Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Dec 15;185(12):7596-604.
doi: 10.4049/jimmunol.1002846. Epub 2010 Nov 8.

Semen protects CD4+ target cells from HIV infection but promotes the preferential transmission of R5 tropic HIV

Emmanuel Balandya  1 , Siddharth Sheth, Katherine Sanders, Wendy Wieland-Alter, Timothy Lahey
Affiliations

Semen protects CD4+ target cells from HIV infection but promotes the preferential transmission of R5 tropic HIV

Emmanuel Balandya et al. J Immunol. .

Abstract

Sexual intercourse is the major means of HIV transmission, yet the impact of semen on HIV infection of CD4(+) T cells remains unclear. To resolve this conundrum, we measured CD4(+) target cell infection with X4 tropic HIV IIIB and HC4 and R5 tropic HIV BaL and SF162 after incubation with centrifuged seminal plasma (SP) from HIV-negative donors and assessed the impact of SP on critical determinants of target cell susceptibility to HIV infection. We found that SP potently protects CD4(+) T cells from infection with X4 and R5 tropic HIV in a dose- and time-dependent manner. SP caused a diminution in CD4(+) T cell surface expression of the HIVR CD4 and enhanced surface expression of the HIV coreceptor CCR5. Consequently, SP protected CD4(+) T cells from infection with R5 tropic HIV less potently than it protected CD4(+) T cells from infection with X4 tropic HIV. SP also reduced CD4(+) T cell activation and proliferation, and the magnitude of SP-mediated suppression of target cell CD4 expression, activation, and proliferation correlated closely with the magnitude of the protection of CD4(+) T cells from infection with HIV. Taken together, these data show that semen protects CD4(+) T cells from HIV infection by restricting critical determinants of CD4(+) target cell susceptibility to HIV infection. Further, semen contributes to the selective transmission of R5 tropic HIV to CD4(+) target cells.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
SP protects CD4+ target cells from infection by R5 tropic and X4 tropic HIV. CD4+ T cells incubated with SP were protected from infection by X4 tropic HIV IIIB (A, C, G) and HC4 (E, n = 20) and R5 tropic HIV BaL (B, D, H) and SF162 (F, n = 20) at an MOI of 0.1 as assessed by intracellular HIV p24 staining. We observed a dose-response relationship, with incubation with increasing concentrations of SP associated with increasing protection of CD4+ TZM-bl cells from infection with HIV IIIB and HIV BaL (G, H, n = 20). **p < 0.01; ***p < 0.001. RLU, relative light units.
FIGURE 2
FIGURE 2
SP modulates the expression of the HIVR CD4 and the HIV coreceptors CCR5 and CXCR4. Incubation with SP reduced CD4+ T cell expression of the HIVR CD4 in a time-dependent fashion compared with medium controls (A, n = 6). CD4+ T cell expression of the HIVR CD4 by confocal microscopy was reduced after 24-h incubation with SP compared with medium control (B). There was a rapid and robust increase in surface expression of CCR5 in CD4+ T cells incubated with 0.5% SP (C, n = 6), along with a late and limited repression of surface CXCR4 expression (D, n = 6). We found that simultaneous with the increase in surface expression of CCR5, SP reduces intracellular CCR5 staining (E, n = 10). By real-time PCR, there was a clear SP-mediated reduction in CD4+ T cell transcription of CD4, CXCR4, and CCR5 (F, n = 10). Fold change was calculated via the 2−ΔΔCT method using the difference in CD4, CXCR4, and CCR5 mRNA Ct values between the SP-treated and media controls after normalization of CD4, CXCR4, and CCR5 mRNA expression using CD71 housekeeping gene mRNA levels. SP protects CD4+ T cells from X4 tropic HIV IIIB infection more potently than it protects CD4+ T cells from R5 tropic HIV BaL (G, n = 20) and X4 tropic HIV HC4 more potently than R5 tropic HIV SF162 (H, n = 20). Error bars depict SD. *p < 0.05; **p < 0.01; ***p < 0.001.
FIGURE 3
FIGURE 3
SP reduces T cell activation and proliferation. CD4+ T cell incubation with SP reduced CD4+ T cell expression of the activation marker CD38 (A, n = 20) and PHA- and IL-2–stimulated CD4+ T cell proliferation as measured by CFSE dye dilution (B, n = 20). ***p < 0.001.
FIGURE 4
FIGURE 4
Magnitude of protection of CD4+ target cells from HIV infection by SP is influenced by SP concentration, incubation duration, and cell contact, but not by target cell apoptosis. Incubation with higher concentrations of SP conferred greater CD4+ TZM-bl cell protection from HIV IIIB infection at an MOI of 0.2 (A, n = 8). Incubation with SP for greater than 2 h was associated with greater protection of CD4+ TZM-bl cells from infection with HIV BaL (B, n = 8). SP inhibits both cell-associated and cell-free HIV IIIB infection of TZM-bl cells, but the magnitude of SP inhibition of cell-associated HIV infection of TZM-bl cells was smaller than the magnitude of SP inhibition of cell-free HIV infection of TZM-bl cells (C, n = 10). Incubation with 0.5% SP for 24 h did not induce CD4+ T cell apoptosis as measured by intracellular expression of activated caspase-3 (D, n = 20) or by MTT viability assay in TZM-bl cells (E, n = 10). Staurosporine 0.25 μM was used as a positive control for intracellular activated caspase-3 expression. Error bars depict SD. *p < 0.05; **p < 0.01; ***p < 0.001. RLU, relative light units.
FIGURE 5
FIGURE 5
SP-mediated protection from HIV infection correlates closely with SP-mediated reductions in CD4+ T cell expression of CD4 and CD38 as well as CD4+ T cell proliferation. The magnitude of the reduction in CD4+ T cell infection by HIV IIIB correlated positively with the magnitude of the SP-mediated reduction in CD4+ T cell MFI of the HIVR CD4 (A), the MFI of the activation marker CD38 (B), and with the reduction in CD4+ T cell proliferation (C) by CFSE staining. Likewise, the magnitude of the reduction in CD4+ T cell infection by HIV BaL correlated positively with the magnitude of the SP-mediated reduction in CD4+ T cell CD4 MFI (D), CD4+ T cell CD38 MFI (E), and CD4+ T cell proliferation (F). SP contains multiple cytokines and chemokines (G). n = 20 for A–G.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009;373:48–57. - PubMed
    1. Galvin SR, Cohen MS. The role of sexually transmitted diseases in HIV transmission. Nat. Rev. Microbiol. 2004;2:33–42. - PubMed
    1. Ball JK, Curran R, Irving WL, Dearden AA. HIV-1 in semen: determination of proviral and viral titres compared to blood, and quantification of semen leukocyte populations. J. Med. Virol. 1999;59:356–363. - PubMed
    1. Butler DM, Delport W, Kosakovsky Pond SL, Lakdawala MK, Cheng PM, Little SJ, Richman DD, Smith DM. The origins of sexually transmitted HIV among men who have sex with men. Sci. Transl. Med. 2010;2:18re1. - PMC - PubMed
    1. Marcelin AG, Tubiana R, Lambert-Niclot S, Lefebvre G, Dominguez S, Bonmarchand M, Vauthier-Brouzes D, Marguet F, Mousset-Simeon N, Peytavin G, Poirot C. Detection of HIV-1 RNA in seminal plasma samples from treated patients with undetectable HIV-1 RNA in blood plasma. AIDS. 2008;22:1677–1679. - PubMed

Publication types