Abstract
BackgroundBoth cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel®) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model.MethodsHuman lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs.ResultsProgressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected).ConclusionThese results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV.
Highlights
Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIVinfected individuals
We report the effect of Carbopol®, the buffering agent contained in BufferGel, on leukocyte motility and Peripheral blood mononuclear cell (PBMC) viability
Monocyte, macrophage, and lymphocyte chemokinesis were observed in RPMI containing FMLP and 0.125% Carbopol or 50 mM MES by videotaping cells migrating on glass slides
Summary
Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIVinfected individuals. Free virus transmits infection in monkey [8], chimpanzee [9], and cat [10] vaginal-challenge models, the amount of virus used [8] has generally been greater than the amount of infectious virus found in semen of HIVinfected men [4]. Studies of cell-vectored transmission include an unsuccessful attempt to establish a model of vaginal transmission with cryopreserved SIV-infected cells in the monkey [8], but, fresh HIV-infected cells transmitted infection in the chimpanzee when applied to the cervical os [9], fresh FIV-infected cells transmitted infection after vaginal deposition in the cat [10,11], and fresh HIVinfected human peripheral blood leukocytes transmitted infection to SCID mice after vaginal deposition [12,13]. The presence of both free HIV virions and HIV-infected cells in sexual secretions, and the demonstrated ability of both to transmit infection in diverse animal models, suggests that microbicide candidates should protect against cell-associated HIV as well as cell-free HIV
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