Issues around childhood disclosure of HIV status - findings from a qualitative study in West Bengal, India.

INTRODUCTION: Informing the children living with HIV (CLH) about their disease (disclosure) is important from the perspective of disease treatment and overall psychosocial development. There are no published studies that qualitatively explored HIV disclosure-related issues among CLH in India. Our aim was to provide insights into the perceptions of informal caregivers of CLH regarding childhood disclosure. METHODS: Children were defined as those aged <16 years. In-depth interviews were conducted with 34 primary caregivers of CLH aged 8 to 15 years old who were residing in West Bengal, India. The participants were recruited with the help of a community-based organization that provides need-based services to people living with HIV. RESULTS: We obtained caregivers' perspectives on the motivators and barriers of childhood disclosure. Health benefits such as medication adherence emerged as an important motivator, while distress caused by disclosure and potential for stigma were identified as barriers. Health care providers were the preferred disclosers for most caregivers, followed by the caregivers themselves. Some caregivers wanted their child to learn about his/her HIV status by him/herself. There was no consensus among the caregivers about the ideal age for disclosure. Many preferred to wait until the child attained maturity or was of marriageable age. DISCUSSION: Disclosure of HIV status to children is an emotional issue, both for the caregiver and the child. Like most low-or middle-income countries, no standardized, age-appropriate disclosure guidelines exist in India. Our findings advocate adoption of a multi-faceted approach, including increased availability of social and familial support, for childhood HIV disclosure.

Timing of antiretroviral therapy initiation after diagnosis of recent human immunodeficiency virus infection and CD4(+) T-cell recovery.

We retrospectively examined the timing of antiretroviral therapy (ART) initiation and CD4(+) T-cell recovery over 36 months among recent human immunodeficiency virus (HIV) infections using BED (HIV-1 subtypes B, E and D) immunoglobulin G capture enzyme immunoassay (BED-CEIA). Regardless of baseline CD4(+) counts, individuals (n = 393) who initiated ART >2 months after diagnosis had significantly decreased probability and rate of achieving CD4(+) counts ≥900 cells/µL or ≥600 cells/µL than those individuals (n = 135) who started ART earlier (≤2 months). But the mean CD4(+) counts in two groups converged after 30 months of treatment. Early ART initiation leads to accelerated CD4(+) recovery, but does not offer a long-term advantage in CD4(+) counts.

Differences in hepatitis C virus prevalence and clearance by mode of acquisition among men who have sex with men.

We examined the characteristics associated with hepatitis C virus (HCV) antibody (anti-HCV) prevalence and HCV clearance between injection drug using (IDU) and non-IDU men who have sex with men (MSM). Stored serum and plasma samples were tested for anti-HCV and HCV RNA to determine the HCV status of 6925 MSM at enrolment into the Multicentre AIDS Cohort Study (MACS). Prevalence and clearance ratios were calculated to determine the characteristics associated with HCV prevalence and clearance. Multivariable analyses were performed using Poisson regression methods with robust variance estimation. Anti-HCV prevalence was significantly higher among IDU than among non-IDU MSM (42.9% vs 4.0%), while clearance was significantly lower among IDU MSM (11.5% vs 34.5% among non-IDU MSM). HIV infection, Black race, and older age were independently associated with higher prevalence in both groups, while smoking, transfusion history, and syphilis were significantly associated with prevalence only among non-IDU MSM. The rs12979860-C/C genotype was the only characteristic independently associated with HCV clearance in both groups, but the effects of both rs12979860-C/C genotype [clearance ratio (CR) = 4.16 IDUs vs 1.71 non-IDUs; P = 0.03] and HBsAg positivity (CR = 5.06 IDUs vs 1.62 non-IDUs; P = 0.03) were significantly larger among IDU MSM. HIV infection was independently associated with lower HCV clearance only among non-IDU MSM (CR = 0.59, 95% CI = 0.40-0.87). IDU MSM have higher anti-HCV prevalence and lower HCV clearance than non-IDU MSM. Differences in the factors associated with HCV clearance suggest that the mechanisms driving the response to HCV may differ according to the mode of acquisition.

Rapid operation assessment of voluntary HIV counselling and testing services in three cities in China, 2009.

