Human immunodeficiency virus type 2 (HIV-2) is known to be less pathogenic than HIV-1. However, the mechanism(s) underlying the decreased HIV-2 pathogenicity is not fully understood. Herein, we report that β-chemokine CCL2 expression was increased in HIV-1-infected human monocyte-derived macrophages (MDM) but decreased in HIV-2-infected MDM when compared to uninfected MDM. Inhibition of CCL2 expression following HIV-2 infection occurred at both protein and mRNA levels. By microarray analysis, quantitative PCR, and Western blotting, we identified that Signal Transducer and Activator of Transcription 1 (STAT1), a critical transcription factor for inducing CCL2 gene expression, was also reduced in HIV-2-infected MDM. Blockade of STAT1 in HIV-infected MDM using a STAT1 inhibitor significantly reduced the production of CCL2. In contrast, transduction of STAT1-expressing pseudo-retrovirus restored CCL2 production in HIV-2-infected MDM. These findings support the concept that CCL2 inhibition in HIV-2-infected MDM is meditated by reduction of STAT1. Furthermore, we showed that STAT1 reduction in HIV-2-infected MDM was regulated by the CUL2/RBX1 ubiquitin E3 ligase complex-dependent proteasome pathway. Knockdown of CUL2 or RBX1 restored the expression of STAT1 and CCL2 in HIV-2-infected MDM. Taken together, our findings suggest that differential regulation of the STAT1—CCL2 axis may be one of the mechanisms underlying the different pathogenicity observed for HIV-1 and HIV-2.

Human immunodeficiency virus (HIV) type 2 (HIV-2) is less pathogenic than HIV-1. However, the factors responsible for the differences in pathogenicity are still not well defined. To investigate this issue, we performed infection of primary human monocyte-derived macrophages (MDMs) with individual HIV-1 or HIV-2 strains and compared the levels of M-CSF, a cytokine shown to promote HIV-1 infection and replication in our previous studies, and CXCL7, a chemokine identified as being expressed at levels correlated with HIV type by our preliminary gene-expression analysis. We tested several HIV-2 isolates able to replicate in human MDMs and observed that all of them induced the production of M-CSF at high levels similar to those previously established for HIV-1 infection. In addition, the production of M-CSF in MDMs infected with HIV-1 or HIV-2 isolates correlated with the extent of virus replication. In contrast to M-CSF, the chemokine CXCL7 was differentially expressed between MDMs infected with HIV-1 or HIV-2 isolates, as revealed by qPCR and ELISA testing. Together, these results suggest that M-CSF induction may play similar roles in promoting the replication of HIV-1 and HIV-2, while differential regulation of chemokine expression may be an important factor contributing to the differential pathogenicity of the two HIV subtypes.