**5. Conclusions**

To summarize, CCR5 strains induce chronic and productive infection in MDM whereas CXCR4-tropic strains induce abortive infection. Moreover, the abrogation of HIV-1-dependent killing due to the specific CXCR4 inhibitor AMD3100 indicates the obligatory role of CXCR4. Phosphorylation of p38 (MAP Kinase family), reported to be activated after exposure to many forms of cellular stress, is enhanced by the CXCR4-tropic strain NL4-3 and IIIB and not by CCR5-tropic strain 81A and BaL; also, this induction is modulated by CXCR4. CXCR4-tropic strains activate inflammatory genes in MDM whereas CCR5-tropic HIV-1 strains do not induce a death program in MDM.

Taken together, our results correlate with in vitro and in vivo evidence about an uncoupling between viral replication and cytopathocity [88] and confirm what we observed previously [9,99] in later phases of infection: MDM homeostasis is up-regulated where infection is sustained by CCR5-tropic strains. All the CXCR4-tropic strains we used, in contrast, induce MDM apoptosis and lead to consequent clearance of HIV replication. Further studies are necessary to investigate if gp120 interaction with CXCR4 in MDM can also induce the activation of pro-inflammatory pathways.

Our findings provide important implications for HIV-1 pathogenesis and design of pharmacological targets aimed at achieving HIV-1 cure.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1010-660X/55/6/297/s1, Table S1: Di fferent changes in genes in R5 virus versus X4 virus-infected incubated MDM.

**Author Contributions:** S.A. and C.F.P. conceived of and designed the experiments. A.R., M.P., M.C.B. and R.S. performed the experiments. A.B., A.R., V.S. and S.A. analyzed the data. M.C.B., M.V.M. and F.C.-S. contributed reagents, materials, and analysis tools. A.B., A.R., V.S. and S.A. wrote the paper.

**Acknowledgments:** Authors would like to thank D. Schols for providing both antiviral compounds and clinical isolates. This work was supported by PRIN (Progetti di Rilevante Interesse Nazionale) Grant 2015W729WH\_007 and 2017M8R7N9\_004 from the MIUR, Italy and by GAIN (Agencia Gallega de Innovación) Grant IN606B-2016/012 from the Consellería de Cultura, Educación e Ordenación Universitaria e a Consellería de Economía, Emprego e Industria (Xunta de Galicia), Spain.

**Conflicts of Interest:** The authors declare no conflict of interest.
