Immunogenetic influences on acquisition of HIV-1 infection: consensus findings from two African cohorts point to an enhancer element in IL19 (1q32.2).

Numerous reports have suggested that immunogenetic factors may influence human immunodeficiency virus (HIV)-1 acquisition, yet replicated findings that translate between study cohorts remain elusive. Our work aimed to test several hypotheses about genetic variants within the IL10-IL24 gene cluster that encodes interleukin (IL)-10, IL-19, IL-20 and IL-24. In aggregated data from 515 Rwandans and 762 Zambians with up to 12 years of follow-up, 190 single-nucleotide polymorphisms passed quality control procedures. When HIV-1-exposed seronegative subjects (n=486) were compared with newly seroconverted individuals (n=313) and seroprevalent subjects (n=478) who were already infected at enrollment, rs12407485 (G>A) in IL19 showed a robust association signal in adjusted logistic regression models (odds ratio=0.64, P=1.7 × 10(-4) and q=0.033). Sensitivity analyses demonstrated that (i) results from both cohorts and subgroups within each cohort were highly consistent; (ii) verification of HIV-1 infection status after enrollment was critical; and (iii) supporting evidence was readily obtained from Cox proportional hazards models. Data from public databases indicate that rs12407485 is part of an enhancer element for three transcription factors. Overall, these findings suggest that molecular features at the IL19 locus may modestly alter the establishment of HIV-1 infection.

SNP screening of central MHC-identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi's sarcoma.

The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi's sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and human herpes virus-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls. We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a fourfold increase of risk (odds ratio (OR)=4.09; 95% confidence interval (CI)=1.90-8.80; P=0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI=2.54-43.6; P=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120-kb-long haplotype (OR=1.52; 95% CI=1.01-2.28; P=0.047) formed by rs7029 A>G (GPANK1 3' untranslated region), rs1065356 G>A (LY6G6C), rs3749953 A>G (MSH5-SAPCD1 read through) and rs707926 G>A (VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.

Host genetics and immune control of HIV-1 infection: fine mapping for the extended human MHC region in an African cohort.

Multiple major histocompatibility complex (MHC) loci encoding human leukocyte antigens (HLA) have allelic variants unequivocally associated with differential immune control of HIV-1 infection. Fine mapping based on single nucleotide polymorphisms (SNPs) in the extended MHC (xMHC) region is expected to reveal causal or novel factors and to justify a search for functional mechanisms. We have tested the utility of a custom fine-mapping platform (the ImmunoChip) for 172 HIV-1 seroconverters (SCs) and 449 seroprevalent individuals (SPs) from Lusaka, Zambia, with a focus on more than 6400 informative xMHC SNPs. When conditioned on HLA and nongenetic factors previously associated with HIV-1 viral load (VL) in the study cohort, penalized approaches (HyperLasso models) identified an intergenic SNP (rs3094626 between RPP21 and HLA-E) and an intronic SNP (rs3134931 in NOTCH4) as novel correlates of early set-point VL in SCs. The minor allele of rs2857114 (downstream from HLA-DOB) was an unfavorable factor in SPs. Joint models based on demographic features, HLA alleles and the newly identified SNP variants could explain 29% and 15% of VL variance in SCs and SPs, respectively. These findings and bioinformatics strongly suggest that both classic and nonclassic MHC genes deserve further investigation, especially in Africans with relatively short haplotype blocks.

Dimorphic HLA-B signal peptides differentially influence HLA-E- and natural killer cell-mediated cytolysis of HIV-1-infected target cells.

