Tissue Myeloid Cells in SIV-Infected Primates Acquire Viral DNA through Phagocytosis of Infected T Cells

Calantone, Nina; Wu, Fan; Klase, Zachary; Deléage, Claire; Perkins, Molly R.; Matsuda, Kenta; Thompson, Elizabeth A.; Ortiz, Alexandra M.; Vinton, Carol L.; Ourmanov, Ilnour; Loré, Karin; Douek, Daniel C.; Estes, Jacob D.; Hirsch, Vanessa M.; Brenchley, Jason M.

doi:10.1016/j.immuni.2014.08.014

Cited by 98 publications

(119 citation statements)

References 50 publications

(64 reference statements)

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“…In agreement with our findings in macaques in vivo, the preferential infection of resident macrophages was recently described in human urethral tissue exposed ex vivo to HIV-1 (87). It was recently suggested that myeloid cells in the gut and lymphoid tissues from SIV-infected primates are resistant to infection and acquire SIV DNA primarily through the phagocytosis of infected T cells (90). However, it was reported that macrophages in lymph nodes and mucosal tissues get heavily infected in macaques depleted in CD4 ϩ T cells (91) and that the uptake of HIV-infected T lymphocytes by blood-derived macrophages leads to their infection (92).…”

Section: Discussionsupporting

confidence: 92%

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

J Virol

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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...

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Section: Discussionsupporting

confidence: 92%

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

J Virol

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“…7,35 Finally, it is noteworthy that myeloid cells (macrophages, monocytes, and dendritic cells) have been shown to become infected with HIV following phagocytosis of infected T cells in the SIV model of infection. 38 A limitation of our study is the small sample size and the limited number of clones analyzed per compartment. The challenges in amplifying the HIV genome from tissue restricted our use of limiting dilution techniques such as single genome amplification, which have been shown to mitigate the problem of variant resampling within quasispecies.…”

Section: Discussionmentioning

confidence: 99%

“…36 Second, the influx of activated immune cells including differentiated macrophages to the site of infection regardless of HIV status and the concomitant HIV-related T cell depletion 19 mean that an environment permissive to exploiting macrophages may be created in spinal TB granulomas. However, there remains controversy around this paradigm with conflicting reports showing that CD4 depletion either has an impact 37 or has no impact 38 on HIV infection of myeloid cells. Third, longlived HIV lineages have previously been correlated with macrophage-targeting HIV variants in the CNS.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

Danaviah

Oliveira

Gordon³

et al. 2016

AIDS Research and Human Retroviruses

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Extrapulmonary tuberculosis (TB) is a significant public health challenge in South Africa and worldwide, largely fuelled by the HIV epidemic. In spinal TB, Mycobacteria infect the spinal column without dissemination to the spinal cord. The immune microenvironment, target cell characteristics, and other evolutionary forces within granulomas during HIV/TB coinfection are poorly characterized. We investigated whether spinal TB granulomas represent a sequestered anatomical site where independent HIV evolution occurs, and assessed the role of macrophages as a target cell for both HIV and mycobacteria. RNA was extracted from plasma and granulomatous tissue from six antiretroviral-naive HIV-1/spinal TB-coinfected patients, RT-PCR amplified, and the C2-V5 env segment was cloned and sequenced. Analysis of genetic diversity, phylogeny and coalescence patterns was performed on clonal sequences. To investigate their role in HIV sequestration, macrophages and the HIV-1 p24 protein were immune localized and ultrastructural features were studied. Intercompartment diversity measurements and phylogenetic reconstruction revealed anatomically distinct monophyletic HIV-1 clusters in four of six patients. Genotypic CCR5-tropic variants were predominant (98.9%) with conservation of putative N-linked glycosylation sites in both compartments. CD68+ reactivity was associated with higher tissue viral load (r = 1.0; p < 0.01) but not greater intrapatient diversity (r = 0.60; p > 0.05). Ultrastructural imaging revealed the presence of bacterial and virus-like particles within membrane-bound intracellular compartments of macrophages. Spinal tuberculosis granulomas may form anatomically discreet sites of divergent viral evolution. Macrophages in these granulomas harbored both pathogens, suggesting that they may facilitate the process of viral sequestration within this compartment.

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“…It will be necessary to investigate cells other than CD4 + lymphocytes and tissues other than blood, especially the CNS. Also of note, the problem of measuring DNA in CD4 + lymphocytes is further compounded in macrophages, which may contain viral DNA and protein as a result of their phagocytic function, rather than their role in replication (86).…”

Section: Latency In Cells Other Than Cd4 + Lymphocytesmentioning

confidence: 99%

Measuring the latent reservoir in vivo

Massanella¹,

Richman²

2016

Journal of Clinical Investigation

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Tissue Myeloid Cells in SIV-Infected Primates Acquire Viral DNA through Phagocytosis of Infected T Cells

Cited by 98 publications

References 50 publications

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

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

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

Measuring the latent reservoir in vivo

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