Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1

Abstract

Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also in regeneration and homeostasis. Their remarkable plasticity in their phenotypes and function provides them with the ability to quickly respond to environmental changes and infection. Recent work shows that macrophages undergo cell cycle transition from a G0/terminally differentiated state to a G1 state. This G0-to-G1 transition presents a window of opportunity for HIV-1 infection. Macrophages are an important target for HIV-1 but express high levels of the deoxynucleotide-triphosphate hydrolase SAMHD1, which restricts viral DNA synthesis by decreasing levels of dNTPs. While the G0 state is non-permissive to HIV-1 infection, a G1 state is very permissive to HIV-1 infection. This is because macrophages in a G1 state switch off the antiviral restriction factor SAMHD1 by phosphorylation, thereby allowing productive HIV-1 infection. Here, we explore the macrophage cell cycle and the interplay between its regulation and permissivity to HIV-1 infection.

Host Restriction Factors Modulating HIV Latency and Replication in Macrophages

“…A peculiar property of macrophages is their long survival in culture in a nonproliferating state (whereas, in vivo, tissue-resident macrophages, TRM, undergo a slow homeostatic proliferation driven by cytokines secreted in an autocrine fashion in order to persist indefinitely in the host [ 4 , 5 ]) caused by a physiological arrest of their cell cycle. This aspect of their biology has been recently revisited for its relevance to HIV infection and the role of restriction factors, with particular regard to SAMHD1 (SAM domain and HD domain-containing protein 1), a hydrolase processing deoxynucleotides triphosphates (dNTPs) physiologically involved in DNA repair mechanisms [ 13 , 89 ]. SAMHD1 acts by depleting the pool of dNTPs, the “building blocks” necessary for the reverse transcription process to synthesize viral DNA before its integration into the host cell genome.…”

“…As HIV-1 is devoid of Vpx, it has been highly debated whether a similar mechanism would be carried out by other accessory viral proteins. In this regard, Ferreira and colleagues have reported that, although in the absence of cell division [ 13 ], macrophages in the G 0 phase express p21/Waf1 (previously shown to represent a negative regulator of virus replication in macrophages [ 51 ]) together with high levels of SAMHD1, thereby resulting in a highly restricted state for virus replication. A switch to G 1 has been associated with the downregulation of p21/Waf1, increased expression of cyclin-dependent kinase 1 (CDK1) and inactivation of SAMHD1 by phosphorylation, leading to increased dNTP levels and the unleashing of virus replication.…”

“…A switch to G 1 has been associated with the downregulation of p21/Waf1, increased expression of cyclin-dependent kinase 1 (CDK1) and inactivation of SAMHD1 by phosphorylation, leading to increased dNTP levels and the unleashing of virus replication. This pathway was reverted by genotoxic stress and response to “danger signals” that induced a back-transition from G 1 to G 0 , as reviewed in [ 13 ]. The inhibitory activity of SAMHD1 on HIV-1 replication has been also reported in the case of the infection of resting CD4 + T lymphocytes [ 90 ].…”

Replication-competent HIV-1 in human alveolar macrophages and monocytes despite nucleotide pools with elevated dUTP

“…Although CD4 + T cells are the primary targets of HIV, myeloid cells such as monocytes and macrophages are infected by R5 tropic and dual tropic strains of HIV and have unique properties that could lead to persistent HIV infection even in the presence of active retroviral therapy (ART) 1, 2 . For instance, macrophages have distinct and malleable metabolic properties compared to T cells that make them intrinsically resistance to HIV-induced cytopathic effects and less susceptible to some antiretroviral drugs 3, 4 . These properties include, but are not limited to, innate immunity pathways that involve viral nucleic acid lethal mutation by enzymatic cytidine deamination 5, 6 , dramatically reduced dNTP pools and composition through the action of SAMHD1 dNTPase 7, 8 , and the ability to transiently access G0 and G1 stages of the cell cycle 4, 9, 10 .…”

G2-S16 Polyanionic Carbosilane Dendrimer Can Reduce HIV-1 Reservoir Formation by Inhibiting Macrophage Cell to Cell Transmission

“…Based on the mechanism of action of this dendrimer against HIV-1 both in vitro and in vivo, we studied the possibility that our G2-S16 dendrimer was able to inhibit the HIV-1 within macrophages. Macrophages play a major role as potential viral reservoirs, not only because they appear to have greater resistance to cytopathic effects than T cells [10,11], but they also are capable of containing competent viruses for weeks in lymphoid organs, preventing the interaction of ART. Thus, during the acute phase of HIV-1 infection, macrophages establish primary infection but perivascular macrophages deliver the virus to different organs, including the brain [12,13], establishing itself as an immune sanctuary [14].…”