Development of an in vitro organ culture model to study transmission of HIV-1 in the female genital tract

Collins, Kathryn S.; Patterson, Bruce K.; Naus, Gregory J.; Landers, Daniel V.; Gupta, Phalguni

doi:10.1038/74743

Cited by 169 publications

(168 citation statements)

References 18 publications

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“…Such prototypic non-primary R5 and X4 strains have been widely used to test the susceptibility to HIV infection of a range of tissues including the cervix, prostate gland, foreskin, and penis. 26,[31][32][33][34][35] With use of these two strains, we demonstrated that the human seminal vesicles are selectively infected by macrophage-tropic HIV-1 R5 ex vivo and release infectious virions. The R5 SF162 strain consistently replicated in the seminal vesicle tissues, as assessed by increased reverse transcriptase activity in seminal vesicle supernatants during culture, increased level of viral DNA in the explants, PBMC infection by the viral particles recovered from the infected seminal vesicle supernatants, and in situ detection of infected cells in the explants using immunohistochemistry for HIV p24.…”

Section: Discussionmentioning

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

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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.

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Section: Discussionmentioning

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

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“…Collins and colleagues (42) reported that in an in vitro organ culture system transmission of cell-associated virus occurred over a much longer time period than that observed for the cell-free virus. Cell-associated transmission, therefore, may occur under conditions that are suboptimal for cell-free virus survival and transmission.…”

Section: Discussionmentioning

confidence: 99%

Lactobacilli-Expressed Single-Chain Variable Fragment (scFv) Specific for Intercellular Adhesion Molecule 1 (ICAM-1) Blocks Cell-Associated HIV-1 Transmission across a Cervical Epithelial Monolayer

Chancey

Khanna

Seegers

et al. 2006

The Journal of Immunology

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The vaginal and cervical epithelia provide an initial barrier to sexually acquired HIV-1 infection in women. To study the interactions between HIV-1-infected cells or cell-free HIV-1 and the reproductive epithelium, the transmission of HIV-1 by infected cells or cell-free virus across human cervical epithelial cells was examined using a Transwell culture system. Cell-associated HIV-1 was transmitted more efficiently than cell-free virus, and monocyte-associated virus was transmitted most efficiently. Abs to ICAM-1 added to the apical side of the epithelium blocked cell-mediated transepithelial HIV-1 transmission in vitro. When used in a previously described model of vaginal HIV-1 transmission in human PBL-SCID mice, anti-murine ICAM-1 Abs (0.4 μg/10 μl) also blocked vaginal transmission of cell-associated HIV-1 in vivo. To evaluate a candidate delivery system for the use of this Ab as an anti-HIV-1 microbicide, anti-ICAM single-chain variable fragment Abs secreted by transformed lactobacilli were evaluated for their protective efficacy in the Transwell model. Like the intact Ab and Fab derived from it, the single-chain variable fragment at a concentration of 6.7 μg/100 μl was able to reduce HIV-1 transmission by 70 ± 5%. These data support the potential efficacy of an anti-ICAM Ab delivered by lactobacilli for use as an anti-HIV-1 microbicide.

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“…Although presently available in vivo models, including the tissue explant systems (1,9,15) and the human tissue xenograft model (16), can be used to factor the impact of the stratified vaginal epithelial structure into studies of microbicide cytotoxicity, these assays may be limited in scale by tissue sample size and availability. In vitro methodologies using readily available cell lines are better suited to reproducibly screen large numbers of agents for cytotoxicity as well as for effectiveness against HIV-1-infected cells of immune origin.…”

mentioning

confidence: 99%

Comparative In Vitro Sensitivities of Human Immune Cell Lines, Vaginal and Cervical Epithelial Cell Lines, and Primary Cells to Candidate Microbicides Nonoxynol 9, C31G, and Sodium Dodecyl Sulfate

Krebs

Miller

Catalone

et al. 2002

Antimicrob Agents Chemother

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In experiments to assess the in vitro impact of the candidate microbicides nonoxynol 9 (N-9), C31G, and sodium dodecyl sulfate (SDS) on human immune and epithelial cell viability, cell lines and primary cell populations of lymphocytic and monocytic origin were generally shown to be equally sensitive to exposures ranging from 10 min to 48 h. However, U-937 cells were more sensitive to N-9 and C31G after 48 h than were primary monocyte-derived macrophages. Cytokine activation of monocytes and lymphocytes had no effect on cell viability following exposure to these microbicidal compounds. Primary and passaged vaginal epithelial cultures and cell lines differed in sensitivity to N-9 and C31G but not SDS. These studies provide a foundation for in vitro experiments in which cell lines of human immune and epithelial origin can be used as suitable surrogates for primary cells to further investigate the effects of microbicides on cell metabolism, membrane composition, and integrity and the effects of cell type, proliferation, and differentiation on microbicide sensitivity.

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Development of an in vitro organ culture model to study transmission of HIV-1 in the female genital tract

Cited by 169 publications

References 18 publications

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

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

Lactobacilli-Expressed Single-Chain Variable Fragment (scFv) Specific for Intercellular Adhesion Molecule 1 (ICAM-1) Blocks Cell-Associated HIV-1 Transmission across a Cervical Epithelial Monolayer

Comparative In Vitro Sensitivities of Human Immune Cell Lines, Vaginal and Cervical Epithelial Cell Lines, and Primary Cells to Candidate Microbicides Nonoxynol 9, C31G, and Sodium Dodecyl Sulfate

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