As a mechanism of self-protection, signal peptides cleaved from human leukocyte antigen (HLA) class I products bind to HLA-E before the complex interacts with the natural killer (NK) cell receptor CD94/NKG2A to inhibit NK-mediated cell lysis. Two types of the signal peptides differ in their position 2 (P2) anchor residue, with P2-methionine (P2-M) having higher HLA-E binding affinity than P2-threonine (P2-T). All HLA-A and HLA-C molecules carry P2-M, whereas HLA-B products have either P2-M or P2-T. Epidemiological evidence suggests that P2-M is unfavourable in the context of HIV-1 infection, being associated with accelerated acquisition of HIV-1 infection in two African cohorts. To begin elucidating the functional mechanism, we studied NK-mediated killing of CD4(+) T cells and monocyte-derived macrophages infected with two laboratory-adapted HIV-1 strains and two transmitted/founder (T/F) viruses. In the presence of target cells derived from individuals with the three HLA-B P2 genotypes (M/M, M/T and T/T), NK-mediated cytolysis was elevated consistently for P2-T in a dose-dependent manner for all cell and virus combinations tested (P = 0·008-0·03). Treatment of target cells with an anti-HLA-E monoclonal antibody restored NK-mediated cytolysis of cells expressing P2-M. Observations on cell lysis were also substantiated by measurements of HIV-1 p24 antigen in the culture supernatants. Overall, our experiments indicate that the anti-HIV-1 function mediated by NK cells is compromised by P2-M, corroborating the association of HLA-B genotype encoding P2-M with accelerated HIV-1 acquisition.

Genetic variations and heterosexual HIV-1 infection: analysis of clustered genes encoding CC-motif chemokine ligands.

Several CC-motif chemokine ligands (CCLs) can block HIV-1-binding sites on CC-motif chemokine receptor 5 (CCR5) and inhibit viral entry. We studied single-nucleotide polymorphisms (SNPs) in genes encoding three CCR5 ligands (CCL3 (MIP-1a), CCL4 (MIP-1b)and CCL5 (RANTES)) along with an adjacent gene encoding a CCR2ligand (CCL2 (MCP-1)) to identify candidate markers for HIV-1 infection and pathogenesis. Analyses of 567 HIV-1 serodiscordant Zambian couples revealed that rs5029410C (in CCL3 intron 2) was associated with lower viral load (VL) in seroconverters, adjusted for gender and age (regression ß=-0.57 log(10), P=4x10(-6)). Inaddition, rs34171309A in CCL3 exon 3 was associated with increased risk of HIV-1 acquisition in exposed seronegatives(hazard ratio=1.52, P=0.006 when adjusted for VL of the initially seropositive partner and genital ulcer/inflammation). SNPrs34171309 encodes a conservative Glu-to-Asp substitution. Fiven eighboring SNPs in tight linkage disequilibrium with rs34171309all showed similar associations with HIV-1 acquisition. How these multiple CCL3 SNPs may alter the occurrence or course of HIV-1 infection remains to be determined [corrected].

The role of HLA-DR-DQ haplotypes in variable antibody responses to anthrax vaccine adsorbed.

Host genetic variation, particularly within the human leukocyte antigen (HLA) loci, reportedly mediates heterogeneity in immune response to certain vaccines; however, no large study of genetic determinants of anthrax vaccine response has been described. We searched for associations between the immunoglobulin G antibody to protective antigen (AbPA) response to Anthrax Vaccine Adsorbed (AVA) in humans, and polymorphisms at HLA class I (HLA-A, -B, and -C) and class II (HLA-DRB1, -DQA1, -DQB1, -DPB1) loci. The study included 794 European-Americans and 200 African-Americans participating in a 43-month, double-blind and placebo-controlled clinical trial of AVA (clinicaltrials.gov identifier NCT00119067). Among European-Americans, genes from tightly linked HLA-DRB1, -DQA1, -DQB1 haplotypes displayed significant overall associations with longitudinal variation in AbPA levels at 4, 8, 26 and 30 weeks from baseline in response to vaccination with three or four doses of AVA (global P=6.53 × 10(-4)). In particular, carriage of the DRB1-DQA1-DQB1 haplotypes (*)1501-(*)0102-(*)0602 (P=1.17 × 10(-5)), (*)0101-(*)0101-(*)0501 (P=0.009) and (*)0102-(*)0101-(*)0501 (P=0.006) was associated with significantly lower AbPA levels. In carriers of two copies of these haplotypes, lower AbPA levels persisted following subsequent vaccinations. No significant associations were observed amongst African-Americans or for any HLA class I allele/haplotype. Further studies will be required to replicate these findings and to explore the role of host genetic variation outside of the HLA region.

Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection.

Major histocompatibility complex (MHC) genes (HLA in humans) regulate the immune response to foreign antigens. Molecular and serologic techniques were used to identify products of HLA class I, class II and transporter (TAP) genes (also part of the MHC) in homosexual seroconverters to human immunodeficiency virus type 1 (HIV-1). Comprehensive statistical analysis produced an HLA profile that predicted time from HIV-1 infection to the onset of AIDS. The profile was developed in a cohort of 139 men and evaluated in a second unrelated cohort of 102 men. In the evaluation cohort, the profile discriminated a sixfold difference between groups with the shortest and longest times to AIDS (P = 0.001). These findings support current theory about control of antigen processing by HLA genes and have implications for immunopathogenesis of HIV-1 and other infections.

AIDS repository.

In the article "Spotlight falls on science policy" (News and Comment, 10 May, p. 691) by Mark H. Crawford, the findings of a General Accounting Office report on the operating costs of the Continuous Electron Beam Accelerator Facility (CEBAF) were overstated. The report found that the Department of Energy's operating costs would rise by $80 million if both CEBAF and the Relativistic Heavy Ion Collider are constructed. CEBAF's operating cost is estimated to be $30 million. The report also found problems in accommodating the operating costs of the proposed Superconducting Super Collider in the department's budget.

HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage.

A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study.

The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.

Associated factors and impact of myocarditis in patients with SLE from LUMINA, a multiethnic US cohort (LV). [corrected].

OBJECTIVE: To examine the factors associated with myocarditis and its impact on disease outcomes in SLE patients. METHODS: SLE patients aged > or = 16 yrs, disease duration < or = 5 yrs from LUMINA (LUpus in Minorities: NAture vs nurture), a multiethnic US cohort, were studied. Myocarditis was defined as per the category 3 of the pericarditis/myocarditis item of the SLAM-Revised (SLAM-R). Patients with concurrent pericardial involvement were excluded. Patients with myocarditis were compared with those without myocarditis or its sequelae in the preceding year. The association between myocarditis and baseline variables (T(0)) was first examined. The impact of myocarditis on disease activity over time (SLAM-R), damage accrual [SLICC Damage Index (SDI)] at last visit (T(L)) and mortality was evaluated. RESULTS: Fifty-three of the 496 patients studied had myocarditis. African American ethnicity [Odds ratio (OR) = 12.6; 95% CI 1.6, 97.8] and SLAM-R at diagnosis (OR = 1.1, 95% CI 1.0, 1.1) were significantly and independently associated with myocarditis. Myocarditis did not predict disease activity over time, but approached significance as a predictor of SDI at T(L) in multivariable analyses P = 0.051. Kaplan-Meier curves indicated that myocarditis was associated with shorter survival (log-rank = 4.87, P = 0.02), particularly in patients with > or = 5 yrs disease; however, myocarditis was not retained in the Cox proportional hazards regression model. CONCLUSIONS: Ethnicity and disease activity at diagnosis were associated with the occurrence of myocarditis in SLE. Myocarditis did not significantly impact on disease activity over time, but impacts some on damage accrual and survival, reflecting overall the more severe disease those patients experience.

Biochemical epidemiology of cervical neoplasia: measuring cigarette smoke constituents in the cervix.

In preparation for an epidemiological investigation of cigarette smoking and cervical neoplasia, we studied methods of measuring cervical exposure to tobacco smoke. The measurement of cotinine in cervical flushes by radioimmunoassay proved to be highly accurate in distinguishing smokers from nonsmokers, achieving 100% sensitivity and 97% specificity. In most subjects, quantitative levels of cervical cotinine and nicotine mirrored recent smoking intensity. Some of the apparent exceptions may have resulted from metabolic/secretory traits of the subjects. If so, the biochemical measurement of smoke constituents in the cervix might prove more valuable for epidemiological studies of cervical neoplasia than data on current smoking behavior collected by interview.

Prospects for an emergency department-based adult immunization program.

