Herpes simplex virus type-2 stimulates HIV-1 replication in cervical tissues: implications for HIV-1 transmission and efficacy of anti-HIV-1 microbicides.
Herpes Simplex virus Type-2 (HSV-2) increases the risk of HIV-1 acquisition, yet the mechanism for this viral pathogen to regulate the susceptibility of the cervicovaginal mucosa to HIV-1 is virtually unknown. Using ex vivo human ectocervical tissue models, we report greater levels of HIV-1 reverse transcription, DNA integration, RNA expression, and virions release in HIV-1/HSV-2 co-infected tissues compared with HIV-1 only infected tissues (P<0.05). Enhanced HIV-1 replication was associated with increased CD4, CCR5, and CD38 transcription (P<0.05) and increased number of CD4(+)/CCR5(+)/CD38(+) T cells in HIV-1/HSV-2 co-infected tissues compared with tissues infected with HIV-1 alone. Tenofovir (TFV) 1% gel, the leading microbicide candidate, demonstrated only partial protection against HIV-1, when applied vaginally before and after sexual intercourse. It is possible that mucosal inflammation, in particular that induced by HSV-2 infection, may have decreased TFV efficacy. HSV-2 upregulated the number of HIV-1-infected cells and elevated the concentration of TFV needed to decrease HIV-1 infection. Similarly, only high concentrations of TFV inhibited HSV-2 replication in HIV-1/HSV-2-infected tissues. Thus, HSV-2 co-infection and mucosal immune cell activation should be taken into consideration when designing preventative strategies for sexual transmission of HIV-1.
1] V.A. Medical Center, White River Junction, Vermont, USA [2] Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
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Rollenhagen
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
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Lathrop
V.A. Medical Center, White River Junction, Vermont, USA.
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Macura
CONRAD, Eastern Virginia Medical School, Norfolk, Virginia, USA.
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Doncel
1] V.A. Medical Center, White River Junction, Vermont, USA [2] Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
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Asin
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology; D002584:Cervix Uteri / Q000821:virology*; D005260:Female; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000635:transmission* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D018258:Herpesvirus 2, Human / Q000502:physiology*; D006801:Humans; D016133:Polymerase Chain Reaction; D000068698:Tenofovir / Q000494:pharmacology*; D014779:Virus Replication
D000998:Antiviral Agents; D000068698:Tenofovir; D051997:ADP-ribosyl Cyclase 1