Clinical and Mucosal Immune Correlates of HIV-1 Semen Levels in Antiretroviral-Naive Men

Osborne, B.; Marsh, Angie K.; Huibner, Sanja; Shahabi, Kamnoosh; Liu, Cindy H.; Contente, Tania; Nagelkerke, Nico; Kovacs, Colin; Benko, Erika; Price, Lance B.; MacDonald, Kelly S.; Kaul, Rupert

doi:10.1093/ofid/ofx033

Cited by 8 publications

(7 citation statements)

References 40 publications

(44 reference statements)

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“…Because viral load in semen has been correlated in several studies to the seminal concentrations of various inflammatory cytokines ( 17 – 21 ), we also tested whether inflammation levels in male genital organs could influence tissue viral load and shedding in semen. Using mRNAs of 6 cytokines, which are known to correlate with HIV semen levels (tumor necrosis factor alpha [TNF-α], interleukin 1β [IL-1β], gamma interferon [IFN-γ], CCL2, and IL-10) ( 18 , 19 , 21 , 22 ) or are elevated in HIV-infected patients (IL-8) ( 20 , 23 , 24 ), we measured inflammation levels within all the male genital organs, excluding the urethra due to limited material ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To this end, we first examined the infection level and inflammation status of all of the 4 organs (testis, epididymis, seminal vesicles, and prostate) involved in semen elaboration, as well as of 2 ducts involved in semen transport (vas deferens and urethra) from 8 chronically infected macaques. Numerous studies reported a significant correlation between HIV shedding and elevated cytokine concentrations in semen, along with specific pattern of cytokine network in semen compared with blood, suggesting that inflammation favors the burst/release of virus from local sources ( 17 – 21 , 25 – 30 ). Our data showed no correlation between semen viral load and expression levels of proinflammatory cytokines such as TNF-α and IL-1β in infected semen-producing organs, preventing initial discrimination of potential tissue sources.…”

Section: Discussionmentioning

confidence: 99%

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Seminal Simian Immunodeficiency Virus in Chronically Infected Cynomolgus Macaques Is Dominated by Virus Originating from Multiple Genital Organs

Houzet

Pérez‐Losada

Matusali

et al. 2018

J Virol

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The sexual transmission of viruses is responsible for the spread of multiple infectious diseases. Although the human immunodeficiency virus (HIV)/AIDS pandemic remains fueled by sexual contacts with infected semen, the origin of virus in semen is still unknown. In a substantial number of HIV-infected men, viral strains present in semen differ from the ones in blood, suggesting that HIV is locally produced within the genital tract. Such local production may be responsible for the persistence of HIV in semen despite effective antiretroviral therapy. In this study, we used single-genome amplification, amplicon sequencing (env gene), and phylogenetic analyses to compare the genetic structures of simian immunodeficiency virus (SIV) populations across all the male genital organs and blood in intravenously inoculated cynomolgus macaques in the chronic stage of infection. Examination of the virus populations present in the male genital tissues of the macaques revealed compartmentalized SIV populations in testis, epididymis, vas deferens, seminal vesicles, and urethra. We found genetic similarities between the viral strains present in semen and those in epididymis, vas deferens, and seminal vesicles. The contribution of male genital organs to virus shedding in semen varied among individuals and could not be predicted based on their infection or proinflammatory cytokine mRNA levels. These data indicate that rather than a single source, multiple genital organs are involved in the release of free virus and infected cells into semen. These findings have important implications for our understanding of systemic virus shedding and persistence in semen and for the design of eradication strategies to access viral reservoirs.IMPORTANCE Semen is instrumental for the dissemination of viruses through sexual contacts. Worryingly, a number of systemic viruses, such as HIV, can persist in this body fluid in the absence of viremia. The local source(s) of virus in semen, however, remains unknown. To elucidate the anatomic origin(s) of the virus released in semen, we compared viral populations present in semen with those in the male genital organs and blood of the Asian macaque model, using single-genome amplification, amplicon sequencing (env gene), and phylogenetic analysis. Our results show that multiple genital tissues harbor compartmentalized strains, some of them (i.e., from epididymis, vas deferens, and seminal vesicles) displaying genetic similarities with the viral populations present in semen. This study is the first to uncover local genital sources of viral populations in semen, providing a new basis for innovative targeted strategies to prevent and eradicate HIV in the male genital tract.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Seminal Simian Immunodeficiency Virus in Chronically Infected Cynomolgus Macaques Is Dominated by Virus Originating from Multiple Genital Organs

