Vitamin A deficient mice exhibit increased viral antigens and enhanced cytokine/chemokine production in nasal tissues following respiratory virus infection despite the presence of FoxP3+ T cells.

The World Health Organization (WHO) estimates that 250 million children under the age of five suffer from vitamin A deficiencies (VAD). Individuals with VAD experience higher rates of mortality and increased morbidity during enteric and respiratory infections compared with those who are vitamin A sufficient. Previously, our laboratory has demonstrated that VAD mice have significantly impaired virus-specific IgA and CD8(+) T-cell responses in the airways. Here, we demonstrate that VAD mice experience enhanced cytokine/chemokine gene expression and release in the respiratory tract 10 days following virus infection compared with control vitamin A sufficient animals. Cytokines/chemokines that are reproducibly up-regulated at the gene expression and protein levels include IFNγ and IL-6. Despite previous indications that cytokine dysregulation in VAD animals might reflect low forkhead box P3 (FoxP3)-positive regulatory T-cell frequencies, we found no reduction in FoxP3(+) T cells in VAD respiratory tissues. As an alternative explanation for the high cytokine levels, we found that the extent of virus infection and the persistence of viral antigens were increased on day 10 post-infection in VAD animals compared with controls, and consequently that respiratory tract tissues had an increased potential to activate virus-specific T cells. Results encourage cautious management of viral infections in patients with VAD, as efforts to enhance FoxP3(+) T cell frequencies and quell immune effectors could potentially exacerbate disease if the virus has not been cleared.

A vitamin A deficient diet enhances proinflammatory cytokine, Mu opioid receptor, and HIV-1 expression in the HIV-1 transgenic rat.

The HIV-1 (HIV) transgenic (Tg) rat develops several immune abnormalities in association with clinical impairments that are similar to what are seen with HIV infection in humans. In HIV infection, retinoids and opioids can have separate and potentially combined effects on the clinical course of HIV disease. In these studies, the effects of a vitamin A deficient diet on T cell proinflammatory cytokine and mu opioid receptor (MOR) expression were examined in the Tg and in wild-type (WT) rats. The effects of the diet on HIV gene expression were also analyzed in the Tg rats. Phytohemagglutinin-stimulated T cells from WT rats on the vitamin A diet and from Tg rats on either diet were more likely to either produce increased percentages of T cells expressing intracytoplasmic IFN-gamma, secrete higher levels of TNF-alpha, and express higher levels of MOR mRNA and surface MOR. Mitogen stimulation also increased Tg rat HIV env, tat, and nef mRNA expression with even higher env and nef mRNA produced in association with the vitamin A deficient diet. All together, these data suggest that a vitamin A deficient diet can result in cellular effects that increase T cell proinflammatory responses and HIV expression, which may alter the course of disease in the HIV Tg rat model.

Selected vitamins in HIV infection: a review.

In this article we review published studies on the role of serum micronutrient levels in the natural history of HIV infection. Specifically, we have focused on vitamins B12, E, A, and beta-carotene. Deficiencies of one or several of these vitamins have been associated with an accelerated progression of HIV infection to AIDS. Most investigators have used serum micronutrient levels as an indicator of vitamin nutriture. However, serum levels are not always the most sensitive or specific indicators of vitamin status. Nonetheless, serum vitamin levels are relatively easy to obtain and have been studied in various HIV-infected populations in individuals at different stages of disease. Low serum B12 levels have been associated with increased neurologic abnormalities, more rapid HIV disease progression, and increased AZT-related bone marrow toxicity. Low serum vitamin E levels have been associated with an increase in oxidative stress in HIV-infected individuals. However, early studies of vitamin E supplementation suggest that vitamin E may have important immunostimulatory properties. Studies of vitamin A deficiency in HIV-infected populations have shown that low serum vitamin A levels are associated with increased mortality, more rapid disease progression, and increased maternal-fetal transmission. However, there is little evidence that vitamin A supplementation, beyond the correction of deficiency, is beneficial in HIV infection. Finally, several clinical trials of beta-carotene supplementation have failed to show significant or sustained improvements in the immune response of patients with HIV infection or AIDS.

Influence of vitamin A status on the antiviral immunity of children with hand, foot and mouth disease.

