In people living with HIV (PLWH) who are failing or unable to access combination antiretroviral therapy (cART), monocytes and macrophages are important drivers of pathogenesis and progression to AIDS. The relevance of the monocyte/macrophage reservoir in PLWH receiving cART is debatable as in vivo evidence for infected cells is limited and suggests the reservoir is small. Macrophages were assumed to have a moderate life span and lack self-renewing potential, but recent discoveries challenge this dogma and suggest a potentially important role of these cells as long-lived HIV reservoirs. This, combined with new HIV infection animal models, has led to a resurgence of interest in monocyte/macrophage reservoirs. Infection of non-human primates with myeloid-tropic SIV implicates monocyte/macrophage activation and infection in the brain with neurocognitive disorders, and infection of myeloid-only humanized mouse models are consistent with the potential of the monocyte/macrophage reservoir to sustain infection and be a source of rebound viremia following cART cessation. An increased resistance to HIV-induced cytopathic effects and a reduced susceptibility to some antiretroviral drugs implies macrophages may be relevant to residual replication under cART and to rebound viremia. With a reappraisal of monocyte circulation dynamics, and the development of techniques to differentiate between self-renewing tissue-resident, and monocyte-derived macrophages in different tissues, a new framework exists to contextualize and evaluate the significance and relevance of the monocyte/macrophage HIV reservoir. In this review, we discuss recent developments in monocyte and macrophage biology and appraise current and emerging techniques to quantify the reservoir. We discuss how this knowledge influences our evaluation of the myeloid HIV reservoir, the implications for HIV pathogenesis in both viremic and virologically-suppressed PLWH and the need to address the myeloid reservoir in future treatment and cure strategies.

Latent HIV reservoirs persist in people living with HIV despite effective antiretroviral therapy and contribute to rebound viremia upon treatment interruption. Macrophages are an important reservoir cell-type, but analysis of agents that modulate latency in macrophages is limited by lack of appropriate in vitro models. We therefore generated an experimental system to investigate this by purifying non-productively-infected human monocyte-derived macrophages (MDM) following in vitro infection with an M-tropic EGFP reporter HIV clone, and quantified activation of HIV transcription using live-cell fluorescence microscopy. The proportion of HIV-infected MDM was quantified by qPCR detection of HIV DNA, and GFP expression was validated as a marker of productive HIV infection by co-labelling of HIV Gag protein. HIV transcription spontaneously reactivated in latently-infected MDM at a rate of 0.22% ± 0.04 cells per day (mean ± SEM, n=10 independent donors), producing infectious virions able to infect heterologous T cells in coculture experiments, and both T cells and TZM-bl cells in a cell-free infection system using MDM culture supernatants. Polarization to an M1 phenotype with IFNγ + TNF resulted in a 2.3 fold decrease in initial HIV infection of MDM (p<0.001, n=8) and 1.4 fold decrease in spontaneous reactivation (p=0.025, n=6) whereas M2 polarization using IL-4 prior to infection led to a 1.6 fold decrease in HIV infectivity (p=0.028, n=8), but a 2.0 fold increase in the rate of HIV reactivation in latently-infected MDM (p=0.023, n=6). The latency reversing agents bryostatin and vorinostat, but not panobinostat, significantly induced HIV reactivation in latently infected MDM (p=0.031 and p=0.038, respectively, n=6). Importance: Agents which modulate latent HIV reservoirs in infected cells are of considerable interest to HIV cure strategies. The present study characterizes a robust, reproducible model enabling quantification of HIV reactivation in primary HIV-infected human MDM which is relatively insensitive to the monocyte donor source and hence suitable for evaluating latency modifiers in MDM. The rate of initial viral infection was greater than the rate of HIV reactivation, suggesting different mechanisms regulate these processes. HIV reactivation was sensitive to macrophage polarization, suggesting cellular and tissue environments influence HIV reactivation in different macrophage populations. Importantly, latently infected MDM showed different susceptibility to certain latency reversing agents known to be effective in T cells, indicating dedicated strategies may be required to target latently-infected macrophage populations in vivo .

Background Statins may help prevent cardiovascular disease (CVD) in people with human immunodeficiency virus (PWH) with chronic inflammation owing to their pleotropic lipid-lowering and anti-inflammatory properties. Methods The impact of 48 weeks of rosuvastatin therapy on inflammation and immune activation in a double-blind, placebo-controlled trial in PWH at moderate cardiovascular disease risk was assessed. Results Rosuvastatin did not alter plasma levels of interleukin 6, soluble tumor necrosis factor receptor type 2, CXCL10, soluble CD14, or soluble vascular cellular adhesion molecule 1 (P ≥ .1 for all). Proportions of CD16+ monocyte subsets were increased in PWH receiving rosuvastatin. Conclusions The potential benefits of statin use in PWH with normal lipid levels requires further clinical outcome research.