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Primary immunodeficiency (PI) diseases are a group of primarily single-gene disorders of the immune system. Approximately 100 separate PI diseases have been described, but <20 probably account for >90% of cases. Although diverse, PI diseases share the common feature of susceptibility to infection and result in substantial morbidity and shortened life spans. Most important, prompt diagnosis and treatment can now lead to life-saving treatment and result in marked improvements in the quality and length of life for persons with PI diseases. In November 2001, a workshop was convened by CDC in Atlanta, Georgia, to discuss ways to improve health outcomes among persons with PI disease. A multidisciplinary panel of persons knowledgeable in PI diseases and public health met to identify and discuss public health strategies that can be applied to PI diseases and possibly for other genetic disorders. A systematic assessment based on the established public health framework was applied to the growing group of PI diseases, whose diverse genetic mutations span multiple components of the immune system but all lead to increased incidence and severity of infections. During the meeting, specialists in clinical immunology, public health, genetics, pediatrics, health communication, and ethics from state and federal agencies, academic centers, professional organizations, and advocacy foundations discussed the four components of the public health framework as they relate to PI diseases. These four components include 1) public health assessment (application of traditional public health methods to assess the occurrence and impact of PI diseases on communities); 2) population-based interventions (development, implementation, and evaluation of screening tests administered to newborns and clinical algorithms for early recognition of symptomatic persons to facilitate the earliest possible diagnosis and treatment for PI diseases); 3) evaluation of screening and diagnostic tools (to ensure their quality and appropriateness for identification of patients with PI diseases); and 4) communication (communication with and information dissemination to health-care providers and the public to facilitate prompt and appropriate diagnosis and intervention). The working group's deliberations focused on challenges and opportunities, priority research questions, and recommendations for future action for these four components. These recommendations, developed by workshop participants, will be useful to medical and public health professionals who are evaluating methods to increase recognition of PI diseases and other genetic disorders. [ABSTRACT FROM AUTHOR]

The recent Ebola virus outbreak in West Africa clearly demonstrated the critical role of laboratory systems and networks in responding to epidemics. Because of the huge challenges in establishing functional laboratories at all tiers of health systems in developing countries, strengthening specimen referral networks is critical. In this review article, we propose a platform strategy for developing specimen referral networks based on 2 models: centralized and decentralized laboratory specimen referral networks. These models have been shown to be effective in patient management in programs in resource-limited settings. Both models lead to reduced turnaround time and retain flexibility for integrating different specimen types. In Haiti, decentralized specimen referral systems resulted in a 182% increase in patients enrolling in human immunodeficiency virus treatment programs within 6 months. In Uganda, cost savings of up to 62% were observed with a centralized model. A platform strategy will create a network effect that will benefit multiple disease programs., (Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: During 2004-2009, >12,000 children (<15 years old) initiated antiretroviral therapy (ART) in Mozambique. Nationally representative outcomes and temporal trends in outcomes were investigated., Methods: Rates of death, loss to follow-up (LTFU) and attrition (death or LTFU) were evaluated in a nationally representative sample of 1054 children, who initiated ART during 2004-2009 at 25 facilities randomly selected using probability-proportional-to-size sampling., Results: At ART initiation during 2004-2009, 50% were male; median age was 3.3 years; median CD4% was 13%; median CD4 count was 375 cells/μL; median weight-for-age Z score was -2.1. During 2004-2009, median time from HIV diagnosis to care initiation declined from 33 to 0 days (P = 0.001); median time from care to ART declined from 93 to 62 days (P = 0.004); the percentage aged <2 at ART initiation increased from 16% to 48% (P = 0.021); the percentage of patients with prior tuberculosis declined from 50% to 10% (P = 0.009); and the percentage with prior lymphocytic interstitial pneumonia declined from 16% to 1% (P < 0.001). Over 2652 person-years of ART, 183 children became LTFU and 26 died. Twelve-month attrition was 11% overall but increased from 3% to 22% during 2004-2009, mainly because of increases in 12-month LTFU (from 3% to 18%)., Conclusion: Declines in the prevalence of markers of advanced HIV disease at ART initiation probably reflect increasing ART access. However, 12-month LTFU increased during program expansion, and this negated any program improvements in outcomes that might have resulted from earlier ART initiation.