Houzet

Pérez‐Losada

Matusali

et al. 2018

J Virol

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“…HIV-1 infection is associated with dysregulation of seminal cytokines (38,39) as well as an increased semen/blood cytokine ratio (10,38,39). This proinflammatory environment has been suggested to increase viral replication, as semen viral load often correlates with cytokine levels (40), as well as the fact that several cytokines, including TNF-␣, directly act on the virus to increase replication (41) (reviewed in reference 42). A similar phenomenon is observed in men with classical STI such as gonorrhea or trichomoniasis (20).…”

Section: Discussionmentioning

confidence: 99%

Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without Sexually Transmitted Infection-Associated Urethritis

Council

Zhou

McCann

et al. 2020

J Virol

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Concurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from antiretroviral therapy (ART)-naive men living in Malawi with (n = 19) and without (n = 5) STI-associated urethritis; for a subset of samples, full-length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of proinflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population, indicating a recent bottleneck followed by limited viral replication. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, and where specific genotypes can be amplified, perhaps initially by cellular proliferation but further by limited viral replication. IMPORTANCE HIV-1 infection is a sexually transmitted infection that coexists with other STI. Here, we examined the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI.

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“…HIV load in semen is usually lower than in blood, but patients with an exceptionally high semen viral load were reported (533,671,741). Factors associated with HIV shedding prevalence in semen are blood viral load (104,176,267,313,329), STIs (329,548), seminal CMV or EBV (226,227,229,394,482,523,628) and seminal cytokine levels (394,395,523,548); the two latter reflecting elevated inflammation, which enhances HIV replication.…”

Section: Prevalence and Pattern Of Virus Shedding In Semenmentioning

confidence: 99%

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

Tortorec

Matusali

Mahé

et al. 2020

Physiological Reviews

103

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The male genital tract (MGT) is the target of a number of viral infections that can have deleterious consequences at the individual, offspring, and population levels. These consequences include infertility, cancers of male organs, transmission to the embryo/fetal development abnormalities, and sexual dissemination of major viral pathogens such as human immunodeficiency virus (HIV) and hepatitis B virus. Lately, two emerging viruses, Zika and Ebola, have additionally revealed that the human MGT can constitute a reservoir for viruses cleared from peripheral circulation by the immune system, leading to their sexual transmission by cured men. This represents a concern for future epidemics and further underlines the need for a better understanding of the interplay between viruses and the MGT. We review here how viruses, from ancient viruses that integrated the germline during evolution through old viruses (e.g., papillomaviruses originating from Neanderthals) and more modern sexually transmitted infections (e.g., simian zoonotic HIV) to emerging viruses (e.g., Ebola and Zika) take advantage of genital tract colonization for horizontal dissemination, viral persistence, vertical transmission, and endogenization. The MGT immune responses to viruses and the impact of these infections are discussed. We summarize the latest data regarding the sources of viruses in semen and the complex role of this body fluid in sexual transmission. Finally, we introduce key animal findings that are relevant for our understanding of viral infection and persistence in the human MGT and suggest future research directions.

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Clinical and Mucosal Immune Correlates of HIV-1 Semen Levels in Antiretroviral-Naive Men

Cited by 8 publications

References 40 publications

Seminal Simian Immunodeficiency Virus in Chronically Infected Cynomolgus Macaques Is Dominated by Virus Originating from Multiple Genital Organs

Seminal Simian Immunodeficiency Virus in Chronically Infected Cynomolgus Macaques Is Dominated by Virus Originating from Multiple Genital Organs

Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without Sexually Transmitted Infection-Associated Urethritis

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

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