Background:  In contrast to in vitro infection models, no data to date have described circulating monocyte gene expression patterns in HIV-infected persons.

Methods:  We characterized constitutive and toll-like receptor-2-induced gene expression (15,000 unique gene identities) in monocytes from 13 HIV-1 patients (viremic and without ART) as compared to 12 control donor monocytes. Total RNA was isolated from unstimulated monocytes and monocytes SAC stimulated for 5 hours, RNA amplified and hybridized. Significance was defined by a 2-fold change and a p <0.05. From each original group, 4 subjects were re-tested a year later and methods repeated and results compared. Protein expression and functional correlates were pursued with regard to monocyte apoptosis via Annexin-V.

Results:  Differential gene expression between HIV-infected and uninfected monocytes was observed in unstimulated (524 genes) and SAC-stimulated (668 genes) groups. Transcriptional factors, inflammatory genes, and stress and anti-apoptotic transcripts were among differentially expressed genes. Approximately 6.3% of constitutive gene expression was found to be significantly associated with viral load; 20% of the genes constitutively expressed in HIV-1 monocytes were observed to be toll-like receptor-2 (TLR-2)-induced in uninfected monocytes, indicating an activated gene expression as a constitutive feature of circulating monocytes in HIV-1 infection. In the absence of stimulation, a predominant stress/anti-apoptotic gene signature was present in monocytes from infected subjects, confirmed by real-time polymerase chain reaction (PCR) and in samples obtained a year later as described above. Up-regulated anti-apoptotic genes‑such as SERPINB2, IER3, MT-1G, MT-1H, MT-1E‑defined an anti-apoptotic state as supported by apoptosis measurements performed in additional viremic subjects. Furthermore, MT-1G/H/E and viral load were positively associated (p <0.05).

Conclusions:  Circulating monocyte subsets in HIV-1 infection bear an activated gene expression pattern supporting a constitutive state of cellular activation. This in addition is associated with an anti-apoptotic state of relevance to monocyte retention, disease progression, and macrophage viral reservoirs.