Dean L. Mann

A Prospective Study of Human Immunodeficiency Virus Type 1 Infection and the Development of AIDS in Subjects with Hemophilia

We evaluated a multicenter cohort of 1219 subjects with hemophilia or related disorders prospectively, focusing on 319 subjects with documented dates of seroconversion to human immunodeficiency virus type 1 (HIV-1). The incidence rate of the acquired immunodeficiency syndrome (AIDS) after seroconversion was 2.67 per 100 person-years and was directly related to age (from 0.83 in persons 1 to 11 years old up to 5.66 in persons 35 to 70 years old; Ptrend = 0.00003). The annual incidence of AIDS ranged from zero during the first year after seroconversion to 7 percent during the eighth year, with eight-year cumulative rates (+/- SE) of 13.3 +/- 5.3 percent for ages 1 to 17, 26.8 +/- 6.4 percent for ages 18 to 34, and 43.7 +/- 16.4 percent for ages 35 to 70. Serial immunologic and virologic markers (total numbers of CD4 lymphocytes, presence of serum interferon or HIV-1 p24 antigen, and low or absent serum levels of anti-p24 or anti-gp120) predicted a high risk for the subsequent development of AIDS. Adults 35 to 70 years old had a higher incidence of low CD4 counts than younger subjects (P less than or equal to 0.005), whereas adolescents had a low rate of anti-p24 loss (P = 0.0007) and subjects 1 to 17 years old had a lower incidence of AIDS after loss of anti-p24 (P = 0.03). These findings not only demonstrate that the risk of AIDS is related directly to age but also suggest that older adults are disproportionately affected during the earlier phases of HIV disease, that adolescents may have a low replication rate of HIV, and that children and adolescents may tolerate severe immunodeficiency better because they have fewer other infections or because of some unmeasured, age-dependent cofactor or immune alteration in the later phase of HIV disease.

Sjögren's Syndrome (Sicca Syndrome): Current Issues

This paper outlines the clinical, serologic, and immunogenetic differences and similarities of Sjögrens syndrome alone (primary) and Sjögrens syndrome associated with rheumatoid arthritis and systemic lupus erythematosus (secondary). The immunoregulation in Sjögrens syndrome is discussed and the incidence of immune complex-like material, its nature, pathophysiology, and clearance by the Fc recptor of the reticuloendothelial system presented.

B-lymphocyte alloantigens associated with systemic lupus erythematosus.

We examined B-lymphocyte alloantigens in 41 patients with systemic lupus erythematosus and 184 controls, using a panel of 47 pregnancy serums, and compared reaction frequencies of individual serums. One serum, la-715, reacted with B lymphocytes from 75.6 per cent of patients and 14.1 per cent of controls (Pc less than 0.005, relative risk 18.8). Twenty-eight of the patients were also typed with a panel of HLA-D-related serums from the Seventh International Histocompatibility Workshop, HLA-DRw types assigned, and compared to 490 Workshop controls. Both HLA-DRw2 (57.1 per cent vs. 26.4 per cent, Pc less than 0.004) and HLA-DRw3 (46.4 per cent vs. 22.2 per cent, Pc less than 0.03) were increased in systemic lupus erythematosus. This study demonstrates that select B-lymphocyte alloantigens, which are controlled by genes in the major histocompatibility complex, are present in increased frequency in systemic lupus erythematosus.

Genetic differences between primary and secondary sicca syndrome.

SICCA syndrome occurs alone or in association with another autoimmune disease, frequently rheumatoid arthritis. We recently proposed that sicca syndrome be termed primary when it occurs alone and s...

