Figure 1. Model of the Early Stages of Mucosal HIV Infection (Modified from [11]) and Vaccine-Induced Enhancement of Infection.

Free virus crosses the epithelial barrier of the mucosa through breaks or by transport on dendritic cells (DC), transcytosis, or infection of intraepithelial DC, macrophages, or CD4+ T cells. Initially, this will lead to a single HIV-infected cell (1) located in the lamina propria. Further spread can be blocked by infection of the first cell with a replication-deficient virus mutant, integration into a transcriptionally silent genomic region, or absence of susceptible secondary target cells, leading to abortive infection once the infected cell dies. If the virus is transmitted to secondary target cells (2), occult infections can occur if the reproductive rate of HIV-infected cells is reduced to less than one. These occult HIV infections are reported to be associated with detectable levels of HIV-specific cellular immune responses and can be defined by transient detection of virus in the absence of subsequent seroconversion. Transient viremia suggests that occult infections can still occur after spread of the virus to the regional lymph node (3). As outlined in the text, enhancement of the incidence of established, seropositive HIV infections in a subgroup of vaccinated volunteers of the STEP study could be explained by vaccine-induced, HIV-specific enhancer cells (EC) promoting virus spread by acting on secondary target cells (2) and/or a localized nidus of infection in the draining lymph node (3). If the enhancer cells indeed increase the number of established HIV infections by acting at stage 2 or 3, early HIV infections must resolve spontaneously in the absence of the vaccine-induced enhancer cells. An approximate 2-fold increase in the incidence of seropositive HIV infections in the vaccine subgroup compared to the placebo subgroup therefore suggests that less than half of all stage 2 or 3 infections in the placebo subgroup progress to established infections.