Referee 1's review:

**********
N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.
**********

Review of the original submission:
Schlaepfer et al. set out to investigate the effect of toll-like receptor (TLR) triggering on HIV replication in lymphoid tissues and peripheral blood ex vivo. Using several compounds specific for TLR-7 and TLR-8, the authors demonstrated that: 1) dendritic cells play a major role in initiating NK and/or CD8+ T cell-mediated antiviral activities, 2) these antiviral effects were mediated by soluble factors that may include unidentified molecules, and 3) the soluble factors produced by TLR-triggered cultures inhibited HIV replication by blocking integration of HIV DNA.

The manuscript by Schlaepfer et al. is largely descriptive and lacks any explanations regarding the possible mechanism by which TLR-triggered cells inhibit HIV replication. Having said that, the present manuscript does offer very important insights into the pathogenesis of HIV infection and may have significant implications for future therapeutic strategies.

There are two technical comments that need to be addressed by the authors to strengthen the manuscript.

1) The amount of anti-IFN-a receptor antibody used by the authors in various experiments is sub-optimal and may not be effective enough to block IFN-a binding to its receptor. Hence, it may be premature to think that other unidentified soluble factors played a major role in suppressing HIV replication. It has been shown that IFN-a alone (whether from plasmacytoid dendritic cells or commercially available reagent) can profoundly suppress HIV replication in vitro.

2) The claim that anti-HIV factors released by the TLR-triggered culture inhibit HIV replication by blocking integration of HIV DNA is not substantiated based on the data presented in this manuscript. It is possible that integration of HIV DNA occurred; rather expression of HIV transcription was down-regulated in Fig. 6.

Review of the first revised manuscript:
I believe the authors have addressed my previous concerns (all relatively minor) more than adequately.