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CD34+ monocyte subset is highly susceptible to HIV-1 infection

ABSTRACT: HIV-1 persists in cellular reservoirs despite effective antiretroviral therapy (ART). CD4+ T cells are the well-known reservoir, but there is growing evidence that myeloid cells, including circulating monocytes, are also a clinically relevant reservoir. However, it is unclear what are preferentially infected monocyte subsets in vivo. Here, we show that a monocyte fraction expressing the stem cell marker CD34 is more susceptible to HIV-1 infection than the CD34-negative major subset. In ART-untreated viremic patients, CD34+ fraction increased in the percentage in total monocytes, and harbored more proviral DNA than the major subset. Consistent with this, when compared to the major subset, CD34+ fraction expressed HIV-1 receptors (CD4 and CCR5) at higher levels and HIV-1 restriction factors (MX2 and SAMHD1) at lower levels. Interestingly, proviral DNA was detected in CD34+ fraction of ART-treated virologically suppressed patients. CD34+ monocytes were also present in lymph nodes, and expressed CD4 and CCR5 at higher levels than the major subset, as observed for peripheral blood. Moreover, CD34+ monocytes present in peripheral blood and lymph nodes highly expressed CCR7 and sphingosine-1-phosphate receptor 1 (S1PR1), critical regulators of in vivo cellular trafficking. Our findings suggest that circulating CD34+ monocytes are infected with residual HIV-1 after migrating into tissues including lymph nodes and return to circulation, which explains the detection of proviral DNA in the cells even after long-term ART.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229346 | GEO | 2024/01/01

REPOSITORIES: GEO

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Project description:The chemokine receptor CCR5 is a major co-receptor for human immunodeficiency virus 1 (HIV-1) mediating infection of target cells1,2. Beyond its function as co-receptor, CCR5 also influences the course of HIV disease and progression to AIDS3. However, it is unclear how CCR5 affects HIV-associated damage to the central nervous system (CNS) and development of HIV-associated neurocognitive disorders (HAND) independently of its co-receptor function. Here we show in a transgenic model of brain damage induced by HIV envelope protein gp1204 that genetic ablation of CCR5 prevents neuronal injury and loss and limits microglial activation, but fails to abrogate astrocytosis. CCR5 deficiency also protected gp120-transgenic mice against impairment of spatial learning and memory. Thus, CCR5-deficiency revealed that astrocytosis, a prominent pathological feature of AIDS brains5, can occur independently from neuronal demise and behavioral impairment. Since the viral envelope protein expressed in the transgenic mouse model originated from HIV-1 LAV4, a CXCR4-preferring virus that can infect macrophages6, CCR5 appeared to exert its control of neuronal injury predominantly in an indirect fashion and independently from its function as a co-receptor. Using analysis of genome-wide CNS gene expression we identified a subset of 734 genes that were differentially regulated in association with neuronal injury in the presence of CCR5. This subset of genes indicated that neuronal injury was associated with activation of macrophages and microglia. A set of 1305 genes was only differentially regulated in association with gp120 in the absence of CCR5 and indicated changes to leukocyte function and the anti-viral immune response besides a down-regulation of components in the GABAergic neurotransmission system. Interestingly, the most significantly differentially expressed genes were observed in a separate subset of 461 genes that was regulated in association with gp120 but independently of the CCR5 genotype. The finding that differential regulation of the 461 and 1305 gene sets was not necessarily linked to neuronal damage and loss suggested that altered expression of at least some of these factors may represent a protective adaptive response of the brain to the presence of viral gp120. Additional experiments using quantitative RT-PCR, protein assays and flow cytometry further supported the notion that CCR5 deficiency blunted microglial activation, a hallmark of HIV-associated brain injury7-9 without significantly affecting the expression of viral gp120. These results provide in vivo evidence for a significant role of CCR5 in HIV-associated CNS injury and behavioral impairment that is independent of the molecules’ function as HIV co-receptor. To characterize the neuroprotective effect of CCR5 ablation in the presence of HIV gp120, we next performed a genome-wide gene expression analysis using whole brain RNA preparations of mice from lines 1 and 2. We decided to collect samples from two time points before and after the ages of when we analyzed histopathology (6 months) and behavior (8 to 9 months) in order to identify genes for which differential regulation may be affected by an interaction of HIVgp120 expression and age. Accordingly, we collected brain tissue of gp120tg, CCR5KO x gp120tg, WT and CCR5KO mice at five different ages: 1.5, 3, 6, 12, and 20 (line 1) or 16 (line 2) months.

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CD34+ monocyte subset is highly susceptible to HIV-1 infection

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