Plasma and salivary IgG subclasses in HIV type 1 infection: evidence of both transudation and local synthesis of IgG in parotid saliva

In this study we measured the levels of plasma and salivary IgG subclasses in 81 HIV-1-infected individuals and 30 uninfected controls. Salivary IgG1 was increased in HIV-1-infected patients, while salivary IgG2 and IgG4 were decreased. Patients with high levels of plasma anti-HIV-1 IgG antibodies presented a higher CD4+ cell count and lower viral load. High levels of anti-HIV-1 IgG antibodies in plasma were also associated with high levels of anti-HIV-1 IgG antibodies in parotid saliva. In comparing the HIV-1 recognition patterns of salivary IgG with plasma IgG, we determined that plasma and salivary IgG antibodies had similarities as well as differences in their reactivity to HIV-1 antigens. The present study demonstrates that HIV-1 infection affects both plasma and salivary IgG and provides evidence that the origin of HIV-1-specific IgG antibodies in parotid saliva is primarily transudated from plasma; however, some local synthesis of IgG in parotid saliva also occurs.     

Sialochemistry in human immunodeficiency virus associated salivary gland disease.

Human immunodeficiency virus (HIV) associated salivary gland disease is defined as the presence of enlargement of one or more major salivary glands and/or diminished salivary function in an HIV infected individual. It has a number of similarities to, as well as differences from, Sj?gren's syndrome (SS). We studied the sialochemistry of stimulated parotid saliva of 11 patients with HIV associated salivary gland disease and bilateral parotid gland enlargement, and compared these findings with those of 15 HIV negative controls, 13 HIV positive individuals with no salivary gland involvement and 18 individuals with SS. The patients with HIV associated salivary gland disease had a significant decrease in the level of salivary protein, with increases in salivary IgA, lysozyme and albumin compared to the HIV negative controls. There were no changes in concentration of electrolytes. The sialochemistry among the patients with HIV associated salivary gland disease was unrelated to the degree of immune suppression and did not change over a 6 month period. The observed changes were similar to those of SS but less pronounced. The similar clinical, histologic and sialochemical features of HIV associated salivary gland disease and SS suggest that these conditions share common pathogenetic mechanisms, which may be modified in the former by the HIV infection.     

Role of salivary tumour necrosis factor alpha in HIV-positive patients with oral manifestations

In HIV-1-infected patients, oral manifestations such as recurrent apthous ulcers are often seen. A total of 29 HIV-infected patients were examined to determine salivary tumour necrosis factor alpha (TNFalpha) concentrations by enzyme-linked immunosorbent assay, the amount of HIV-1 RNA copy by Amplicor HIV-1 Monitor test, number of CD4 cells by flow cytometry and oral manifestations by oral examination. TNFalpha concentration was significantly correlated with the amount of HIV-1 RNA, however, not with the number of CD4 cells in HIV-1-infected patients. Further, patients with oral manifestations showed significantly higher concentrations of TNFalpha in saliva and HIV-1 RNA copies in serum than those without oral manifestations. Following recovery from oral ulcers, TNFalpha concentration was decreased by half to 20 times lower than the level of that during ulcer incidence. Our results suggest that salivary TNFalpha is a good indicator for oral manifestations and HIV RNA amounts in HIV-1-infected patients.     

HIV in body fluids during primary HIV infection: implications for pathogenesis, treatment and public health