OBJECTIVES: To assess the operation of voluntary counselling and testing (VCT) services forhuman immunodeficiency virus (HIV) in three cities in China. STUDY DESIGN: A cross-sectional study using mixed methods, including focus group discussions,in-depth interviews, field assessment, archive checking and structured questionnaire interviews, was conducted to assess different aspects of VCT services. METHODS: Surveys were undertaken in six counties of three China Global Fund AIDS Program (Round Five) cities, including 11 VCT clinics, 38 counsellors, 83 clients and 332 individuals at risk for HIV infection. RESULTS: All counsellors were trained and approved for providing counselling. As there were adequate numbers of clinics and counsellors, VCT services ran smoothly. Clients were generally satisfied with VCT services and considered service operation to be adequate. Problems with the VCT programme included fewer VCT services in general hospitals, lack of a referral mechanism, and long delays between testing and receipt of results. CONCLUSIONS: The operation of VCT services in the three cities was generally adequate, but referral services were poor. More attention needs to be paid to HIV testing and counselling in general hospitals, and referral networks need to be strengthened.

Impact of paediatric human immunodeficiency virus infection on children's and caregivers' daily functioning and well-being: a qualitative study.

BACKGROUND: Human immunodeficiency virus (HIV) infection impacts not only upon the physical health of affected children, but also their psychosocial functions, family relationships and economical status. Caregivers are confronted with complex challenges related to the physical, emotional and financial demands of raising these children. The purpose of this study was to enhance our understanding of the impact of HIV disease on both children's and caregivers' well-being, using a qualitative inquiry approach. METHODS: A total of 35 primary caregivers of HIV-infected children participated in in-depth interviews. The issues discussed included the major negative impacts on children's daily functioning and well-being, and the perceived caregiver/parental burden. Participants included parents (40%), grandparents (22.8%), other relatives (e.g. uncles, aunts) (34.3%) and one foster parent (2.8%). RESULTS: Qualitative analysis revealed that the major negative impacts of HIV/AIDS included physical symptoms, school performance and relationship changes. The major negative impacts on caregivers' well-being included acceptance of the diagnosis, dealing with the financial burden and keeping the diagnosis private. CONCLUSIONS: Approaches are needed to address these challenges by enhancing families' coping skills and building supportive networks.

The multicenter AIDS Cohort Study, 1983 to .

The Multicenter AIDS Cohort (MACS), initiated in 1983 at the Johns Hopkins School of Public Health, the University of Pittsburgh School of Public Health, Northwestern University School of Medicine, and the UCLA School of Public Health, continues to conduct studies and publish key papers on the natural history of untreated and treated HIV infection in 6972 men-who-have-sex-with-men. Through May 2011, 1,490,995 specimens have been collected, 86,883 person-years of data accrued and 1195 scientific papers published in international journals.

Factors associated with HIV infection among Indian women.

There is still a paucity of research on the sociodemographic and other underlying factors associated with HIV transmission among women in India. This study was designed to investigate such factors in sexually experienced Indian women. We used data from the National Family Health Survey 3 (NFHS-3), which tested 52,853 women for HIV, including 27,556 husband and wife pairs. Significant risk factors for all women and married women only were: aged 26-35 years (adjusted odds ratios [AORs] = 3.65 and 2.53, respectively), being poor (AORs = 1.57 and 1.79), having had a genital sore in the last 12 months (AORs = 3.16 and 3.01) and having more than one sexual partner (AORs = 5.95 and 5.15). For husband and wife pairs, suffering sexual violence (AOR = 2.63), husband having other wife/wives (AOR = 3.40) and husband's education being secondary level or higher (AOR = 0.43) were significant. Intervention strategies in India should target young married (aged 25-35 years) and formerly married urban women who are poor, as well as those who have suffered sexual violence from their husbands, and/or are (or whose husbands are) multi-partnered. Empowerment of women is fundamental to HIV/AIDS prevention in India.

Family support, quality of life and concurrent substance use among methadone maintenance therapy clients in China.

