Antiviral Inhibition of Enveloped Virus Release by Tetherin/BST-2: Action and Counteraction

Tetherin (BST2/CD317) has been recently recognized as a potent interferon-induced antiviral molecule that inhibits the release of diverse mammalian enveloped virus particles from infected cells. By targeting an immutable structure common to all these viruses, the virion membrane, evasion of this antiviral mechanism has necessitated the development of specific countermeasures that directly inhibit tetherin activity. Here we review our current understanding of the molecular basis of tetherin’s mode of action, the viral countermeasures that antagonize it, and how virus/tetherin interactions may affect viral transmission and pathogenicity

Impact of short term HAART initiated during the acute or chronic stage on SIV infection of the male genital tract

International audiencen.

Human prostate supports more efficient replication of HIV-1 R5 than X4 strains ex vivo

<p>Abstract</p> <p>Background</p> <p>In order to determine whether human prostate can be productively infected by HIV-1 strains with different tropism, and thus represent a potential source of HIV in semen, an organotypic culture of prostate from men undergoing prostatic adenomectomy for benign prostate hypertrophy (BPH) was developed. The presence of potential HIV target cells in prostate tissues was investigated using immunohistochemistry. The infection of prostate explants following exposures with HIV-1 R5, R5X4 and X4 strains was analyzed through the measure of RT activity in culture supernatants, the quantification of HIV DNA in the explants and the detection of HIV RNA+ cells <it>in situ</it>.</p> <p>Results</p> <p>The overall prostate characteristics were retained for 2^1/2weeks in culture. Numerous potential HIV-1 target cells were detected in the prostate stroma. Whilst HIV-1 R5_SF162strain consistently productively infected prostatic T lymphocytes and macrophages, the prototypic X4_IIIBstrain and a primary R5X4 strain showed less efficient replication in this organ.</p> <p>Conclusion</p> <p>The BPH prostate is a site of HIV-1 R5 replication that could contribute virus to semen. A limited spreading of HIV-1 X4 and R5X4 in this organ could participate to the preferential sexual transmission of HIV-1 R5 strains.</p

Impact of Short-Term HAART Initiated during the Chronic Stage or Shortly Post-Exposure on SIV Infection of Male Genital Organs

International audienceBACKGROUND: The male genital tract is suspected to constitute a viral sanctuary as persistent HIV shedding is found in the semen of a subset of HIV-infected men receiving effective antiretroviral therapy (HAART). The origin of this persistent shedding is currently unknown. Phylogenetic studies indicated that HIV in semen from untreated men arises from local sources and/or passive diffusion from the blood. We previously demonstrated in human and macaque low levels and localized infection of several semen-producing organs by HIV/SIV. Using a macaque model, this study investigates the impact of short term HAART (2-4 weeks) initiated either during the asymptomatic chronic stage or 4 h post-intravenous inoculation of SIVmac251 on the infection of male genital organs. METHODOLOGY/PRINCIPAL FINDINGS: Short term HAART during the chronic stage decreased blood viral load. No major impact of HAART was observed on SIV DNA levels in male genital organs using a sensitive nested PCR assay. Using in situ hybridization, SIV RNA+ cells were detected in all male genital tract organs from untreated and treated animals with undetectable blood viral load following HAART. Infected CD68+ myeloid cells and CD3+ T lymphocytes were detected pre- and post-HAART. In contrast, short term HAART initiated 4 h post-SIV exposure led to a drastic decrease of the male genital tissues infection, although it failed to prevent systemic infection. In both cases, HAART tended to decrease the number of CD3+ T cells in the male organs. CONCLUSIONS: Our results indicate that the established infection of male genital organs is not greatly impacted by short term HAART, whereas the same treatment during pre-acute phase of the infection efficiently impairs viral dissemination to the male genital tract. Further investigations are now needed to determine whether infection of male genital organs is responsible for long term persistent HIV shedding in semen despite HAART

Infection of Semen-Producing Organs by SIV during the Acute and Chronic Stages of the Disease

