Detection of Infectious HIV in Circulating Monocytes From Patients on Prolonged Highly Active Antiretroviral Therapy

A pproximately 2 to 3% of human T cell leukemia virus type 1 (HTLV-1)-infected individuals develop adult T-cell leukemia/lymphoma (ATL) and another 2 to 3% develop HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) in their lifetimes (1-4). In addition to HAM/TSP (5, 6), HTLV-1 is also associated with other inflammatory conditions, such as uveitis (6) Sjögren's syndrome (7), bronchoalveolitis and arthritis (8), and polymyositis (9). It is noteworthy that some patients present with more than one of these inflammatory conditions (10). HTLV-1 primarily infects CD4 ϩ and CD8 ϩ effector and memory T cells and regulatory CD4 ϩ CD25 ϩ T cells (11,12). A high viral DNA burden in peripheral blood mononuclear cells (PBMCs) is a risk factor for HAM/TSP (13) and ATL development (14-16), and patients with HAM/TSP have a higher virus level in the cerebrospinal fluid (CSF) than in the peripheral blood (12). The virus level alone is not sufficient to differentiate symptomatic patients from healthy carriers, suggesting the importance of other factors, including the host immune response (16)(17)(18)(19)(20). HAM/TSP patients present diverse immunological alterations, such as increased levels of spontaneous lymphocyte proliferation (21, 22), tax-specific cytotoxic CD8 ϩ T cell expansion, and the production of high levels of inflammatory cytokines (23)(24)(25). Several studies have also suggested that monocytes are involved in immune reg-

Section: Cd16mentioning

confidence: 99%

Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans

Castro-Amarante

Pise-Masison

McKinnon

et al. 2016

“…Monocytes productively infected with HIV have been found in the peripheral blood and constitute a significant, continually evolving viral reservoir (20)(21)(22)(23)(24). These infected monocytes can further differentiate in the tissues into mature, virus-harboring macrophages that can disseminate HIV to other cell types, including T cells (15,22,25).…”

Section: Cd16mentioning

confidence: 99%

CD4 Ligation on Human Blood Monocytes Triggers Macrophage Differentiation and Enhances HIV Infection

Zhen

Krutzik

Levin

et al. 2014

A unique aspect of human monocytes, compared to monocytes from many other species, is that they express the CD4 molecule. However, the role of the CD4 molecule in human monocyte development and function is not known. We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. Importantly, we determined that CD4 activation induces intracellular signaling in monocytes and that inhibition of the MAPK and Src family kinase pathways blocked the ability of CD4 ligation to trigger macrophage differentiation. We observed that ligation of CD4 by MHC-II on activated endothelial cells induced CD4-mediated macrophage differentiation of blood monocytes. Finally, CD4 ligation by MHC-II increases the susceptibility of blood-derived monocytes to HIV binding and subsequent infection. Altogether, our studies have identified a novel function for the CD4 molecule on peripheral monocytes and suggest that a unique set of events that lead to innate immune activation differ between humans and mice. Further, these events can have effects on HIV infection and persistence in the macrophage compartment. IMPORTANCEThe CD4 molecule, as the primary receptor for HIV, plays an important role in HIV pathogenesis. There are many cell types that express CD4 other than the primary HIV target, the CD4 ؉ T cell. Other than allowing HIV infection, the role of the CD4 molecule on human monocytes or macrophages is not known. We were interested in determining the role of CD4 in human monocyte/macrophage development and function and the potential effects of this on HIV infection. We identified a role for the CD4 molecule in triggering the activation and development of a monocyte into a macrophage following its ligation. Activation of the monocyte through the CD4 molecule in this manner increases the ability of monocytes to bind to and become infected with HIV. Our studies have identified a novel function for the CD4 molecule on peripheral monocytes in triggering macrophage development that has direct consequences for HIV infection.

“…Myeloid cell types especially are thought to be a minor latent-HIV-1 reservoir population compared to CD4 T lymphoid cells, which are considered a major population. Although clinical studies have indicated the existence of HIV-1 latency in myeloid cells and ex vivo analysis also indicated the potential of myeloid cells as a latent-HIV-1 reservoir, the establishment of an optimal model of HIV-1 latency reflecting HIV/AIDS patients is required (60)(61)(62). Recently, a latent HIV-1 infection model was established by using isolated CD4 T cells from peripheral blood mononuclear cells (63,64).…”

Section: Discussionmentioning

confidence: 99%

COMMD1/Murr1 Reinforces HIV-1 Latent Infection through IκB-α Stabilization

Taura

Kudo

Kariya

et al. 2015