OBJECTIVES: The methadone maintenance therapy (MMT) programme has been scaled up rapidly in China. This study explored the family support perceived by MMT clients and its association with their quality of life and concurrent illicit drug use. STUDY DESIGN: Cross-sectional study. METHODS: Five hundred and sixty MMT clients were selected at random from 28 MMT clinics and services in Zhejiang and Jiangxi Provinces, China for participation in a face-to-face interview study. The participants' perceived family support and quality of life were measured through face-to-face structured interviews conducted by trained interviewers. Self-reported information about illicit drug use was obtained from clients. Urine specimens were collected from the participants to test for heroin use. RESULTS: Among the 560 participants, 471 (84.1%) were male and 168 (30.0%) were unemployed at the time of the study. In total, 398 (71.1%) were injecting drug users and 309 (55.2%) had a history of drug use of more than 10 years. Around one-third (n = 211, 37.7%) of the participants reported concurrent illicit drug use or had a positive urine test. Perceived family support was associated with increased physical health, psychological health, environmental health and social health. In addition, perceived family support was negatively correlated with concurrent substance use. CONCLUSIONS: Drug use and MMT is a family issue in China. Based on the findings of this study, it is suggested that involving family members in recruitment and interventions of the MMT programme will achieve higher rates of participation and compliance.

Multiple viral coinfections among HIV/AIDS patients in China.

A cross-sectional survey was conducted to determine seroprevalence and correlates of coinfections of hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Bar virus (EBV), herpes simplex virus including type 1 (HSV-1) and type 2 (HSV-2) among human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients in China. A total of 1,110 HIV/AIDS patients from Shanxi (Central area, n = 287), Zhejiang (Eastern area, n = 163), Yunnan (Southwestern area, n = 300) and Xinjiang (Northwestern area, n = 360) provinces were analyzed. The overall seroprevalence was 6.3% for HBsAg, 59.0% for anti-HCV IgG, 96.6% for anti-EBV IgG, 91.5% for anti-HSV-1 IgG, and 34.1% for anti-HSV-2 IgG. Eleven (1.0%) HIV/AIDS patients were coinfected with all five viruses, 177 (15.9%) with four viruses, 611 (55.0%) with three viruses, 288 (25.9%) with two viruses, 23 (2.1%) with single virus, and 1 (0.1%) with none of the five viruses. Multiple logistic regression analyses indicated that neither HBV, nor EBV and HSV-1 coinfection was associated with sociodemographic characteristics and HIV transmission mode, but HCV coinfection was associated with geographic region, age, gender, ethnicity, marital status, and HIV transmission mode, whereas HSV-2 coinfection was associated with geographic region, ethnicity and HIV transmission mode. This study suggests that HIV/AIDS patients with different regional and sociodemographic backgrounds and HIV transmission mode in China have different profiles of viral coinfections and should be subject to differential considerations in related health care programs.

Higher risk of AIDS or death in patients with lower CD4 cell counts after virally suppressive HAART.

BACKGROUND: The clinical implications of a failure to achieve high CD4 cell counts while receiving virally suppressive highly active antiretroviral therapy (HAART) are uncertain. METHODS: We analysed data from HIV-infected men participating in the Multicenter AIDS Cohort Study (MACS) to elucidate associations between CD4 cell counts achieved during virally suppressive HAART and risks of AIDS or death. Inclusion criteria were: CD4 cell count <200 cells/microL before HAART initiation; >or=2 viral load (VL) determinations after HAART initiation; and sustained viral suppression, defined as all VL <50 HIV-1 RNA copies/mL, but allowing a single VL of 50-1000 copies/mL. RESULTS: One hundred and twenty-one men were included; median age was 42 years. After first VL <50 copies/mL, six participants had a new AIDS diagnosis and seven died. The median CD4 cell count change/year (cells/microL) after first VL <50 copies/mL was zero among patients who either developed AIDS or died vs. 39 among those who did not meet either endpoint (P=0.119). After controlling for time from HAART initiation to first VL <50 copies/mL, age at first VL <50 copies/mL, history of AIDS and antiretroviral therapy (ART) experience before HAART, the hazard ratio for AIDS or death at CD4 cell count of 350 cells/microL was 10.7 (P=0.013), and at CD4 cell count of 201-350 vs. >350 cells/microL was 8.54 (P=0.014). CONCLUSION: In this cohort, lower CD4 cell count at the time of viral suppression was associated with increased risk of AIDS or death.

Herpes simplex virus-2 infection in male rural migrants in Shanghai, China.

