Myeloid differentiation and susceptibility to HIV-1 are linked to APOBEC3 expression

Abstract

IntroductionThe complex life cycle of HIV-1 involves critical functional interactions with CD4 ϩ host-cell factors. In addition to CD4 ϩ T cells, CD4 ϩ CCR5 ϩ macrophages represent a primary target and host of HIV-1. Infected macrophages replicate copious amounts of virus at their surface and at intracellular membranes where the virions accumulate in vesicles. 1 Macrophages are not typically subject to viral-induced death and may persist as reservoirs of virus in tissues for long periods of time. 2,3 In addition, infected macrophages may be resistant to antiviral agents, 3-6 and the unique attributes and factors that are enabling for this persistent viral host remain elusive. Critically, all monocytic cells are neither equally permissive to HIV-1 nor supportive of the viral life cycle. In vitro or in vivo, dendritic cells (DCs) may or may not become infected, depending on maturational status 7 ; peripheral-blood monocytes are nearly impervious (Ͻ 1% HIV-1 DNA ϩ ) 8,9 ; and of longstanding interest is the enhanced susceptibility of macrophages to HIV-1 compared with immature monocytes, the basis of which remains a mystery. The fact that macrophages, in culture and in tissues, are more susceptible to infection than monocytes cannot be attributed to levels of membrane CD4 or HIV-1 coreceptor expression 10 or multiple other criteria that have been considered. 11 This fundamental question has obvious significance in that if the monocyte-resistance factor(s) can be identified, opportunities may emerge for manipulating susceptible myeloid populations to impose a restrictive barrier to HIV-1. Limited evidence supports an early postentry block that occurs in association with or shortly after reverse transcription (RT). 8 Beyond the well-established CD4 and CCR5/CXCR4 entry requirements, recent evidence implicates additional membrane and intracellular factors that influence early host-cell responsiveness to productive infection. [11][12][13][14][15][16][17] Among the potential innate intracellular viral antagonists, initially characterized in T cells 18 and more recently in monocytes, 19,20 are cytidine deaminases that edit viral RNA and mutate DNA. These cytoplasmic apolipoprotein B mRNA-editing enzyme catalytic polypeptidelike (APOBEC) subunits, particularly APOBEC3G (hA3G), become incorporated into virions, leading to mutation of nascent HIV-1 DNA formed during reverse transcription and its subsequent degradation. 18,21,22 HIV-1, in turn, inhibits hA3G via HIV-1-encoded viral infectivity factor (Vif)-dependent and -independent pathways to thwart this antiviral defense within the target cell. Vif not only facilitates 26S proteasome-mediated degradation of hA3G but also diminishes its synthesis to collectively exclude hA3G incorporation into the budding virions. [23][24][25] Nonetheless, whether differential HIV-1 susceptibility in myeloid populations could be attributed to constitutively expressed hA3G or any other components of this defensive superfamily had not been addressed.In this study, by oligonucleotide microarr...

APOBEC proteins and intrinsic resistance to HIV-1 infection

“…APOBEC3B (A3B) inhibits HIV-1 in cultured cell assays, is resistant to inhibition by Vif (A3B can therefore inhibit wild-type HIV-1), has two CDA domains that are each capable of catalysing deamination, but is barely expressed in human CD4 T cells so is unlikely to impact HIV-1 substantially during natural infection (Bishop et al 2004a;Doehle et al 2005;Bogerd et al 2007). APOBEC3A (A3A) contains a single CDA domain, is expressed in immature monocytes, and has been reported to restrict HIV-1 infection (Peng et al 2007). APOBEC3C (A3C) also contains a single CDA domain, is expressed in CD4 T cells, and can act in target cells to introduce infrequent G-to-A mutations (i.e.…”

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

“…Monocytes were purified from the mononuclear cell layer using centrifugal elutriation 18 and divided into three groups for immature monocytes and generation of macrophages and DCs as described 19,20 in three independent experiments with cells from three donors. Freshly isolated monocytes were used immediately after elutriation, whereas donor-matched macrophage and DC studies were initiated after confirmation of differentiation on day 7.…”

“…Preparation of biotin-labeled cRNA, hybridization, and scanning were performed according to protocol (Affymetrix, Santa Clara, CA) as described. 19 Affymetrix GCOS version 1.2 software was used to calculate signal and present call values that were stored in the NIHLIMS, a database for storage and retrieval of chip data maintained at the National Institutes of Health. The signal values for the 18 chips were subjected to S10 quantile-normalizing transformation.…”

“…The signal values for the 18 chips were subjected to S10 quantile-normalizing transformation. 19 Principal components analysis on the S10-transformed data were also performed to permit the visualization of the samples in bivariate plots of the low-order principal components, to detect possible outliers and to provide a global view of the study results. Statistical tests and data calculations were with MSCL Analyst's Toolbox (http://abs.cit.nih.gov/ main/geneexpression.html).…”

p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

“…Contrary to HIV-1, SIV and HIV-2 have evolved a protein, Vpx, that relieves SAMHD1-mediated restriction by targeting SAMHD1 for proteasome-dependent degradation (21)(22)(23). In addition to SAMHD1, other cellular factors, in particular antiviral pathways induced by type I IFN, affect early postentry steps of HIV-1 replication in macrophages (24)(25)(26)(27).…”