A comparison of methods for measuring rectal HIV levels suggests that HIV DNA resides in cells other than CD4+ T cells, including myeloid cells

Yukl, Steven A.; Sinclair, Elizabeth; Somsouk, Ma; Hunt, Peter W.; Epling, Lorrie; Killian, Martin; Girling, Valerie; Li, Peilin; Havlir, Diane V.; Deeks, Steven G.; Wong, Joseph K.; Hatano, Hiroyu

doi:10.1097/qad.0000000000000166

Cited by 61 publications

(48 citation statements)

References 22 publications

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“…Despite its potency to suppress HIV-1 replication, ART does not eliminate HIV-1 reservoirs, and it needs lifelong adherence to regimens that are associated with toxic effects. Although resting memory CD4 + T cells are the important HIV-1 reservoir (1), there is increasing evidence that HIV-1 exists also in other cells (2)(3)(4)(5)(6)(7). A clear demonstration that macrophages are an HIV-1 reservoir is lacking because of the difficulty in obtaining tissue samples (62).…”

Section: Discussionmentioning

confidence: 99%

Fibrocytes Differ from Macrophages but Can Be Infected with HIV-1

Hashimoto

Nasser

Bhuyan

et al. 2015

The Journal of Immunology

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Fibrocytes (fibroblastic leukocytes) are recently identified as unique hematopoietic cells with features of both macrophages and fibroblasts. Fibrocytes are known to contribute to the remodeling or fibrosis of various injured tissues. However, their role in viral infection is not fully understood. In this study, we show that differentiated fibrocytes are phenotypically distinguishable from macrophages but can be infected with HIV-1. Importantly, fibrocytes exhibited persistently infected cell-like phenotypes, the degree of which was more apparent than macrophages. The infected fibrocytes produced replication-competent HIV-1, but expressed HIV-1 mRNA at low levels and strongly resisted HIV-1–induced cell death, which enabled them to support an extremely long-term HIV-1 production at low but steady levels. More importantly, our results suggested that fibrocytes were susceptible to HIV-1 regardless of their differentiation state, in contrast to the fact that monocytes become susceptible to HIV-1 after the differentiation into macrophages. Our findings indicate that fibrocytes are the previously unreported HIV-1 host cells, and they suggest the importance of considering fibrocytes as one of the long-lived persistently infected cells for curing HIV-1.

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Section: Discussionmentioning

confidence: 99%

Fibrocytes Differ from Macrophages but Can Be Infected with HIV-1

Hashimoto

Nasser

Bhuyan

et al. 2015

The Journal of Immunology

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“…Likewise, Josefsson et al (41) found that myeloid cells isolated from the gut-associated lymphoid tissue (GALT) of HIV patients on antiretroviral therapy were positive for HIV. Yukl et al (42) observed that infected myeloid cells in the gut accounted for ϳ4% of the total HIV DNA. Moore et al (43) showed that mucosal macrophages isolated from the small intestinal mucosa of rhesus macaques either acutely or chronically infected with simian immunodeficiency virus (SIV) carried viral DNA, albeit at levels lower than memory CD4 T cells in the gut.…”

Section: The Gut Macrophage Reservoir In Hiv Infectionmentioning

confidence: 99%

Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Brown¹,

Mattapallil²

2014

Clin. Vaccine Immunol.

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The gastrointestinal tract (GIT) is a primary site for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection, replication, and dissemination. After an initial explosive phase of infection, HIV establishes latency. In addition to CD4 T cells, macrophages are readily infected, which can persist for long periods of time. Though macrophages at various systemic sites are infected, those present in the GIT constitute a major cellular reservoir due to the abundance of these cells at mucosal sites. Here, we review some of the important findings regarding what is known about the macrophage reservoir in the gut and explore potential approaches being pursued in the field to reduce this reservoir. The development of strategies that can lead to a functional cure will need to incorporate approaches that can eradicate the macrophage reservoir in the GIT. Macrophages are one of the most abundant immune cells in the gut (1, 2). Morphologically, gut macrophages are similar to most resident tissue macrophages, with a mononuclear shape and a granular cytoplasm, and they are highly phagocytic and microbicidal (3-5). They express major histocompatibility complex (MHC) class II, CD36, CD68, CD163 (6, 7), and CD209 (7) but have low levels of CD80, CD86, and CD40 (8-11). Unlike monocytes in peripheral blood that are largely CD14 ϩ , human mucosal macrophages in the gut have been shown to express aϪ phenotype (12, 13). The expression of CD4 and CCR5/CXCR4 key receptors for human immunodeficiency virus (HIV) infection, on macrophage populations has been shown to differ based on the sites the cells reside in. Shen et al. (14) showed that vaginal macrophages expressed CD4 and CCR5/CXCR4 similarly to blood monocytes, whereas intestinal macrophages expressed little or no detectable CD4 and CCR5/CXCR4 (15-17).Interestingly, under normal conditions or in response to Tolllike receptor (TLR) ligands, gut macrophages constitutively secrete anti-inflammatory cytokines, such as interleukin-10 (IL-10), rather than proinflammatory mediators, such as IL-12, IL-23, tumor necrosis factor alpha (TNF-␣), IL-1, IL-6, and interferoninducible protein 10 (IP-10) (18)(19)(20)(21)(22), suggesting that intestinal macrophages may be critical for maintaining immune homeostasis in the gastrointestinal tract (6). Smythies et al. (23) reported that intestinal macrophages displayed significant inflammation anergy even though they had avid phagocytic and bactericidal activity. Depletion of mucosal macrophages was shown to be associated with increased susceptibility to colitis and graft-versus-host disease in mice (24-26). Likewise, altering the phenotype of macrophages to that of a proinflammatory phenotype as seen during HIV replication was associated with increased inflammation and tissue damage (27).In addition to their role in maintaining mucosal immune homeostasis, gut macrophages, like dendritic cells (DC), have been shown to sample microbes directly from the intestinal lumen and transfer these antigens to DC for processing or tran...

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“…Non-CD4 T cells harbored less HIV DNA than CD4 T cells in the gut, but the infection level of non-T leukocytes was higher in GALT than in blood (161). Myeloid cells also harbor HIV DNA in GALT (162). A recent study of patients with acute infection showed that HIV DNA in the gut was significantly lower at Fiebig stage I than at Fiebig stages II to IV (79).…”

Section: Gut-associated Lymphoid Tissuementioning

confidence: 99%

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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A comparison of methods for measuring rectal HIV levels suggests that HIV DNA resides in cells other than CD4+ T cells, including myeloid cells

Cited by 61 publications

References 22 publications

Fibrocytes Differ from Macrophages but Can Be Infected with HIV-1

Fibrocytes Differ from Macrophages but Can Be Infected with HIV-1

Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

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