BACKGROUND & AIMS: Vitamin A (VA) deficiency has been shown to affect antiviral immunity and thus may be related to the progress and outcome of hand, foot and mouth disease (HFMD) in young children. Our objective was to determine whether children with HFMD associated with VA insufficiency displayed a decline in antiviral immunity. METHODS: 450 children with HFMD and 113 non-infected children were included in this study. Dietary investigations were performed using a 24-h dietary questionnaire. The serum concentrations of VA were measured by high-performance liquid chromatography. The serum levels of interferon-α (IFN-α) and enterovirus 71 (EV71) IgM antibodies were detected using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean serum VA concentration for all patients was 0.73 ± 0.26 µmol/L, and 237 (52.7%) of them presented low concentrations (≤ 0.7 µmol/L). Both serum concentrations of VA and IFN-α in the patients with complications were significantly lower than in patients without complications (P < 0.01). The decreased concentrations of IFN-α and EV71-IgM were positively related to lower VA levels (correlation coefficient = 0.58 and 0.41, respectively, P < 0.001). CONCLUSIONS: Most of the children with HFMD presented VA insufficiency, which was associated with their reduced immunity and more severe illness.

Human immunodeficiency virus type 1-infected cells in breast milk: association with immunosuppression and vitamin A deficiency.

Breast milk samples from human immunodeficiency virus type 1 (HIV-1)-seropositive women were analyzed by polymerase chain reaction to determine the prevalence and determinants of HIV-1-infected cells in breast milk. Breast milk samples (212) were collected from 107 women, and 58% of the samples had detectable HIV-1 DNA. The proportion of HIV-1-infected cells in the milk samples ranged from 1 to 3255/10(4) cells. Breast milk samples with detectable HIV-1 DNA were more likely to be from women with absolute CD4 cell counts of < 400 (odds ratio, 3.1; 95% confidence interval [CI], 1.5-7.0). Severe vitamin A deficiency (< 20 micrograms/dL) was associated with a 20-fold increased risk of having HIV-1 DNA in breast milk among women with < 400 CD4 cells/mm3 (95% CI, 2.1-188.5). Women with CD4 cell depletion, especially those with vitamin A deficiency, may be at increased risk of transmitting HIV-1 to their infants through breast milk.

Vitamin A and retinoids in antiviral responses.

Vitamin A deficiency results in multiple derangements that impair the response to infection. This review focuses on experimental models of specific virus infections and on cytokines and cells with cytolytic activity important to antiviral defenses. Altered specific antibody responses and greater epithelial damage in vitamin A-deficient hosts are consistent findings. The cytolytic activity of natural killer cells and various cytokine responses are altered. The inflammatory response to infection may also result in derangements in the transport and metabolism of retinol. We speculate that interaction of several factors may combine to explain the greater severity of infection seen in vitamin A-deficient animals and children. In addition to a preexisting lack of tissue vitamin A, these factors may include reduced mobilization and increased excretion of retinol during the acute phase response to infection, poor innate and specific immune response to virus, and delayed repair of damaged epithelia. Foci of vitamin A-deficient epithelia may be sites of penetration of bacteria and other agents, leading to secondary infections and contributing to an increased severity of infections and poor outcome in vitamin A-deficient animals and humans.

Selenium deficiency is associated with shedding of HIV-1--infected cells in the female genital tract.

OBJECTIVE: To assess the relation between selenium deficiency and vaginal or cervical shedding of HIV-1-infected cells. DESIGN: Cross-sectional study of 318 HIV-1 seropositive women in Mombasa, Kenya. METHODS: Vaginal and cervical swab specimens were tested for the presence of HIV-1 DNA by polymerase chain reaction. Multivariate logistic regression models, adjusting for CD4 count and vitamin A deficiency, were used. RESULTS: Selenium deficiency (defined as levels <85 microg/L) was observed in 11% of the study population. In unstratified multivariate analyses, there was no significant association between selenium deficiency and vaginal or cervical shedding. In stratified analyses, however, significant associations became apparent after excluding women with predictors of shedding with strong local effects on the genital tract mucosa. Among women who did not use oral contraceptives and who did not have vaginal candidiasis, selenium deficiency was significantly associated with vaginal shedding (adjusted odds ratio [AOR] 2.9, 95% confidence interval [CI] 1.0--8.8, p =.05). Effect modification was also observed in the relation between selenium deficiency and cervical shedding, with a significant association seen among those women who were not using oral contraceptive pills or depot medroxyprogesterone acetate and who did not have Neisseria gonorrhoeae infection (AOR 2.8, 95% CI 1.1--7.0, p =.02). CONCLUSIONS: We found selenium deficiency to be associated with a nearly threefold higher likelihood of genital mucosal shedding of HIV-1--infected cells, suggesting that deficiency may increase the infectiousness of women with HIV-1. Nutritional interventions to prevent HIV-1 transmission warrant investigation.