Late-Onset 21-Hydroxylase Deficiency Mimicking Idiopathic Hirsutism or Polycystic Ovarian Disease: An Allelic Variant of Congenital Virilizing Adrenal Hyperplasia with a Milder Enzymatic Defect

The importance of late-onset congenital adrenal hyperplasia as a cause of hirsutism is controversial. Two of 35 women with a chief complaint of hirsutism met the criteria of 21-hydroxylase deficiency. In one, who presented with hirsutism, oligomenorrhea, obesity, infertility, and enlarged cystic ovaries, the initial diagnosis was polycystic ovarian syndrome. Family data showed that her disorder was autosomal recessive and linked to the histocompatibility leukocyte antigens (HLA), as in the classic form of congenital adrenal hyperplasia. Carriers were thus detectable by HLA typing. Thus late-onset congenital adrenal hyperplasia appears to be an allelic variant of congenital virilizing adrenal hyperplasia with a milder enzymatic defect. The diagnosis cannot be made clinically because the disease has the same presentation as idiopathic hirsutism or polycystic ovarian disease. Basal plasma 17-hydroxyprogesterone levels, unlike in classic congenital adrenal hyperplasia, can be normal, and an ACTH stimulation test or sequential measurements of plasma 17-hydroxyprogesterone throughout the day may be needed to show the abnormality. The incidence among hirsute women is estimated to be 6% to 12%, and the calculated gene frequency for the allele coding for attenuated expression of 21-hydroxylase deficiency is 0.015 to 0.057.

Haplotypic variation of the transporter associated with antigen processing (TAP) genes and their extension of HLA class II region haplotypes

Stable cell surface presentation of HLA class I molecules requires active transport of antigenic peptides across the endoplasmic reticulum by products of two genes, TAP1 and TAP2, which map in the major histocompatibility complex class II region. Alleles of each gene are derived from a combination of variable sitesaat each locus. In this study, TAP1 and TAP2 alleles were identified in homozygous typing cell (HTC) lines, allowing resolution of specific haplotypes in conjunction with the highly polymorphic HLA class II region haplotypes. Three alleles at each TAP locus were found from which eight haplotypes could be assigned. Determination of TAP1 and TAP2 alleles in cell lines homozygous at DR, DQ, and DP created eight additional haplotypes beyond the number observed with these class II genes alone. Complete analysis of DR, DQ, TAP, and DP genotypes in 66 HTCs resulted in the following groups: 1) 46 homozygotes; 2) nine homozygous at DR, DQ, and TAP, but heterozygous at DP; 3) four homozygous at DR, DQ, and DP, but heterozygous at one or both TAP genes; 4) four homozygous at DR and DQ, but heterozygous at TAP and DP; and 5) three complex genotypes heterozygous at DP, TAP, and at least one of DQA1, DQB1, or DRB1 loci. TAP1 and TAP2 genes map in an area of frequent recombination. TAP alleles were determined in five DQB1, DPB1 recombinant individuals, three of which were informative. Recombination was found between DQB1 and the TAP loci in two individuals and between TAP and DPB1 in the other individual.

Cross-Clade Cytotoxic T Cell Response to Human Immunodeficiency Virus Type 1 Proteins among HLA Disparate North Americans and Thais

A globally effective vaccine will need to elicit cytotoxic T lymphocytes (CTL) capable of recognizing diverse human immunodeficiency virus type 1 (HIV-1) clades. Study of the cellular immune responses of HIV-1-infected persons may allow predictions to be made regarding useful vaccine antigen components. The frequency and magnitude of CTL responses to clade E and B Gag, Pol-RT, Env, and Nef proteins were compared in 12 HLA-characterized, clade E-infected Thais and in 10 clade B-infected North Americans using vaccinia recombinant constructs for protein expression. While responses were detected against all proteins, they were most frequent and cross-reactive to Gag in both groups. Pol-RT was recognized less frequently in Thais than North Americans. Cross-clade protein recognition was common but not uniformly present among these HLA-disparate individuals. Population-specific CTL data are needed to adequately prepare for vaccine trials outside of North America and Europe.