The overall herpes simplex virus (HSV)-2 seroprevalence was 5.5% among male rural migrants working in construction sites, markets and factories, 5.4% among those reporting having had sexual intercourse and 5.8% among those reporting no sexual intercourse. Multiple logistic regression analyses indicate that migrants having higher income were more likely to have HSV-2 infection. None of the HSV-2-positives realized their infection status. Future sexually transmitted disease (STD) intervention programmes should target migrants with higher income and migrant market vendors and should not exclude those who self-report no STDs or no history of sexual intercourse.

Protease inhibitors and cardiovascular disease: analysis of the Los Angeles County adult spectrum of disease cohort.

Since protease inhibitors (PIs) were first introduced in 1995, research has shown that use of PIs greatly improves rates of survival, while slowing HIV disease progression. However, there are concerns that use of PIs may be associated with an increased risk of cardiovascular disease (CVD). To examine the relationship between PI use and CVD among HIV-infected patients, a large retrospective/prospective observational study was conducted. The study population was a clinic-based population seeking HIV treatment services between 1990 and 2000 at several sites in Los Angeles County. CVD was defined as ischemic heart disease/coronary artery disease (ICD-9 codes 410-414, 428, and 429.7) and cerebrovascular disease/stroke (ICD-9 codes 430-438). Multiple imputation was performed on missing data, and survival analysis was performed on the imputed datasets using an extended Cox Proportional Hazards Model. The 5,667 HIV-infected individuals contributed 15,550 person-years of follow-up. Eighty incident cases of CVD were identified. Use of PIs (hazard ratio (HR)=6.22 [95% CI: 3.13-12.39], p-value <0.001) and time-dependent non-PI use (HR 3.18 [1.99-5.09], p<0.001) were associated with CVD. Clinicians should monitor treatment of HIV-infected patients for adverse CVD events, and consider alternate forms of drug therapy and CVD-preventing drugs, particularly for those with a personal or family history of CVD.

Stigmatization and shame: consequences of caring for HIV/AIDS patients in China.

Using a representative sample of 478 doctors, nurses, and lab technicians working with people living with HIV/AIDS (PLWHA), a cross-sectional study was conducted to assess the impact of the AIDS epidemic on medical care systems and service providers in China. Correlation analyses showed significant association between internalized shame reported by service providers and their perception of being stigmatized due to working with PLWHA. Multivariate analyses revealed that the perceived level of institutional support for AIDS care was significantly related to the stigmatization and shame reported by the service providers. The study findings suggest that improved institutional support for AIDS care at the facility level and HIV-related stigma reduction intervention are crucial to maintain a high quality performance by the workforce in the health care system.

Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study.

The stromal-derived factor-1 (SDF-1) chemokine gene encodes the only natural ligand for CXCR4, the coreceptor for the pathogenic X4 HIV-1 strains. A single-nucleotide polymorphism (SNP) in the 3' untranslated region (SDF1-3'A=rs1801157) of SDF-1 was reported to be protective against infection and progression in some, but not other, epidemiological studies. To identify additional alleles that may influence HIV-1 infection and progression to AIDS, nine SNPs (including rs1801157) spanning 20.2 kb in and around the SDF-1 gene were genotyped in over 3000 African American (AA) and European American (EA) participants enrolled in five longitudinal HIV-1/AIDS natural cohort studies. Six or five haplotypes were present at frequencies greater than 5% in AA or EA, respectively. Six of the nine SNPs occur on only one common haplotype (>5%), while the remaining three SNPs were found on multiple haplotypes, suggesting a complex history of recombination. Among EA, rs754618 was associated with an increased risk of infection (OR=1.50, P=0.03), while rs1801157 (=SDF1-3'A) was associated with protection against infection (OR=0.63, P=0.01). In the MACS cohort, rs1801157 was associated with AIDS-87 (RH=0.31, P=0.02) and with death (RH=0.18, P=0.02). Significant associations to a single disease outcome were found for two SNPs and one haplotype in AA.

Fraction of cases of acquired immunodeficiency syndrome prevented by the interactions of identified restriction gene variants.

