In vitro suppression of latent HIV-1 activation by vitamin E: potential clinical implications
Heredia, Alonso; Davis, Charles; Amoroso, Anthony; Taylor, Greg; Le, Nhut; Bamba, Douty; Redfield, Robert R
Division of Clinical Research, Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, MD, USA.
Received 10 December, 2004
Accepted 18 February, 2005
We evaluated the effect of vitamin E in controlling HIV-1 production upon activation of the patients’ reservoir of resting CD4 lymphocytes in tissue culture experiments. The addition of vitamin E to patients’ cultures resulted in significantly reduced levels of p24 virus production (P = 0.0015). These results suggest that vitamin E supplementation may interfere with the emergence of drug-resistant HIV-1 variants archived in the resting cell reservoir and delay or limit virus rebound upon treatment interruptions.
Micronutrient supplements have been suggested as low-cost immunomodulating interventions that may slow disease progression in HIV-1 infection [1,2]. Two studies in north American HIV-1-infected individuals have shown that higher intakes of vitamins are associated with slower disease progression [3,4]. More recently, a study conducted on HIV-infected pregnant women in Tanzania  found that vitamin supplementation is associated with a reduced likelihood of progression to advanced stages of disease, better preservation of CD4 cell counts, lower viral loads, and reduced morbidity and mortality rates. The possible mechanisms underlying the beneficial effects of vitamins in HIV-1 disease might be related to their ability to modulate cellular activation and enhance immunity, as well as to their antioxidant properties . Such studies suggested that the use of multivitamins may delay the need to initiate antiretroviral therapy.
On the basis of reported data, we postulated that vitamin supplementation may also delay virus rebound after treatment interruption. Patients interrupt antiretroviral therapy for many reasons, including among others medication side-effects, interrupted drug supply, acute illness and hospitalization. After treatment withdrawal a rapid increase in plasma viral loads occurs, which becomes detectable within 7–14 days . Treatment interruptions pose the risk of virus rebound, which can lead to the emergence of drug-resistant variants and to an increased risk of virus transmission . Latently infected, resting CD4 T cells serve as one possible source of rebounding virus upon treatment discontinuation . HIV-1 gene expression on latently infected resting T cells is dependent on host transcriptional factors, such as nuclear factor kappa B, which are induced upon cellular activation . The antioxidant activity of vitamin E has been demonstrated to inhibit nuclear factor kappa B activation and HIV-1 gene transcription . In the present in-vitro study we evaluated the effect of adding vitamin E to cultures of patients’ resting CD4 T cells under conditions of cellular activation that promote virus expression.
Blood (50 ml) was drawn from 10 patients on antiretroviral therapy, whose viral loads were less than 400 copies/ml and whose CD4 cell counts were greater than 300 cells/μl. Resting CD4 T cells were purified by negative selection using beads and monoclonal antibodies against B cells, natural killer cells, monocytes, granulocytes, CD8 lymphocytes and activated CD4 lymphocytes (Dynal, Lake Success, NY, USA). Purified cells were activated by co-culture with γ-irradiated peripheral blood mononuclear cells from normal donors in the presence of 1 μg/ml anti-CD3 antibody (Coulter, Miami, FL, USA) and 100 units/ml rhIL-2 (Roche, Indianapolis, IN, USA). Cultures were set up in the absence or continuous presence of 5 μg/ml of vitamin E (vitamin E succinate; Sigma, St Louis, MO, USA), with medium replenishment every 3 or 4 days. Cultures were maintained for 14 days. Virus production was monitored by measuring p24 antigen (NEN, Boston, MA, USA) in the culture supernatants on days 7 and 14. Cell viability was measured by trypan blue staining.
On day 14, virus isolation was positive in nine out of 10 untreated cultures and in seven out of 10 vitamin E-containing cultures. Virus isolation was unsuccessful in one patient under either condition. Figure 1 shows paired (untreated and vitamin E treated) virus culture results obtained in the nine patients in which HIV-1 replication was detected. Virus production was higher in the absence (mean log p24 3.58) than in the presence of vitamin E (mean log p24 2.06), and this difference was statistically significant (two-tailed, paired t test, P = 0.0015). A similar pattern of antiviral results was obtained on day 7. Neither cell viability nor cell proliferation was affected by the concentration of vitamin E used on days 7 or 14 (data not shown).
The in-vitro results demonstrate that vitamin E suppresses the production of HIV-1 by patients’ resting CD4 T cells upon cellular activation. These data suggest that vitamin E supplementation in HIV-infected individuals undergoing antiretroviral treatment interruption may help minimize virus rebound, and therefore reduce the risk of the emergence of HIV-1 resistance.
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