Anti-HIV therapeutic approaches targeting chemokine receptor CCR5

Nowadays, human immunodeficiency virus type 1 continues to be a major global public health issue, due also to antiretroviral therapy (ART) drawbacks. ART is the standard of care for HIV infected people and even though it constitutes an important milestone that has changed the course of the infection, it is not able to eliminate latent virus in HIV reservoirs, leading to viral rebound when ART is interrupted. In this context, this thesis aims to analyze novel therapeutic approaches against HIV-1 infection targeting chemokine receptor CCR5. The role of CCR5 in HIV-1 as a possible target for anti-HIV therapy has already been demonstrated; important evidence derives from the two clinical cases of the “Berlin” and “London” patients, cured from HIV-1 infection after CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT). As further evidence, the study by Jensen et al., presented the clinical case of IciStem no.19 HIV-1 patient, the third documented case of long-term HIV-1 remission after allogenic CCR5Δ32/Δ32 HSCT. Through the analysis of several peripheral blood and tissue samples collected at different months after HSCT or after analytical treatment interruption of ART, the authors demonstrated that patient viral load was almost completely undetectable. The authors also proved that CCR5Δ32/Δ32 HSCT determined a reduction of HIV-1 reservoir, revealing its potential as a HIV-1 future cure. In the study by Bellini et al., the authors exploited RNA interference to develop a novel CCR5-targeting anti-HIV-1 therapeutic agent. The studied microRNA-103 was able to downregulate CCR5 expression in activated-to-memory CD4+ T cells, that in turn led to the decrease of CCR5-dependent HIV-1 infection and also negatively affected cells susceptibility to HIV-1 latent infection. Of note, they demonstrated that HIV-1 elite controllers (ECs) possess low CCR5 and high miRNA-103 mRNAs levels, suggesting miRNA-103 possible role in the lower CCR5 expression of ECs and in their ability to control the infection without ART. On the other hand, a genome editing approach was undertaken by Liu et al., that aimed to ablate CCR5 gene through CRISPR/AsCpf1 technology. The authors showed that edited CD4+ T cells have lower susceptibility to HIV-1 R5-tropic infection and possess a selective advantage over unedited cells. Thus, these results further highlight the essential role of CCR5 in HIV-1 infection and propose CCR5 as a promising target for novel therapies against HIV-1.