OBJECTIVE: To describe initial viral dissemination to peripheral tissues and infectious body fluids during human primary HIV infection. DESIGN: Observational cohort study. METHODS: Blood plasma, cerebrospinal fluid (CSF), seminal plasma, cervicovaginal lavage fluid and/or saliva were sampled from 17 individuals with primary HIV infection (range of time from symptoms onset to sampling, 8--70 days) and one individual with early infection (168 days). Subjects' HIV-1 RNA levels in each fluid were compared with levels from antiretroviral-naive controls with established HIV infection. For study subjects, correlations were assessed between HIV-1 RNA levels and time from symptoms onset. Responses to antiretroviral therapy with didanosine + stavudine + nevirapine +/- hydroxyurea were assessed in each compartment. RESULTS: HIV-1 RNA levels were highest closest to symptoms onset in blood plasma (18 patients) and saliva (11 patients). CSF HIV-1 RNA levels (five patients) appeared lower closer to symptoms onset, although they were higher overall in primary versus established infection. Shedding into seminal plasma (eight patients) and cervicovaginal fluid (two patients) was established at levels observed in chronic infection within 3--5 weeks of symptoms onset. High-level seminal plasma shedding was associated with coinfection with other sexually transmitted pathogens. Virus replication was suppressed in all compartments by antiretroviral therapy. CONCLUSIONS: Peak level HIV replication is established in blood, oropharyngeal tissues and genital tract, but potentially not in CSF, by the time patients are commonly diagnosed with primary HIV infection. Antiretroviral therapy is unlikely to limit initial virus spread to most tissue compartments, but may control genital tract shedding and central nervous system expansion in primary infection.     

In vitro inhibition of HIV-1 infectivity by human salivas

Inhibitory factors to human immunodeficiency virus type 1 (HIV-1) in saliva may be responsible for the infrequent isolation of virus from saliva and also may account for the marked infrequency of salivary and/or oral transmission of HIV-1. Incubation of HIV-1 with human saliva followed by addition of the mixture to susceptible cells leads to partial or complete suppression of viral replication in vitro. We investigated the inhibitory effects of whole saliva and specific glandular salivas on HIV-1 infectivity as measured by viral-induced cytopathic effects in susceptible cells. Whole saliva contained marked inhibitory activity to HIV-1, strain HTLV-IIIB, and to virus infected cells. Submandibular saliva contained inhibitory activity, but of lesser quantity. Parotid saliva demonstrated no HIV-inhibitory activity. Whole saliva also appeared to contain filterable components that were inhibitory to lymphocyte growth. Passage through a .45 micron pore-size filter eliminated the viral inhibitory activity of submandibular saliva and some of the activity in whole saliva. All salivas except parotid incubated with HIV-1 followed by filtration were inhibitory suggesting that complexing of virus with high molecular weight, submandibular mucins may play a role in viral inhibition.     

Salivary secretion and connective tissue disease in man.

Parotid and submandibular gland secretions collected from patients with rheumatoid arthritis or systemic sclerosis have been analysed and the results compared with those obtained from a matched group of healthy individuals. Flow rates were measured and the saliva samples assayed for amylase, kallikrein, protein, and salivary IgA concentration. The results showed that only patients with rheumatoid arthritis had a reduced salivary flow, especially parotid flow, with a significantly increased concentration of salivary IgA in both parotid and submandibular saliva. Patients with systemic sclerosis did not show significantly altered salivary flow rates, but there was a marked depletion of salivary IgA content in both parotid and submandibular saliva. Neither disease states appeared to alter the kallikrein or amylase content of saliva. The possible clinical value of these findings is discussed.     

Differential distribution of an estrogen receptor in the submandibular and parotid salivary glands of female rats

The purpose of this study was to measure the availability of the estrogen receptor in submandibular and parotid salivary glands in female rats. The presence of a specific, competitive, and saturable estrogen binder in rat salivary gland tissue was determined by saturation analysis and steroid competition in cell-free homogenates of salivary gland tissue from adult ovariectomized females. Scatchard analysis of the data indicated an estrogen receptor content of 1971.1 +/- 651.4 femtomoles/gm of tissue in submandibular salivary gland. This was significantly (p less than 0.01) greater than the number of estrogen binding sites in the parotid gland (457.1 +/- 123.4 femtomoles/gm tissue). Thus, there is a differential distribution in estrogen receptor content between parotid and submandibular salivary glands. The presence of an estrogen receptor in salivary gland tissue may serve to promote gender differences in submandibular salivary gland EGF content, to mediate changes in saliva composition during the female reproductive cycle and to regulate EGF release for cyclic uterine growth.     