Previous research has demonstrated isolated effects of host genetic factors on the progression of human immunodeficiency virus type 1 (HIV-1) infection. In this paper, the authors present a novel use of multivariable methods for estimating the prevented fraction of acquired immunodeficiency syndrome (AIDS) cases attributable to six restriction genes after accounting for their epidemiologic interactions. The methods presented will never yield a prevented fraction above 1. The study population consisted of a well-characterized cohort of 525 US men with HIV-1 seroconversion documented during follow-up (1984-1996). On the basis of a regression tree approach using a Cox proportional hazards model for times to clinical AIDS, the combinations of genes associated with the greatest protection, relative to the lack of a protective genotype, consisted of: 1) C-C chemokine receptor 5 (CCR5)-Delta 32 and C-C chemokine receptor 2 (CCR2)-64I (relative hazard = 0.44); 2) interleukin 10 (IL10)-+/+ in combination with CCR5-Delta 32 or CCR2-64I (relative hazard = 0.45); and 3) IL10-+/+ in combination with stromal-derived factor (SDF1)-3 'A and CCR5 promoter P1/approximately P1 (relative hazard = 0.37). Overall, 30% of potential AIDS cases were prevented by the observed combinations of restriction genes (95% confidence interval: 7, 47). However, the combined effect was confined to the first 4 years following HIV-1 seroconversion. Additional research is needed to identify AIDS restriction genes with stronger and long-lasting protection to better characterize the genetic epidemiology of HIV-1.

Effects of asthma on cell components in peripheral blood among smokers and non-smokers.

BACKGROUND: Eosinophils play a central role in asthma, but the interplay of the effects of smoking, eosinophils and asthma remains unclear. OBJECTIVE: The primary objective of our study was to investigate the extent to which smoking modifies the effect of asthma on circulating eosinophils, CD4+ and CD8+ T cell counts. METHODS: Data were collected semiannually between 1987 and 1994 from HIV-negative participants in the Multicenter AIDS Cohort Study. Asthma was defined by a questionnaire at baseline as a self-report of diagnosed asthma. A total of 1420 blood samples from 197 asthmatics and 15 822 from 1997 non-asthmatics were collected. RESULTS: Eosinophil levels were higher in asthmatics (28% of asthmatics had eosinophils >/=4% and 16% of non-asthmatics) regardless of smoking history, but smoking modified the association between eosinophils and asthma. Namely, the odds ratios for eosinophils being >/=4% in asthmatics to non-asthmatics decreased from 2.7 (95% CI: 2.0, 3.6) in never, to 2.1 (1.4, 3.1) in former, and to 1.5 (0.9, 2.3) in current smokers. Cross-sectional and longitudinal analyses coherently showed that smoking increased eosinophils in non-asthmatics, but the converse was true for asthmatics. In contrast, no differences in peripheral blood T cell counts between asthmatics and non-asthmatics were observed. CONCLUSION: Under the established link between increased eosinophils and asthma, these data indicate that smoking modified this relationship. This finding suggests that smoking plays a different immunological role in asthmatics and non-asthmatics.

Do STD clinics correctly diagnose STDs? An assessment of STD management in Hefei, China.

The main purposes of the study were to assess the accuracy of laboratory testing and the diagnosis by physicians in sexually transmitted disease (STD) clinics in Hefei, China. Among 347 men complaining of urethral discharge or dysuria, 240 tested positive at the National Centre for either Neisseria gonorrhoeae or Chlamydia trachomatis, 310 tested positive according to the clinic laboratories, and 347 were diagnosed by the physicians. For chlamydia, the sensitivity and positive predictive value (PPV) of the clinic laboratories were 55% and 26%, and for the diagnosis by the physicians were 61% and 24%. Laboratory testing and the diagnosis by the physicians had low power to detect mixed infection. The PPVs for the diagnosis by the physicians were 50% for syphilis and 43% for herpes simplex virus (HSV), indicating that both syphilis and HSV were over-diagnosed. Over half of those previously infected had not received education to prevent reinfection. Thus, the quality of clinic laboratory testing was not high and physicians often misdiagnosed STDs.

Evaluation of the effectiveness of highly active antiretroviral therapy in persons with human immunodeficiency virus using biomarker-based equivalence of disease progression.

