Lower Genitourinary Tract Sources of Seminal HIV

Coombs, Robert W.; Lockhart, David; Ross, Susan O.; Deutsch, L.; Dragavon, Joan; Diem, Kurt; Hooton, Thomas M.; Collier, Ann C.; Corey, Lawrence; Krieger, John N.

doi:10.1097/01.qai.0000209895.82255.08

Cited by 47 publications

(38 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, several studies in therapy-naive men support such a role: urethral swabs were found to contain significant amounts of HIV RNA (96), and HIV RNA and DNA were detected in the preejaculatory fluid coming from the urethra (97,98). Phylogenetic analysis would be needed to demonstrate that the urethra is indeed a source of virus in semen during HAART.…”

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

J Virol

View full text Add to dashboard Cite

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...

show abstract

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

J Virol

View full text Add to dashboard Cite

show abstract

“…Paradoxically, while they are the major quantitative contributors to the seminal fluid, the seminal vesicles have been the least studied of the male genital organs, both in the context of HIV infection and insofar as their immunobiology. Indirect arguments that suggest that the seminal vesicles represent an important contributor to HIV shedding in semen are that selective sampling of genital fluids from HIV-positive men and prostate biopsy specimens indicated distal genitourinary sources other than the prostate gland (ie, seminal vesicles, urethra, and/or associated glands) as the major sources of seminal HIV in men without urethritis or prostatitis, 21 and in animal models, seminal vesicle infection by SIV was detected in rhesus macaques with AIDS 22,23 and in asymptomatic cynomolgus macaques. 15 To date, HIV infection of human seminal vesicles has not been reported.…”

Section: Discussionmentioning

confidence: 99%

“…21 The present study offers several perspectives including the following. First, the demonstration of infection of several human and macaque semen-producing organs in vitro and in vivo, together with evidence of organ-specific signatures in macaques, paves the way for studies with the objective of determining the respective contribution of these organs to semen contamination.…”

mentioning

confidence: 99%

Human Immunodeficiency Virus Infects Human Seminal Vesicles in Vitro and in Vivo

Deléage

Moreau

Rioux‐Leclercq

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

1 the precise origins of the infected leukocytes and free viral particles contaminating the seminal plasma remain unclear. Phylogenetic studies have established that HIV in semen arises from local sources within the male genital tract and/or from passive diffusion via the blood 2-4 (previous references in Le Tortorec and Dejucq-Rainsford 5 ). The existence of productive sources in the male genital tract is further substantiated through observations of several differences between blood and semen, including i) detection of persistent infectious HIV in the semen of 5% to 30% of men with undetectable blood viral load receiving fully suppressive antiretroviral therapy [5][6][7][8][9] ; ii) higher viral load in semen in a subpopulation of treatment-naïve men 10 ; iii) different rates, kinetics of emergence, and diversity of drug-resistant strains 4,11,12 ; and iv) different ratio of infected versus noninfected leukocytes. 13At present, the nature of the sources of HIV in the male genital tract remains unclear. This knowledge is crucial to the understanding of the biology of HIV sexual transmission and to the design of targeted therapies for eradicating HIV from semen.Semen is composed of secretions and cells from the testes, epididymides, prostate, seminal vesicles, and bulbo urethral glands. Vasectomy has little effect on seminal shedding of HIV-1 RNA, 14 which suggests that the testes and epididymides are not the primary sources of HIV particles in semen. The seminal vesicles, the secretions of which represent more than 60% of the seminal fluid, could be an important source of seminal HIV. We recently demonstrated that the seminal vesicles of asymptomatic macaques are productively infected by simian immunodeficiency virus (SIV) in vivo and, together with the prostate, exhibit the highest level of infection among the male genital tract organs in this animal model. 15 To date, infection of human seminal vesicles by HIV has not been reported.

show abstract

“…HIV-1 RNA levels measured in urethral swab fluid and voided urine after prostatic massage are independent predictors of seminal HIV-1 RNA level, which supports a urethral mucosal (or submucosal) or periurethral source for a good portion of the semen-associated virus [12]. Taken together, these observations suggest that antiretroviral drug levels in seminal plasma may underestimate the levels in any of the aforementioned genital tract sites that contribute HIV-1 to seminal plasma.…”

mentioning

confidence: 48%

“…A variety of mechanisms contribute to poor tissue penetration of ART, and multiple sources of HIV-1 contribute to the final HIV-1 RNA levels measured in seminal plasma [12]. The hypothesis that tissue penetration of ART through the blood-testesbarrier can be blocked by P-glycoprotein and breast cancer resistance protein-like mechanisms and thus, contribute to a drug-impermeable sanctuary for HIV-1 replication and recrudescence is attractive but simplistic, given that there are multiple genital tract sources of HIV-1 that may contribute to the differences in HIV-1 RNA first-phase decay rates noted between plasma (half-life, 4.5 days) and semen (8.6 days) in this study and others [9,13,14].…”

mentioning

confidence: 99%