HIV type 1 and cytomegalovirus coinfection in the female genital tract

The relationship between human immunodeficiency virus (HIV) type 1 and human cytomegalovirus (CMV) was studied in blood, saliva, and cervicovaginal lavage (CVL) specimens from 33 HIV-1-infected women. An association between HIV-1 RNA and CMV DNA was found in the CVL specimens, which also were tested for cytokine levels. Women with detectable CMV DNA in CVL specimens were more likely to have higher interleukin (IL)-1 beta and IL-8 levels than were women with undetectable CMV DNA in CVL specimens. More than 1 strain of CMV was detected in specimens from 2 patients. These results suggest mechanisms by which CMV coinfection could affect HIV-1 disease progression.     

Hepatitis C virus infection of salivary gland epithelial cells: Lack of evidence

Background: Hepatitis C virus genome (HCV-RNA) has been detected in whole salivary gland tissue of chronically infected patients. However, contamination of the tissue by plasma or blood cells was not excluded by the previous reports.Aims: To assess whether HCV infects the salivary gland epithelial cells in patients with chronic HCV liver disease.Methods: Twenty unselected patients with chronic active hepatitis (11 cases) or active cirrhosis (nine cases) were examined. Serum and saliva samples were obtained from all patients, 12 of whom (seven, chronic active hepatitis; five, active cirrhosis) underwent salivary gland biopsy. PCR for HCV-RNA was performed on RNA extracted from serum, saliva and salivary gland epithelial cells collected by isokinetic gradient separation after trypsin digestion of whole salivary gland tissue. Saliva samples were also examined for the presence of secretory IgA anti-HCV by gel chromatography and ELISA testing.Results: HCV-RNA was detected in all sera with titers ranging from 5.42×10⁵ genome equivalents/ml to 123.2×10⁵ genome equivalents/ml. Thirteen patients were infected with genotype 1b, four patients had genotype 1a, two patients had genotype 2a and one patient was unclassifiable. Low titer HCV-RNA (<2×10⁵ genome equivalents/ml) was detected in saliva samples (15%) from highly viremic patients infected with 1b genotype. RNA extracted from salivary gland epithelial cells consistently tested negative for HCV-RNA. In addition, all saliva specimens tested negative for secretory-IgA (S-IgA) anti-HCV, even after a 10-fold concentration of the samples.Conclusions: There was no evidence that HCV infects the salivary gland epithelial cells in our viremic patients with HCV chronic liver disease. Low level HCV-RNA in saliva is most probably due to virus spillover from blood.     

Tropism-restricted neutralization by secretory IgA from parotid saliva of HIV type 1-infected individuals

In this study we examined secretory IgA, isolated from the parotid saliva of 10 HIV-1-infected subjects, for its ability to influence HIV-1 infection of peripheral blood mononuclear cells with two R5 and two X4 primary isolates. Salivary IgA from four subjects was found to inhibit both R5 viruses but not the X4 viruses. In another subject, salivary IgA inhibited both X4 viruses but not the R5 viruses. The specificity of these antibodies seemed to be directed against, but not restricted to, gp160 and gp120. Compared with subjects whose salivary IgA did not inhibit HIV-1 infection, subjects who displayed neutralizing activity were in relatively early stages of disease and had CD4(+) T cell counts greater than 200 cells/microl. Our data indicate the presence of tropism-specific (more frequently R5-specific) neutralizing antibodies in HIV-1-infected subjects. Because mucosal transmission of HIV-1 occurs exclusively in R5 viruses, and X4 viruses often emerge in established infection and account for viral persistence later in disease, our data suggest a potential role for secretory IgA in preventing viral transmission, but a less likely effect on chronic infection.     