Low carotenoid concentration and the risk of HIV seroconversion in Pune, India.

Low vitamin A and carotenoid levels could increase the risk of sexual HIV acquisition by altering the integrity of the genital epithelium or by immunologic dysfunction. We addressed this issue by measuring serum vitamin A and carotenoid levels in patients who were at risk of subsequent HIV infection. In a nested case-control study in individuals attending two sexually transmitted disease (STD) clinics in Pune, India, serum micronutrient levels were measured in 44 cases with documented HIV seroconversion (11 women and 33 men) and in STD patients matched for gender and length of follow-up with no subsequent HIV seroconversion (controls). STD patients in Pune had low vitamin A and carotenoid levels, and low serum beta-carotene levels were independently associated with an increased risk of subsequent HIV seroconversion. STD patients with beta-carotene levels less than 0.075 micromol/L were 21 times more likely to acquire HIV infection than those with higher levels (adjusted odds ratio = 21.1; p =.01). No such association was observed in case of other non-provitamin A carotenoids. This study reports the first evidence of an association between low serum provitamin A carotenoid levels and an increased risk for heterosexual HIV acquisition in STD patients in Pune, India.

Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina.

BACKGROUND: Factors that influence shedding of HIV-1 infected cells in cervical and vaginal secretions may be important determinants of sexual and vertical transmission of the virus. We investigated whether hormonal contraceptive use, vitamin A deficiency, and other variables were risk factors for cervical and vaginal shedding of HIV-infected cells. METHODS: Between December, 1994, and April, 1996, women who attended a municipal sexually transmitted diseases (STDs) clinic in Mombasa, Kenya, and had previously tested positive for HIV-1, were invited to take part in our cross-sectional study. Cervical and vaginal secretions from 318 women were evaluated for the presence of HIV-1 infected cells by PCR amplification of gag DNA sequences. FINDINGS: HIV-1 infected cells were detected in 51% of endocervical and 14% of vaginal-swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion (p = 0.00001 and p = 0.003, respectively). After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depot medroxyprogesterone acetate (odds ratio 2.9, 95% CI 1.5-5.7), and with use of low-dose and high-dose oral contraceptive pills (3.8, 1.4-9.9 and 12.3, 1.5-101, respectively). Vitamin A deficiency was highly predictive of vaginal HIV-1 DNA shedding. After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low normal vitamin A status were associated with 12.9, 8.0, and 4.9-fold increased odds of vaginal shedding, respectively. Gonococcal cervicitis (3.1, 1.1-9.8) and vaginal candidiasis (2.6, 1.2-5.4) were also correlated with significant increases in HIV-1 DNA detection, but Chlamydia trachomatis and Trichomonas vaginalis were not. INTERPRETATION: Our study documents several novel correlates of HIV-1 shedding in cervical and vaginal secretions, most notably hormonal contraceptive use and vitamin A deficiency. These factors may be important determinants of sexual or vertical transmission of HIV-1 and are of public health importance because they are easily modified by simple interventions.

PIP: Correlates of HIV-1 shedding in cervical and vaginal secretions were investigated in a cross-sectional study of 318 women previously diagnosed with HIV who presented to a sexually transmitted disease clinic in Mombasa, Kenya, during 1994-96. HIV-infected cells were detected in 51% of endocervical and 14% of vaginal swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion. After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depo medroxyprogesterone acetate (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.5-5.7) and of low- and high-dose oral contraceptives (OR, 3.8; 95% CI, 1.4-9.9 and OR, 12.3; 95% CI, 1.5-101, respectively). After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low-normal vitamin A status were associated with 12.9, 8.0, and 4.9-fold increased odds of vaginal shedding, respectively. Finally, gonococcal cervicitis (OR, 3.1; 95% CI, 1.1-9.8) and vaginal candidiasis (OR, 2.6; 95% CI, 1.2-5.4), but not Chlamydia trachomatis and Trichomonas vaginalis, were correlated with significant increases in HIV-1 DNA detection. These risk factors, easily modifiable by simple interventions, may be important determinants of sexual or vertical HIV transmission.