Macrophage Infection via Selective Capture of HIV-1-Infected CD4+ T Cells

A number of men receiving prolonged suppressive highly active antiretroviral therapy (HAART) still shed human immunodeficiency virus (HIV) in semen. To investigate whether this seminal shedding may be due to poor drug penetration and/or viral production by long-lived cells within male genital tissues, we analyzed semen and reproductive tissues from macaques chronically infected with simian immunodeficiency virus mac251 (SIVmac251) who were treated for 4 months with HAART, which was intensified over the last 7 weeks with an integrase inhibitor. We showed that a subset of treated animals continued shedding SIV in semen despite efficient HAART. This shedding was not associated with low antiretroviral drug concentrations in semen or in testis, epididymis, seminal vesicles, and prostate. HAART had no significant impact on SIV RNA in the urethra, whereas it drastically reduced SIV RNA levels in the prostate and vas deferens and to a lesser extent in the epididymis and seminal vesicle. The only detectable SIV RNA-positive cells within the male genital tract after HAART were urethral macrophages. SIV DNA levels in genital tissues were not decreased by HAART, suggesting the presence throughout the male genital tract of nonproductively infected cells. In conclusion, our results demonstrate that 4 months of HAART induced variable and limited control of viral infection in the male reproductive organs, particularly in the urethra, and suggest that infected long-lived cells in the male genital tract may be involved in persistent seminal shedding during HAART. These results pave the way for further investigations of male genital organ infection in long-term-treated infected individuals. IMPORTANCEA substantial subset of men receiving prolonged HAART suppressing viral loads in the blood still harbor HIV in semen, and cases of sexual transmission have been reported. To understand the origin of this persistence, we analyzed the semen and male reproductive tissues from SIV-infected macaques treated with HAART. We demonstrated that persistent seminal shedding was not linked to poor drug penetration in semen or semen-producing prostate, seminal vesicle, epididymis, and testis. We revealed that HAART decreased SIV RNA to various extents in all male genital organs, with the exception of the urethra, in which SIV RNA ؉ macrophages were observed despite HAART. Importantly, HAART did not impact SIV DNA levels in the male genital organs. These results suggest that infection of male genital organs, and particularly the urethra, could be involved in the release of virus in semen during HAART.A pproximately 35.3 million people worldwide are living with human immunodeficiency virus (HIV)/AIDS, and 2.3 million new infections occur annually (1). Over 80% of these new infections are caused by unprotected sexual intercourse. The risk of sexual transmission of HIV is strongly correlated with HIV RNA levels in genital secretions (2). Because semen is the most common vector of HIV dissemination worldwide (3-5), preventing HIV transmission by...

Section: Discussionmentioning

confidence: 99%

Detection of Simian Immunodeficiency Virus in Semen, Urethra, and Male Reproductive Organs during Efficient Highly Active Antiretroviral Therapy

Matusali

Dereuddre-Bosquet

Tortorec

et al. 2015

“…Myeloid cells in lymphoid tissues, however, contained viral DNA, but this was not dependent on the presence of Vpx. Rather, viral DNA in myeloid cells arose from phagocytosis of infected T cells (48,49). The phagocytosis of living or dying infected cells also may represent a source of exogenous viral antigens (50,51).…”

Section: Discussionmentioning

confidence: 99%

SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

Ayinde

Bruel

Cardinaud

et al. 2015

Monocyte-derived dendritic cells (MDDC) stimulate CD8؉ cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses. IMPORTANCEUpon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early postentry step. This is due to the presence of SAMHD1, a cellular enzyme that depletes intracellular levels of dNTPs and inhibits viral reverse transcription. We show that the depletion of SAMHD1 in DCs strongly stimulates the presentation of viral antigens derived from newly produced viral proteins, leading to the activation of HIV-1-specific cytotoxic T lymphocytes (CTL). We further show in real time that the enhanced activation of CTL leads to killing of infected DCs. Our results indicate that the antiviral activity of SAMHD1 not only impacts HIV replication but also impacts antigen presentation by DC. They highlight the link that exists between restriction factors and adaptive immune responses.

“…While we were unable to determine whether or not the viral DNA we amplified from lymphoid tissue-resident myeloid cells represented replication-competent virus, it remains possible that virus within phagocytosed T cells could be responsible for latency and/or that macrophages become infected during the phagocytosis process. Indeed, recent work has suggested that HIV can replicate in macrophages after macrophage phagocytosis of HIV-infected T cells (110).…”

Section: Methods For Characterizing Hiv/siv In Macrophagesmentioning

confidence: 99%

Macrophages in Progressive Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections

DiNapoli

Hirsch

Brenchley

2016

The cells that are targeted by primate lentiviruses (HIV and simian immunodeficiency virus [SIV]) are of intense interest given the renewed effort to identify potential cures for HIV. These viruses have been reported to infect multiple cell lineages of hematopoietic origin, including all phenotypic and functional CD4 T cell subsets. The two most commonly reported cell types that become infected in vivo are memory CD4 T cells and tissue-resident macrophages. Though viral infection of CD4 T cells is routinely detected in both HIV-infected humans and SIV-infected Asian macaques, significant viral infection of macrophages is only routinely observed in animal models wherein CD4 T cells are almost entirely depleted. Here we review the roles of macrophages in lentiviral disease progression, the evidence that macrophages support viral replication in vivo, the animal models where macrophage-mediated replication of SIV is thought to occur, how the virus can interact with macrophages in vivo, pathologies thought to be attributed to viral replication within macrophages, how viral replication in macrophages might contribute to the asymptomatic phase of HIV/SIV infection, and whether macrophages represent a long-lived reservoir for the virus. Macrophages are a diverse and functionally important component of the immune system. Evolutionarily conserved in almost all species of the phylum Chordata, macrophages are one of the "oldest" leukocyte lineages and have the highest degree of plasticity across leukocyte subsets (1). Macrophages differentiate from the yolk sac, fetal liver, and peripheral blood monocytes that developed from bone marrow-derived hematopoietic stem cells. With their phenotypic and functional plasticity and presence in disparate tissues, macrophages play supportive roles in multiple aspects of physiology. Their function often depends upon their anatomical location, their individual ontogeny, and extracellular cues. For example, macrophages derived from the yolk sac or fetal liver reside in organs such as the brain (as microglia cells), pancreas, spleen, liver (as Kuppfer cells), and kidney. For many years, yolk sac-and fetal liver-derived macrophages were thought to be very long-lived, perhaps for the life span of the host. Indeed, after differentiating during fetal development, these macrophages can populate tissues for the duration of the host's life. However, recent data suggest that these cells can also divide in vivo to maintain homeostasis (1-3) and are able to rapidly repopulate after chemotherapeutic depletion (in the case of brain-resident microglia cells [4]). Our understanding of macrophage longevity and factors important for their homeostatic proliferation in vivo is incomplete and more data are required. FUNCTIONS OF MACROPHAGES IN HEALTHThough macrophage longevity is not fully understood, many studies have demonstrated that tissue-resident macrophages have critically important functions in tissue immunity and repair, antigen presentation, and tissue homeostasis. Indeed, the importance of their fu...