The adult penile urethra is a novel entry site for HIV-1 that preferentially targets resident urethral macrophages

Ganor, Yonatan; Zhou, Zhicheng; Bodo, J; Tudor, Daniela; Leibowitch, Jacques; Mathez, Dominique; Schmitt, Alain; Mc, Vacher-Lavenu; Revol, M.; Bomsel, Morgane

doi:10.1038/mi.2012.116

Cited by 82 publications

(100 citation statements)

References 37 publications

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“…We evidenced the presence of SIV RNA ϩ macrophages in the urethra from HAART-treated macaques with reduced or undetectable viremia. 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).…”

Section: Discussionsupporting

confidence: 81%

“…Such a high number of macrophages was also reported for the urethra from healthy uninfected men (87)(88)(89). The majority of T lymphocytes in macaques' urethras were CD4 negative, as previously reported for human urethral tissue (87,88). We evidenced the presence of SIV RNA ϩ macrophages in the urethra from HAART-treated macaques with reduced or undetectable viremia.…”

Section: Discussionmentioning

confidence: 64%

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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: 81%

Section: Discussionmentioning

confidence: 64%

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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“…In the first, explants of foreskin, glans, meatus, and urethra were found susceptible to infection with HIV-1 BaL, an R5-tropic strain (Anderson et al 2011). In the second, urethral macrophages were susceptible to infection with cell-associated HIV-1 (Ganor et al 2013). Thus, these studies confirm the infectability of sites other than the foreskin within the male RT.…”

Section: Male Reproductive Tractsupporting

confidence: 60%

Mucosal Immunity to HIV-1

Shacklett¹

2014

Encyclopedia of AIDS

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“…Aside from cell-to-cell HIV-1 transmission, trans infection may play a critical role in the propagation of sexual transmission of HIV-1 (Bobardt et al, 2007; Bomsel, 1997; Devito et al, 2000; Ganor et al, 2013; Gupta et al, 2013; Kinlock et al, 2014; Kohli et al, 2014; Saidi et al, 2007). To determine whether SE are capable of eliciting a block on HIV-1 trans infection, we utilized a trans well chamber system.…”

Section: Resultsmentioning

confidence: 99%

Exosomes in human semen restrict HIV-1 transmission by vaginal cells and block intravaginal replication of LP-BM5 murine AIDS virus complex

2015

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Exosomes are membranous extracellular nanovesicles secreted by diverse cell types. Exosomes from healthy human semen have been shown to inhibit HIV-1 replication and to impair progeny virus infectivity. In this study, we examined the ability of healthy human semen exosomes to restrict HIV-1 and LP-BM5 murine AIDS virus transmission in three different model systems. We show that vaginal cells internalize exosomes with concomitant transfer of functional mRNA. Semen exosomes blocked the spread of HIV-1 from vaginal epithelial cells to target cells in our cell-to-cell infection model and suppressed transmission of HIV-1 across the vaginal epithelial barrier in our trans-well model. Our in vivo model shows that human semen exosomes restrict intravaginal transmission and propagation of murine AIDS virus. Our study highlights an antiretroviral role for semen exosomes that may be harnessed for the development of novel therapeutic strategies to combat HIV-1 transmission.

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The adult penile urethra is a novel entry site for HIV-1 that preferentially targets resident urethral macrophages

Cited by 82 publications

References 37 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

Mucosal Immunity to HIV-1

Exosomes in human semen restrict HIV-1 transmission by vaginal cells and block intravaginal replication of LP-BM5 murine AIDS virus complex

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