Sicca syndrome in patients infected with human immunodeficiency virus-1

We investigated human immunodeficiency virus-1 (HIV-1)-associated sicca syndrome. The average saliva production in HIV-infected patients was 15.9 ± 6.3?ml, and the average tear production was 9.8 ± 4.5?mm. In particular, 6 patients (42.9%) showed a significant decrease in tear production. This sicca syndrome mimicked autoimmune Sjögren's syndrome (SS) because of the presence of dry eye, dry mouth, hyperamylasemia, and hypergammaglobulinemia; however, no antinuclear antibodies, anti-SS-A, or anti-SS-B were detected in sera from HIV-1-infected patients. In addition, no relationship was observed between saliva and tear production and CD4, HIV-RNA. Hepatitis C virus (HCV) and human T-lymphotrophic virus (HTLV-1) are considered to be possible causative agents of SS. However, coinfection with HCV did not affect the decrease of saliva and tear production, and only one patient was coinfected with HTLV-1. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are also potential causative agents of SS, and they are sometimes detected in the saliva of HIV-1-infected patients. However, the detection of EBV and CMV in the saliva was not related to the decrease in saliva production. Furthermore, HIV therapy (highly active anti-retroviral therapy; HAART) did not affect the state of sicca syndrome.The pathogenesis of sicca syndrome in HIV-1-infected patients is not clear, but we did find some infiltration of CD8 lymphocytes in salivary gland biopsy. Usually, CD8 lymphocytosis is found in peripheral blood in HIV-infected patients. Diffuse infiltrative lymphocytosis syndrome by predominant CD8 lymphocytes is occasionally found in HIV-infected patients. Such CD8 infiltration may induce the destruction of both the salivary and lacrimal glands.     

Major salivary gland function in primary Sj?gren's syndrome and its relationship to clinical features

Unstimulated and stimulated salivary secretions of both the parotid and submandibular/sublingual glands were studied in 64 patients with primary Sj?gren's syndrome to define further salivary changes in this disorder. The stimulated flows of the submandibular/sublingual glands were below normal in 56 of 64 patients, while stimulated parotid flows were decreased in only 35. Compositional changes of the submandibular saliva paralleled changes of parotid saliva, and these data suggest that ductal electrolyte resorption is altered in the glands of patients. Finally, stimulated parotid flow rates correlated inversely with focus scores of the minor salivary gland biopsies.     

Ethanol and Human Saliva: Effect of Chronic Alcoholism on Flow Rate, Composition, and Epidermal Growth Factor

Parotid saliva samples from 24 alcoholic subjects without evidence of cirrhosis were analyzed for changes in flow rate, composition, and epidermal growth factor (EGF) secretion. Mean (+/- SE) stimulated parotid saliva flow rate (ml/min/gland) was significantly (p less than 0.01) lower in alcoholic subjects than in matched control subjects. Reduction in parotid saliva flow rate was associated with significant (p less than 0.05) decrease in total protein and amylase secretion in this group of patients. In addition, secretion of immunoreactive EGF, a specific salivary protein, was also markedly reduced (p less than 0.05) in alcoholic patients. None of the parotid saliva samples from the alcoholic subjects had detectable bioactivity of EGF in saliva. These data suggest that chronic alcohol ingestion is associated with significant changes in parotid saliva secretion and its composition, which may perpetuate and compound ethanol-induced injury to the upper gastrointestinal tract.     

Limits on oral transmission of HIV-1

This article discusses the potential of acquiring an HIV-1 infection through an oral route, with a view of offering clues for its prevention. In a study of adult animals given low concentration cell-free simian immunodeficiency virus (SIV) orally, histological examination suggested that SIV infected lymphoid tissue through the antigen-transporting crypt epithelium rather than through dendritic cells. The investigators found no evidence of acquiring SIV via the gastrointestinal tract. For humans, HIV transmission from saliva or intimate family contact seems to be extremely rare. This could be because of the low concentration of HIV-1 in saliva. A study of 40 people found that significantly less HIV was found in salivary secretions than in plasma. Another possible explanation for inefficient oral transmission might be that HIV-1 in the oropharynx is inhibited by components found in salivary secretions. Conversely, studies have noted that risk of oral transmission of HIV from contaminated breast milk and semen is higher than from saliva. Breast-feeding by an HIV-infected woman puts the baby at substantial risk of infection and receptive fellatio cannot be considered a safe sex act.     

