The immune response during acute HIV-1 infection – clues for vaccine development

Nature Reviews Immunology 10, 11-23 (January 2010)

Andrew J. McMichael, Persephone Borrow, Georgia D. Tomaras, Nilu Goonetilleke & Barton F. Haynes

a | Recent analysis of samples from individuals early after infection with HIV-1 has revealed that the first weeks following infection can be divided into clinical stages that are defined by a stepwise gain in positivity for the detection of HIV-1 antigens and HIV-1-specific antibodies in diagnostic assays (in brackets)82. The time between infection and the first detection of viral RNA in the plasma is referred to as the eclipse phase. Plasma virus levels then increase exponentially, peaking at 21–28 days after infection, and this is followed by a slower decrease in plasma viral RNA levels. Patients can be categorized into Fiebig stages I–VI, which are based on a sequential gain in positive HIV-1 clinical diagnostic assays (viral RNA measured by PCR, p24 and p31 viral antigens measured by enzyme-linked immunosorbent assay (ELISA), HIV-1-specific antibody detected by ELISA and HIV-1-specific antibodies detected by western blot). Patients progress from acute infection through to the early chronic stage of infection at the end of Fiebig stage V, approximately 100 days following infection, as the plasma viral load begins to plateau.

b | Fundamental events in acute HIV-1 infection. Following HIV-1 infection, the virus first replicates locally in the mucosa and is then transported to draining lymph nodes, where further amplification occurs.

This initial phase of infection, until systemic viral dissemination begins, constitutes the eclipse phase. The time when virus is first detected in the blood is referred to as T0; after this there is an exponential increase in plasma viraemia to a peak 21–28 days after infection.

By this time, significant depletion of mucosal CD4+ T cells has already occurred. Around the time of peak viraemia, patients may become symptomatic and reservoirs of latent virus are established in cells that have a slower rate of decay than CD4+ T cells.

The ‘window of opportunity’ between transmission and peak viraemia, prior to massive CD4+ T cell destruction and the establishment of viral reservoirs, is the narrow but crucial period in which an HIV-1 vaccine must control viral replication, prevent extensive CD4+ T cell depletion and curb generalized immune activation.

Part a is modified, with permission, from Ref. 12 © (2008) National Academy of Sciences, USA. Part b is modified from Ref. 160.

FIGURE 1 –  Definition of acute HIV-1 infection.

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