Infection of Macaques after Vaginal Exposure to Cell‐Associated Simian Immunodeficiency Virus

Sallé, Bettina; Brochard, Patricia; Bourry, Olivier; Mannioui, Abdelkrim; Andrieu, Thibault; Prévôt, Sophie; Dejucq-Rainsford, Nathalie; Dereuddre‐Bosquet, Nathalie; Grand, Roger Le

doi:10.1086/653619

Cited by 78 publications

(71 citation statements)

References 24 publications

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“…In men under suppressive HAART, the presence of replication-competent virus has been shown in seminal leukocytes for up to 3 years after treatment initiation (7, 10, 23-26, 103, 104). On the basis of the present results and of our previous demonstration of the infection of female macaques following vaginal exposure to infected cells (28), a future study into the ability of persistently infected seminal cells to transmit infection in a sexual partner in macaques is of strong interest.…”

Section: Discussionmentioning

confidence: 66%

“…In addition to viral RNA (vRNA) in the cell-free fraction of semen, infected leukocytes harboring HIV DNA and capable of productive infection have been detected in the semen of men receiving HAART (7,(23)(24)(25)(26). Recent evidence indicates that HIV-infected cells in genital secretions could play a role in the sexual transmission of HIV (27)(28)(29). Although HAART in the infected partner very significantly reduces heterosexual transmission at the population level, a risk for residual transmission remains (30)(31)(32).…”

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confidence: 99%

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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: Discussionmentioning

confidence: 66%

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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

J Virol

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“…It is possible that vaccine-elicited antibodies capable of potent neutralization in the TZM-bl assay lack certain biological properties that are essential for preventing acquisition in vivo (14,47). Cell-to-cell transmission could play a more prominent role in intrarectal SIV infection than is currently recognized (48)(49)(50)(51), and higher concentrations of antibodies with certain specificities could then be necessary to prevent establishment of infection (52,53). It is similarly possible that the atypically high neutralization sensitivity of SIVsmE660 Env variants involves antibody specificities that are greatly enhanced in the TZM-bl assay and have limited relevance to those that neutralize HIV-1 (27).…”

Section: Discussionmentioning

confidence: 99%

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Burton

Kilgore

Smith

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742–1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

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“…Much evidence from animal studies, as well as human studies, supports the concept that cellto-cell HIV-1 transmission can be responsible for initial infection. Lymphocytes infected with SIV and HIV-1 robustly infect macaques and chimpanzees, respectively (9)(10)(11). Indeed, virus-infected lymphocytes are more efficient at establishing infection than free virus (8,10).…”

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confidence: 99%

Slaying the Trojan Horse: Natural Killer Cells Exhibit Robust Anti-HIV-1 Antibody-Dependent Activation and Cytolysis against Allogeneic T Cells

Gooneratne

Richard

Lee

et al. 2015

J Virol

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Many attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1A preventative vaccine is urgently needed to curb the growing human immunodeficiency virus type 1 (HIV-1) epidemic and reduce the global economic burden of supplying lifelong antiretroviral therapies. The induction of antibodies (Abs) capable of neutralizing a broad range of viral strains is a major goal of HIV-1 vaccine research. Such broadly neutralizing Abs (BnAbs) have been isolated from HIV-1-infected individuals, and passive transfer of BnAbs to nonhuman primates has proven sufficient to prevent infection upon challenge with cell-free chimeric simianhuman immunodeficiency viruses (SHIV) (1-3). Despite the potential of BnAbs to prevent HIV-1 infection, a vaccine capable of eliciting BnAbs in HIV-1-uninfected individuals has not yet been designed. The lack of appropriate immunogens and the extensive somatic hypermutation within the variable regions of BnAbs are major impediments to their induction via vaccination (4). This inability to elicit BnAbs through immunization has spurred research interest into the potential of nonneutralizing effector functions of Abs to provide protection against HIV-1.Interest in the potential of the nonneutralizing effector functions of Abs has also been stimulated by the recent phase III human RV144 vaccine trial in Thailand, which provided evidence that nonneutralizing Ab-associated effector functions may be involved in Ab-conferred protection against HIV-1 infection (5, 6). Indeed, correlates of immunity analyses revealed that, in the absence of broadly neutralizing Abs, both high levels of IgG Abs to the V1V2 regions of the HIV-1 Env and low levels of plasma an-

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Infection of Macaques after Vaginal Exposure to Cell‐Associated Simian Immunodeficiency Virus

Abstract: Infection with SIV after exposure of vaginal and cervical mucosa to cell-associated virus represents a new mechanism of sexual transmission of HIV and SIV that may have significant impacts in the development of preventive approaches like microbicides.

Cited by 78 publications

References 24 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

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Slaying the Trojan Horse: Natural Killer Cells Exhibit Robust Anti-HIV-1 Antibody-Dependent Activation and Cytolysis against Allogeneic T Cells

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