The association of different CD4(+) cell counts with the same disease risk in treated and untreated populations reflects the effectiveness of highly active antiretroviral therapy (HAART) in persons with human immunodeficiency virus (HIV). Clinical progression of disease following initiation of HAART was determined for 679 HIV-infected men in the Multicenter AIDS Cohort Study by means of Kaplan-Meier survival analyses. Cox proportional hazards models were used to assess the effects of markers of HIV disease, antiretroviral history, and demographic factors. Men who had been followed since January 1993 (pre-HAART) were used to identify CD4(+) levels associated with the acquired immunodeficiency syndrome (AIDS)-free time equivalent to that of men starting HAART with CD4(+) cell counts of <200 cells/microl. Within 3.5 years following HAART initiation, 11.3% of the subjects developed AIDS and 8.5% died. Determinants of AIDS were a CD4(+) cell count of <200 cells/microl at initiation (relative hazard = 2.25, 95% confidence interval: 1.13, 4.49) and age >45 years at initiation (relative hazard = 1.92, 95% confidence interval: 0.98, 3.77). An increase in CD4(+) cell count of >50 cells/microl immediately after HAART initiation also improved prognosis (relative hazard = 0.34, 95% confidence interval: 0.16, 0.71). AIDS risk in men starting HAART with CD4(+) counts of <200 cells/microl (median = 132) was similar to that of non-HAART users with CD4(+) counts of 375-475 cells/microl (median = 432). The equivalence of disease progression to that of nonusers with approximately 300 more cells per microl demonstrates that HAART users have a broader reconstitution of the immune system beyond that of observed increases in CD4(+) cell count.

Methods to assess population effectiveness of therapies in human immunodeficiency virus incident and prevalent cohorts.

Two methods are presented for measuring population effectiveness (i.e., reduction of disease in a population in which only some receive treatment) of antiretroviral therapy among human immunodeficiency virus (HIV)-infected men at risk for acquired immunodeficiency syndrome (AIDS) and followed between January 1, 1986, and June 30, 1999, in the Multicenter AIDS Cohort Study. Method I, requiring use of a seroincident cohort, estimates relative hazards of AIDS for persons at equal duration of infection. Method II, allowing use of a seroprevalent cohort, estimates relative hazards since the beginning of therapy eras for persons starting at equal levels of prognostic markers of disease stage (CD4 cell count and HIV type 1 RNA). The follow-up interval was divided into four calendar periods to characterize different eras of antiretroviral therapy. For method I, the relative hazards were 1.52 (95% confidence interval (CI): 0.93, 2.49), 0.91 (95% CI: 0.66, 1.26), and 0.30 (95% CI: 0.18, 0.51) for the eras of no therapy, dual nucleoside therapy, and potent combination antiretroviral therapy, respectively (monotherapy was the reference era). For method II, the corresponding relative hazards were 1.52 (95% CI: 1.10, 2.09), 1.03 (95% CI: 0.77, 1.38), and 0.31 (95% CI: 0.21, 0.45). These results extend the measurement of population effectiveness from incident to prevalent cohorts and demonstrate the ability of cohort studies to complement information provided by clinical trials.

Thrush and fever as markers of immune competence in the era of highly active antiretroviral therapy.

The presence of clinical manifestations of HIV-1 infection is one measure of immune function failure. We examined the occurrence of clinical manifestations of HIV-1 infection, in particular fever and oral thrush, before and after the initiation of highly active antiretroviral therapy (HAART). Using data collected from 645 participants in the Multicenter AIDS Cohort Study (MACS) who used HAART, 7517 person-visits from January 1992 through March 2000 were stratified by time relative to HAART initiation (> or =1 year preinitiation, <1 year preinitiation, >1 year postinitiation, and > or =1 year postinitiation) and CD4+ T cell count (< or =100, 101-200, 201-350, and >350 cells/microl). Multivariate logistic regression was used to assess the relationship between HAART, CD4+ T cell count, and each self-reported symptom (oral hairy leukoplakia, diarrhea, fever, and oral thrush). After initiation of HAART, clinical manifestations of HIV-1 infection continued to occur and, similar to patterns seen before HAART, were more likely at lower CD4+ T cell counts than at higher (p < 0.001). Except for diarrhea, symptoms did not occur more frequently after HAART. Rather, beyond 1 year after initiation of HAART, there was less oral thrush even at the same CD4+ T cell count. These results provide evidence that increases in CD4+ T cell count due to HAART represent a reconstitution of immune function.