The Effect of Chronic Ethanol Consumption on Salivary Gland Morphology and Function in the Rat

Chronic ethanol consumption in rats resulted in a striking fat accumulation in the acinar cells of the parotid gland demonstrated by light microscopy. In addition, a significant decrease in parotid wet weight (p greater than 0.02) and in protein content of the gland (p greater than 0.02) was observed following alcohol feeding. Wet weight, protein content, and morphology of the submaxillar gland were not affected by ethanol feeding. Alcohol metabolism, similar to that found in the pancreas, via a cytosolic alcohol dehydrogenase could be demonstrated in both the parotid and the submaxillar gland. However, the activity of this enzyme was not affected by chronic ethanol ingestion. Subsequently, chronic ethanol consumption significantly decreased salivary flow rate stimulated by pilocarpine hydrochloride (p greater than 0.02), salivary alpha-amylase activity (p greater than 0.02), and salivary sodium concentration (p greater than 0.01), whereas potassium concentration of the saliva was increased (p greater than 0.05). In contrast salivary total protein concentration was not affected by alcohol ingestion. The changes of salivary electrolyte composition observed after chronic ethanol feeding could be due to an altered aldosterone metabolism or to a change in aldosterone receptors of the parotid gland caused by ethanol administration. The reduced salivary flow could play a role in the pathogenesis of oropharyngeal cancer in the alcoholic.     

Diminished submandibular salivary flow in dementia of the Alzheimer type

Dementia of the Alzheimer Type (DAT) is the most common type of dementia among the elderly. Alzheimer's disease is a major public health problem, yet little is known about the potential oral consequences of the disease. Because saliva is believed to be essential for the preservation of oral health and function, salivary gland fluid output was evaluated in a population of essentially healthy patients with early-stage DAT. Unstimulated and stimulated parotid and submandibular salivary gland secretions were collected from 28 nonmedicated and otherwise healthy DAT patients, and 35 age-matched healthy controls. Submandibular saliva flow rates were significantly lower among the patients with DAT compared to controls, while parotid flow rates did not differ. The results suggest a selective impairment in submandibular gland function in essentially healthy patients with early-stage DAT.     

The benign cystic lymphoepithelial lesion of the parotid gland is a viral reservoir in HIV type 1-infected patients.

The presence of HIV-1 in cystic fluid aspirates from six cases of benign cystic lymphoepithelial lesion (BLL) of the parotid gland, a rare disorder affecting HIV-1-infected patients, has been investigated. HIV-1 p24 protein was present at a concentration ranging from 3 to 15 ng/ml, while it was undetectable in the peripheral blood of the same patients. The number of RNA copies of HIV-1 in the cystic fluids was high, ranging from 0.5 x 10(7) to 7.2 x 10(7) RNA copies/ml. BLL cystic fluid aspirates, despite the high level of HIV-1 RNA, were found to contain only a few infectious virions. The low infectivity correlated with the infrequent detection by electron microscopy of complete HIV-1 particles. The pathogenic mechanism leading to virus accumulation in the cystic fluid was studied by immunohistochemistry of tissue sections. p24 protein was associated with DRC-1+/S-100+ follicular dendritic reticulum cells, which were also present within the cystic cavities. Our findings are consistent with the possibility that the large amounts of virus present in the fluid derive from continuous shedding of HIV-1-infected cells from the surrounding lymphoid tissue.     