Immunization of adults has been deficient in the United States. According to interviews conducted during their visits to an emergency room, only 20.1% of 350 patients who fit into high-risk categories for immunization had heard of pneumococcal vaccine, whereas 82.7% had heard of influenza vaccine. Only 8.6% and 47.8%, respectively, had ever been given pneumococcal or influenza vaccine. Previous pneumococcal vaccination was six times more common (10.3% vs 1.6%) and prior influenza vaccination twice as common (52.7% vs 25.4%) in the respondents who could identify a primary care provider or clinic than in those who could not. Of the patients who had not received a specific vaccine, about 60% indicated that they would take pneumococcal or influenza vaccine if it was offered while they were in the emergency room setting. Offering vaccine in an emergency room setting promises to complement other approaches to immunizing adults at high risk for complications of influenza and pneumococcal infections.

Epidemiology of acute respiratory illness during an influenza outbreak in a nursing home. A prospective study.

We observed an influenza epidemic caused by influenza A/Arizona/82 (H3N2) in a nursing home during 1982 to 1983. A survey indicated that 59% of the residents were immunized before the outbreak. The outbreak was observed to begin in November, peak in February, and disappear in April. A significant level of herd immunity may have accounted for the slow progression through the nursing home. In addition, serologic evidence of concurrent infection with respiratory syncytial virus, parainfluenza virus, and Mycoplasma pneumoniae was present in many residents. Epidemics of influenza in a closed, partially immunized population in a nursing home may proceed at a slower rate than in an open, largely unimmunized community. By monitoring for infection with other respiratory agents, the complex nature of the outbreak in this nursing home became evident.

Association of influenza immunization with reduction in mortality in an elderly population. A prospective study.

We prospectively studied the efficacy of influenza vaccine during an influenza A/Arizona/80 (H3N2) outbreak at the Jewish Home and Hospital for the Aged in New York in the winter season of 1982 to 1983. All patients had been offered influenza vaccine before the outbreak; 181 chose to be vaccinated and 124 refused vaccination but agreed to participate in the study. Among those with serologic evidence of influenza infection, respiratory illness was significantly more common in the unvaccinated group (six of 14 vs one of 22). The overall mortality was 13 (7.2%) of 181 in the vaccinated group and 22 (17.7%) of 124 in the control group. The vaccinated and the control groups were examined for comparability. A logistic regression analysis, which controlled for differences in sex and level of nursing care, indicated that the difference in mortality was still significant, with a summary odds ratio of 2.7. The relative risk of death in the unvaccinated group was comparable at 2.18. Influenza vaccine reduced the mortality by 59% in the vaccinated group compared with the control group.

Influenza vaccine and pneumonia mortality in a nursing home population.

The effectiveness of immunization against influenza in elderly persons is uncertain. A retrospective cohort study in a New York City nursing home examined the occurrence of pneumonia and its related mortality over three consecutive influenza seasons (Nov 1 through April 30, 1979 to 1980, 1980 to 1981, and 1981 to 1982). Nearly one half of approximately 450 residents (mean age, 84 years) accepted immunization each year. The vaccinated and unvaccinated groups were similar. The attack rate of pneumonia did not differ significantly between the vaccinated and unvaccinated groups in any of the three influenza seasons. When influenza was occurring in the community (1979 to 1980 and 1980 to 1981), however, the risk of death from pneumonia in the unvaccinated group was three-fold higher than in the vaccinated group (60% vs 18% and 73% vs 25%, respectively). In a year when influenza was specifically sought and not found in the facility (1981 to 1982), however, vaccination did not affect pneumonia-related mortality. This study also suggests that estimates of mortality due to pneumonia should include deaths that occur up to 60 days after onset of pneumonia; shorter follow-up may overestimate the protective effect of vaccination.

Recreational drug use and sexual behavior change in a cohort of homosexual men. The Multicenter AIDS Cohort Study (MACS).

