Different Patterns of HIV-1 Replication in MACROPHAGES is Led by Co-Receptor Usage

Abstract

Background and objectives: To enter the target cell, HIV-1 binds not only CD4 but also a co-receptor β-chemokine receptor 5 (CCR5) or α chemokine receptor 4 (CXCR4). Limited information is available on the impact of co-receptor usage on HIV-1 replication in monocyte-derived macrophages (MDM) and on the homeostasis of this important cellular reservoir. Materials and Methods: Replication (measured by p24 production) of the CCR5-tropic 81A strain increased up to 10 days post-infection and then reached a plateau. Conversely, the replication of the CXCR4-tropic NL4.3 strain (after an initial increase up to day 7) underwent a drastic decrease becoming almost undetectable after 10 days post-infection. The ability of CCR5-tropic and CXCR4-tropic strains to induce cell death in MDM was then evaluated. While for CCR5-tropic 81A the rate of apoptosis in MDM was comparable to uninfected MDM, the infection of CXCR4-tropic NL4.3 in MDM was associated with a rate of 14.3% of apoptotic cells at day 6 reaching a peak of 43.5% at day 10 post-infection. Results: This suggests that the decrease in CXCR4-tropic strain replication in MDM can be due to their ability to induce cell death in MDM. The increase in apoptosis was paralleled with a 2-fold increase in the phosphorylated form of p38 compared to WT. Furthermore, microarray analysis showed modulation of proapoptotic and cancer-related genes induced by CXCR4-tropic strains starting from 24 h after infection, whereas CCR5 viruses modulated the expression of genes not correlated with apoptotic-pathways. Conclusions: In conclusion, CXCR4-tropic strains can induce a remarkable depletion of MDM. Conversely, MDM can represent an important cellular reservoir for CCR5-tropic strains supporting the role of CCR5-usage in HIV-1 pathogenesis and as a pharmacological target to contribute to an HIV-1 cure.

The Interplay of HIV and Autophagy in Early Infection

“…CD4 + T cells are susceptible to cell death induced by CXCR4 and CCR5 using viral strains and MDMs infected by CCR5-using viruses show weak autophagy activation and increased viral replication compared to MDMs infected with viral strains that use CXCR4 (Espert et al, 2009). This is consistent with the fact that CCR5-tropic viral strains are more infectious than CXCX4-tropic viral strains in MDMs (Schweighardt et al, 2004;Willey et al, 2005;Petrov et al, 2013;Wang et al, 2015;Bolduc et al, 2017;Quitadamo et al, 2018;Borrajo et al, 2019), and with the in vivo prevalence of viruses that utilize CCR5 in the majority of infected individuals (De Jong et al, 1992;Roos et al, 1992;Schuitemaker et al, 1992;Connor et al, 1993;Zhu et al, 1993;van't Wout et al, 1994;Cornelissen et al, 1995;Spijkerman et al, 1995;Huang et al, 1996;Reece et al, 1998;Keele and Derdeyn, 2009;Salazar-Gonzalez et al, 2009). Likewise, functional CCR5 reduced the expression of autophagy genes, such as BECN1, ATG5 and microtubule associated protein 1 light chain 3 (LC3) alpha (MAP1LC3A), and promoted inflammation in an experimental asthmatic mouse model (Liu et al, 2021).…”

TILRR Promotes Migration of Immune Cells Through Induction of Soluble Inflammatory Mediators

“…In addition, with a novel microfluidic assay, we demonstrated that the THP-1 and MOLT-4 cells migrated further toward the supernatants of the TILRR-overexpressed HeLa cells. THP-1 cells (monocytes) and MOLT-4 cells (T cells) are CD4-expressing cells, the targets of HIV-1 (Berger et al, 1998;Verani et al, 1998;Borrajo et al, 2019). Thus, the supernatants of TILRR-overexpressed HeLa cells, containing multiple pro-inflammatory cytokines (Kashem et al, 2019), attracts HIV-1 target cells.…”

The Interplay of HIV-1 and Macrophages in Viral Persistence

“…Macrophages, like CD4+ T cells, express CD4 and chemokine coreceptors CCR5 and CXCR4 on their cell surface allowing for HIV-1 susceptibility. Macrophages are susceptible to CCR5-tropic and dual-tropic viral infection, but determinants that assist in tropism are much more complicated than coreceptor usage ( Borrajo et al, 2019 ). Specifically, macrophages express significantly lower levels of CD4, meaning macrophage-tropic viruses must have a high degree of affinity to CD4 to mediate fusion with the macrophage cell membrane ( Kazazi et al, 1989 ; Joseph et al, 2014 ).…”