International audienceBACKGROUND: Although indirect evidence suggests the male genital tract as a possible source of persistent HIV shedding in semen during antiretroviral therapy, this phenomenon is poorly understood due to the difficulty of sampling semen-producing organs in HIV+ asymptomatic individuals. METHODOLOGY/PRINCIPAL FINDINGS: Using a range of molecular and cell biological techniques, this study investigates SIV infection within reproductive organs of macaques during the acute and chronic stages of the disease. We demonstrate for the first time the presence of SIV in the testes, epididymides, prostate and seminal vesicles as early as 14 days post-inoculation. This infection persists throughout the chronic stage and positively correlates with blood viremia. The prostate and seminal vesicles appear to be the most efficiently infected reproductive organs, followed by the epididymides and testes. Within the male genital tract, mostly T lymphocytes and a small number of germ cells harbour SIV antigens and RNA. In contrast to the other organs studied, the testis does not display an immune response to the infection. Testosteronemia is transiently increased during the early phase of the infection but spermatogenesis remains unaffected. CONCLUSIONS/SIGNIFICANCE: The present study reveals that SIV infection of the macaque male genital tract is an early event and that semen-producing organs display differential infection levels and immune responses. These results help elucidate the origin of HIV in semen and constitute an essential base to improving the design of antiretroviral therapies to eradicate virus from semen

Infections et réponse antivirale du testicule

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Étude de l infection du tractus génital mâle par le VIH et le SIV

L objectif de mon travail de thèse a été d explorer les modalités d infection par le VIH du tractus génital masculin, réservoir viral potentiel pour ces virus. Nous avons montré chez le modèle macaque infecté par le virus de l immunodéficience simienne (VIS) que l ensemble des organes génitaux participant à l élaboration du sperme est infecté dès la primo-infection. De plus, nous avons confirmél existence d interactions entre les cellules germinales testiculaires et le VIS. Grâce à un modèle de culture organotypique, nous avons mis en évidence in vitro que la prostate humaine avec une inflammation chronique est préférentiellement infectée par des souches utilisant le co-récepteur CCR5.Enfin, dans le modèle macaque infecté VIS, une polychimiothérapie même précoce diminue mais n empêche pas l infection productive des organes génitaux. Ainsi, les organes génitaux mâles sont fortement susceptibles de représenter un réservoir viral qui contribuerait à l infectiosité persistante du sperme.The main goal of my thesis work dealed with the ability of HIV-1 to infect the male genital tract organs, as it represent a potential viral reservoir. Through in vivo and in vitro approaches, we showed that: - In macaques infected by SIV in vivo, all genital organs contributing to the elaboration of semen were infected during the acute stage of the infection. We confirmed the existence of interactions between germinal testicular cells and SIV. -Using an organotypic culture system, we showed that human chronic inflamed prostate is preferentially infected in vitro by HIV-1 strains using the CCR5 coreceptor. - In the macaque model, an early initiated treatment diminishes but does not prevent the viral spread in the male genital organs. Thus, male genital organs are strongly susceptible to represent an early viral reservoir and constitute a productive source of virus in semen.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Le tractus génital masculin : un refuge pour le VIH ?

International audienceDes travaux ont mis en évidence la réplication du VIH dans les organes participant à l'élaboration du sperme. Cette production de virus au sein du tractus génital masculin pose de nombreuses questions : persistance du VIH dans le sperme, interactions entre VIH et spermatozoïdes, transmission sexuelle du VIH par l'homme

Le tractus génital masculin

Alors que le sperme représente le principal vecteur de dissémination du virus de l’immunodéficience humaine (VIH) dans le monde, l’origine du virus dans ce fluide demeure très mal connue. Chez certains hommes sous traitement antirétroviral efficace depuis plusieurs mois voire plusieurs années, le VIH persiste dans le sperme. Il est donc essentiel de déterminer la nature des sources de virus à ce niveau pour améliorer l’efficacité des thérapies actuelles. Nos travaux ont permis de mettre en évidence la réplication du VIH dans les organes participant à l’élaboration du sperme, confortant les analyses phylogénétiques qui indiquent que les particules virales et les cellules infectées présentes dans le sperme sont en partie produites localement. Cette production de virus au sein du tractus génital masculin pose de nombreuses questions : l’infection du testicule et/ou des glandes annexes est-elle impliquée dans la persistance du VIH dans le sperme ? Quelle est la nature des interactions entre le VIH et les spermatozoïdes/ cellules germinales testiculaires ? Des résultats récents indiquent que le sperme d’hommes séronégatifs modifie l’infectivité du VIH : le liquide séminal des hommes séropositifs a-t-il un rôle inhibiteur ou facilitateur de la transmission sexuelle du VIH 

Le tractus génital masculin : un refuge pour le VIH ?

International audienceDes travaux ont mis en évidence la réplication du VIH dans les organes participant à l'élaboration du sperme. Cette production de virus au sein du tractus génital masculin pose de nombreuses questions : persistance du VIH dans le sperme, interactions entre VIH et spermatozoïdes, transmission sexuelle du VIH par l'homme