The relationship between use of recreational drugs and high-risk (HIV-transmitting) homosexual behavior was examined in the Multicenter AIDS Cohort Study (MACS) population. Among the 3916 men who completed both the baseline (1984) and first 6-month follow-up evaluations and were sexually active during the 6 months prior to enrollment, self-reported use of each of 10 classes of recreational drugs in conjunction with sexual activity was analyzed for both cross-sectional and prospective relationships with pattern of sexual behavior using a four-level sexual risk behavior index. At baseline, the proportion of men in the highest risk category (unprotected anal exposures with multiple partners) increased from 36 to 85% when men not using any drugs to men using three or more drugs plus volatile nitrites were examined. In multivariate logistical analyses, volatile nitrite use was significantly associated with failure to maintain or attain lower sexual risk levels after controlling for the effects of age, educational level and numbers of high-risk partners. These results suggest that volatile nitrite use may play an important role in the association between recreational drug use and high-risk sexual behavior among homosexual/bisexual men.

Clinical manifestations of acute infection with human immunodeficiency virus in a cohort of gay men.

During a prospective study of the natural history of human immunodeficiency virus (HIV) infection in a cohort of gay/bisexual men, information on self-reported symptoms lasting for 3 or more days during the previous 6 months was collected without knowledge of the subject's HIV serological status. Twenty-two people were retrospectively found to have seroconverted to HIV during the interval. Each seroconverter was matched to two seronegative and two seropositive controls. Matched case-control analyses using the seronegative controls determined that the following symptoms lasting for 3 or more days were associated with new HIV infection: fever greater than 37.7 degrees C, swollen lymph nodes, night sweats and headaches. Matched case-control analyses using the seropositive controls determined that the following symptoms lasting for 3 or more days were associated with new HIV infection: fatigue, fever greater than 37.7 degrees C, swollen lymph nodes, night sweats and headaches. It was notable that the majority of seroconversions were not associated with any symptoms lasting for 3 or more days. Due to their non-specificity, symptoms associated with seroconversion are not likely to have a high positive predictive value. In high risk populations, however, appearance of these symptoms may facilitate identification of early infection that may be important for studies of natural history or for optimal timing for initiating antiviral therapy.

Racial differences in rate of CD4 decline in HIV-1-infected homosexual men.

OBJECTIVE: To determine whether racial differences exist in the rate of CD4 lymphocyte decline in HIV-1-infected homosexual men. DESIGN: Prospective cohort study. STUDY POPULATION: Non-Hispanic white (n = 321) and black (n = 102) HIV-1-seropositive homosexual and bisexual men were recruited from the Baltimore/Washington, DC metropolitan areas between 1984-1985 and 1987-1990, and evaluated semiannually. MAIN MEASUREMENTS: Changes in CD4 lymphocyte count and CD4 percentage over time were analysed using linear regression methods for the 271 white and 69 black participants who had at least four semiannual CD4 lymphocyte measurements. RESULTS: Rate of decline in CD4 lymphocyte count over 6 months was much slower among black than white seroprevalent men at all levels of baseline CD4 count (baseline 201-400 x 10(6)/l: + 0.24 versus -17.7 x 10(6)/l; 401-600 x 10(6)/l: -11.3 versus -23.9 x 10(6)/l; 601-800 x 10(6)/l: -15.1 versus -35.2 x 10(6)/l; > 800 x 10(6)/l: -4.3 versus -42.7 x 10(6)/l for black versus white, respectively), although this was only statistically significant for the lowest and highest strata of baseline CD4 count. These racial differences persisted after adjustment for recruitment period (1984-1985 or 1987-1990), follow-up duration, age and zidovudine therapy or Pneumocystis carinii pneumonia prophylaxis. Similar findings were observed among the 70 white and 11 black seroconverters. Black participants were also less likely than a subgroup of white participants matched on baseline CD4 lymphocyte count to be HIV-1 p24 antigen-positive. However, after acid dissociation of samples initially p24 antigen-negative, there were no significant differences in the prevalence of p24 antigenemia at enrollment or after 1 year of follow-up. CONCLUSIONS: This analysis suggests a more gradual decline in CD4 lymphocyte count among black than white Americans. The clinical significance of and reasons for this are unclear, but the lower prevalence of p24 antigenemia due to immune complexing among black Americans suggests that racial differences in the immune response to HIV may exist. Additional studies are needed to validate these findings in a larger cohort of non-whites, and to assess their relationship with other measures of cell-mediated immune function.