Langerhans cells in HIV-1 infection

The skin-specific immune surveillance system protects against invading microorganisms and transformed cells expressing tumor-specific neoantigens. This system includes antigen-presenting Langerhans cells, dermal and epidermal T lymphocytes, cytokine-producing keratinocytes, and draining peripheral lymph nodes. In patients infected with human immunodeficiency virus-1 (HIV-1), this surveillance system appears to be compromised, as evidenced by a reduction in the epidermal Langerhans cell population. Because human epidermal Langerhans cell express surface-bound CD4 antigens, HLA-DR antigens, and Fc-IgG receptors, all of which are involved in HIV-1 binding to, or entry into, the target cell, the reduction in Langerhans cells in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) may be a direct consequence of HIV-1 infection and subsequent injury to Langerhans cells. Detailed ultrastructural studies have confirmed moderate to severe morphologic damage in some Langerhans cells of such patients and the presence of HIV-1-like particles on Langerhans cell surface membranes and in the extracellular spaces. The biologic consequences of Langerhans cell infection by HIV-1 could be either impaired antigen presentation function of viable Langerhans cells or possible transmission of the retrovirus to the T-cell compartment in skin or lymph nodes, with subsequent depletion of CD4+ T cells via widespread syncytia formation between HIV-1-infected and noninfected cells. The facts that herpes simplex virus, specific cytokines, and ultraviolet B radiation can activate signals for HIV-1 expression and that epidermal cells can elaborate large amounts of cytokines, particularly with enhanced ultraviolet B exposure, may have important clinical implications for HIV-1-infected patients.

Clonal selection of T lymphocytes infected by cell-free human T-cell leukemia/lymphoma virus type I: Parameters of virus integration and expression

We have successfully transmitted cell-free HTLV-I to normal cord blood and peripheral blood lymphocytes and have exploited this system to study the kinetics of infection and transformation of these cells. Transmission was successful in 4 out of 23 attempts. In all 4 cases, the infected cells progressed from an initial stage of polyclonality to predominantly monoclonal cells within 4-6 weeks. Both complete and defective proviruses were transmitted to the recipient cells initially, but cells with a complete provirus were preferentially maintained. The monoclonally infected cells have persisted in culture for more than 6 months and may be considered immortalized. Expression of core antigens as detected by immunoflourescence and the reverse transcriptase activity in the medium at least in one case was not observed until weeks after the cells had become monoclonal, suggesting that expression of virus or viral structural proteins is not necessary for selected growth of the infected cells in vitro.

Concordance of human leukocyte antigen haplotype-sharing, CD4 decline and AIDS in hemophilic siblings. Multicenter Hemophilia Cohort and Hemophilia Growth and Development Studies.

Objective: To assess the association between human leukocyte antigen (HLA) haplotypes and the incidence rates of CD4 decline to < 20% and to AIDS. Design: Retrospective cohort study of 95 HIV‐1‐infected hemophilic sibling pairs. Methods: HLA haplotype‐sharing between siblings was assigned on the basis of serologic typing of HLA class I alleles and molecular typing of HLA class II alleles. Concordance of time to CD4 decline to < 20% and to AIDS within and between sibling pairs was assessed by analysis of variance models and calculations of intraclass correlation coefficients. The age‐adjusted relative risks of these two endpoints for unique class II haplotypes were determined from proportional hazards models. Results: Sibling pairs sharing one or two haplotypes were significantly concordant in CD4 decline and AIDS status within 5 years of seroconversion. No concordance was found in pairs sharing zero haplotypes. At 6‐10 years after seroconversion, significant concordance of these two endpoints was also observed in the pairs sharing one haplotype. The concordant results were not explained by the use of zidovudine within the pairs. Among the individuals in this cohort, the relative hazards for CD4 decline to < 20% and for AIDS were significantly elevated for one class II haplotype (DQB1*0501, DQA1*0101, DRB1*0101). In addition, the risk for AIDS was significantly increased for two other class II haplotypes (DQB1*0603, DQA1*0103, DRB1*1300, DRB3*0202 and DQB1*0301, DQA1*0501, DRB1*1400, DRB3*0202) and significantly decreased for one haplotype (DQB1*0302, DQA1*0301, DRB1*0401, DRB4*0101). Conclusions: These data demonstrate that HIV‐1 disease progression is associated with the genes in the major histocompatibility complex that regulate the hosts immune response.