an important factor in HIV-1 pathogenesis.