Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Abstract

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...

Dissecting Polyclonal Vaccine-Induced Humoral Immunity against HIV Using Systems Serology

“…Along these lines, HIV is transmitted across mucosal barriers, where FcγR2-expressing monocytes/macrophages are abundant (Brown and Mattapallil, 2014; Zigmond and Jung, 2013). Moreover, ADCP activity was present in the RV144, VAX003, and IPCAVD001 networks (Fig 4), but was not observed in the HVTN204 network (Fig 4C) that was highly skewed to the elicitation of NK cell–mediated activities.…”

Mechanisms of HIV persistence in HIV reservoirs

“…Considering the large size of the GIT-associated mucosa, these cells have been reported as a significant source of viral RNA in this reservoir. 55 Genotypic and phenotypic differences may exist between GIT and blood viral isolates, 56,57 which support the idea of selection in the GIT compartment. However, more recent studies are reporting conflicting results with some finding less evidence of viral evolution and compartmentalization in the GALT over time in chronic HIV patients and in patients initiating HAART during acute HIV infection, 58,59 suggesting suppression of viral replication in the GALT during HAART therapy.…”

“…In addition to CD4+ T lymphocytes, the GIT macrophages and follicular DCs may also significantly contribute to the reservoir size of the GIT. Considering the large size of the GIT‐associated mucosa, these cells have been reported as a significant source of viral RNA in this reservoir …”

In vivo characterization of macrophage-tropic simian immunodeficiency virus molecular clones in rhesus macaques

“…Macrophages are another major cellular target of HIV and SIV infection, and are relatively resistant to the cytopathic effects of infection (Fauci and Desrosiers, 1997; Igarashi et al , 2001; Maartens et al , 2014; Perelson et al , 1996; Swingler et al , 2007). Macrophages are long-lived cells and serve as viral reservoirs in tissues such as the central nervous system (CNS), lymph nodes, and gut (Alexaki et al , 2008; Brown and Mattapallil, 2014). In the CNS, macrophages and microglia are the major cells supporting viral replication, which can cause neurological dysfunction and encephalitis (Albright et al , 2000; Burdo et al , 2013; Dick et al , 1997; Wang et al , 2002; Wiley et al , 1986; Williams et al , 2001).…”