Radioimmunoassay of human salivary amylase: cross-reactivity with human and porcine pancreatic amylase and other salivary proteins

A radioimmunoassay (RIA) of human salivary amylase was developed. Human salivary and pancreatic amylases were purified by Sephacryl S-200 gel filtration and by cation-exchange chromatography. Human salivary amylase antibody, raised in New Zealand white rabbits, did not crossreact with other salivary proteins and there was also no crossreactivity with purified porcine pancreatic amylase. The antibody crossreacted with human pancreatic amylase to the extent of 25%. Amylase concentrations, estimated by RIA, in human saliva, serum, and urine were compared with enzymatic activity. Correlation of results obtained by the two techniques was best for estimation of amylase in saliva, least for serum and intermediate for urine. Amylase concentrations and enzymatic activity in stimulated parotid saliva were not correlated with flow rate of secretion. There was no correlation between amylase concentrations (and enzymatic activity) in parotid saliva and those found either in serum and urine. Amylase comprises approximately 5% of the total parotid salivary protein in humans.     

Salivary secretory leukocyte protease inhibitor is associated with reduced transmission of human immunodeficiency virus type 1 through breast milk

Secretory leukocyte protease inhibitor (SLPI), a protein found in saliva, breast milk, and genital secretions, is capable of inhibiting human immunodeficiency virus (HIV) type 1 in vitro. The aim of this study was to determine whether SLPI in infant saliva provides protection against mother-to-child HIV-1 transmission. In total, 602 saliva specimens were collected from 188 infants at birth and at ages 1, 3, and 6 months. Infants' median salivary SLPI concentrations were higher at birth than at 6 months (341 vs. 219 ng/mL; P=.001). There was no association between SLPI concentration and HIV-1 transmission overall. However, among 122 breast-fed infants who were HIV-1 uninfected at 1 month, higher salivary SLPI levels were associated with a decreased risk of HIV-1 transmission through breast milk (hazard ratio, 0.5; 95% confidence interval, 0.3-0.9; P=.03). These results suggest that SLPI plays an important role in reducing HIV-1 transmission through breast milk.     

A diffuse infiltrative CD8 lymphocytosis syndrome in human immunodeficiency virus (HIV) infection: a host immune response associated with HLA-DR5

STUDY OBJECTIVE: To describe the clinical, immunologic, and immunogenetic features of a diffuse infiltrative lymphocytic disorder resembling Sj?gren syndrome in persons infected with human immunodeficiency virus (HIV). DESIGN: Clinical case study. SETTING: University-affiliated hospitals and outpatient clinics. PATIENTS: Consecutive sample of 17 patients. MEASUREMENTS AND MAIN RESULTS: All of the 17 patients had bilateral parotid gland enlargement; 14 had xerostomia and 6 had xerophthalmia. Of the 17 patients, 14 had generalized lymphadenopathy, 10 had histologically proved lymphocytic interstitial pneumonitis, 4 had neurologic involvement, and 3 had lymphocytic infiltration of the gastrointestinal tract. Gallium scanning in all of 11 tested patients showed abnormal salivary gland uptake. Minor salivary gland biopsies showed more than 2 lymphocytic foci per 4 mm2 tissue in all of 11 tested patients, the infiltrate consisting predominantly of CD8 cells. Fifteen patients had circulating CD8 lymphocytosis; the principal phenotype of these cells was CD8+ CD29+. Rheumatoid factor and antinuclear antibodies were infrequent, and none of the patients had anti-Ro/SS-A or anti-La/SS-B antibodies. HLA-DR5 was significantly more frequent in the black patients (10 of 12) compared with controls (13 of 45). Only one patient developed an opportunistic infection during 544 patient-months of study, and none has died of AIDS. CONCLUSIONS: A distinct syndrome primarily characterized by parotid gland enlargement, sicca symptoms, and pulmonary involvement occurs in HIV infection. This disorder is associated with CD8 lymphocytosis and the presence of HLA-DR5, and appears to be a genetically determined host immune response to HIV.