Background: Measurement of CD4+ T-lymphocytes (CD4) is a crucial parameter in the management of HIV patients, particularly in determining eligibility to initiate antiretroviral treatment (ART). A number of technologies exist for CD4 enumeration, with considerable variation in cost, complexity, and operational requirements. We conducted a systematic review of the performance of technologies for CD4 enumeration., Methods and Findings: Studies were identified by searching electronic databases MEDLINE and EMBASE using a pre-defined search strategy. Data on test accuracy and precision included bias and limits of agreement with a reference standard, and misclassification probabilities around CD4 thresholds of 200 and 350 cells/μl over a clinically relevant range. The secondary outcome measure was test imprecision, expressed as % coefficient of variation. Thirty-two studies evaluating 15 CD4 technologies were included, of which less than half presented data on bias and misclassification compared to the same reference technology. At CD4 counts <350 cells/μl, bias ranged from -35.2 to +13.1 cells/μl while at counts >350 cells/μl, bias ranged from -70.7 to +47 cells/μl, compared to the BD FACSCount as a reference technology. Misclassification around the threshold of 350 cells/μl ranged from 1-29% for upward classification, resulting in under-treatment, and 7-68% for downward classification resulting in overtreatment. Less than half of these studies reported within laboratory precision or reproducibility of the CD4 values obtained., Conclusions: A wide range of bias and percent misclassification around treatment thresholds were reported on the CD4 enumeration technologies included in this review, with few studies reporting assay precision. The lack of standardised methodology on test evaluation, including the use of different reference standards, is a barrier to assessing relative assay performance and could hinder the introduction of new point-of-care assays in countries where they are most needed.

Estimation of HIV-1 incidence is an important public health tool for understanding the status of the epidemic, identifying high-risk populations, and assessing various intervention strategies. Several laboratory-based methods have been developed for distinguishing recent from long-term HIV-1 infection; however, each exhibits some degree of misclassification, particularly among AIDS patients and those taking antiretroviral therapy (ART). To improve upon the limitations associated with measuring responses to a single analyte, we have developed a bead-based, multiplex assay for determination of HIV recent infection based on total antibody binding and antibody avidity to multiple analytes. An HIV-specific, multiplex panel was created by coupling the recombinant HIV-1 proteins p66, gp120, gp160, and gp41 to Bio-Plex COOH microspheres. Longitudinal plasma specimens from recent seroconverters were tested for reactivity to the coupled microspheres using the Bio-Plex 200 System. For each analyte, HIV-specific antibody binding and avidity increased for 1-2 years post-seroconversion, leading to a significant difference in reactivity between recent and long-term specimens. While the potential for misclassification of individuals diagnosed with AIDS or receiving ART appears to be minimal with avidity measures, the impact on total antibody binding was variable, depending on the individual analyte. This bead-based, HIV-specific multiplex assay measures several distinct immune responses in a single assay plate, allowing for sampling of multiple analytes in the determination of recent infection, which could aid in the development of improved statistical methods or algorithms that will more accurately estimate HIV incidence.

HIV-1 group M subtype B was the first HIV discovered and is the predominant variant of AIDS virus in most countries outside of sub-Saharan Africa. However, the circumstances of its origin and emergence remain unresolved. Here we propose a geographic sequence and time line for the origin of subtype B and the emergence of pandemic HIV/AIDS out of Africa. Using HIV-1 gene sequences recovered from archival samples from some of the earliest known Haitian AIDS patients, we find that subtype B likely moved from Africa to Haiti in or around 1966 (1962-1970) and then spread there for some years before successfully dispersing elsewhere. A "pandemic" clade, encompassing the vast majority of non-Haitian subtype B infections in the United States and elsewhere around the world, subsequently emerged after a single migration of the virus out of Haiti in or around 1969 (1966-1972). Haiti appears to have the oldest HIV/AIDS epidemic outside sub-Saharan Africa and the most genetically diverse subtype B epidemic, which might present challenges for HIV-1 vaccine design and testing. The emergence of the pandemic variant of subtype B was an important turning point in the history of AIDS, but its spread was likely driven by ecological rather than evolutionary factors. Our results suggest that HIV-1 circulated cryptically in the United States for approximately 12 years before the recognition of AIDS in 1981.

Persons occupationally exposed to nonhuman primates (NHPs) can be persistently infected with simian foamy virus (SFV). The clinical significance and person-to-person transmissibility of zoonotic SFV infection is unclear. Seven SFV-infected men responded to annual structured interviews and provided whole blood, oral, and urogenital specimens for study. Wives were tested for SFV infection. Proviral DNA was consistently detected by PCR in PBMCs of infected men and inconsistently in oral or urogenital samples. SFV was infrequently cultured from their PBMCs and throat swabs. Despite this and a long period of intimate exposure (median 20 years), wives were SFV negative. Most participants reported nonspecific symptoms and diseases common to aging. However, one of two persons with mild thrombocytopenia had clinically asymptomatic nonprogressive, monoclonal natural killer cell lymphocytosis of unclear relationship to SFV. All participants worked with NHPs before 1988 using mucocutaneous protection inconsistently; 57% described percutaneous injuries involving the infecting NHP species. SFV likely transmits to humans through both percutaneous and mucocutaneous exposures to NHP body fluids. Limited follow-up has not identified SFV-associated illness and secondary transmission among humans.

Objective: We present the largest longitudinal study to date that examines the association between Kaposi's Sarcoma (KS) disease progression and the presence and viral load of human herpesvirus 8 (HHV-8)., Methods: Ninety-six men were enrolled at HIV clinics in Atlanta, Georgia, who had KS (n = 47) or were without KS but seropositive for HHV-8. Visits occurred at 6-month intervals for 2 years at which the patient's KS status was evaluated and oral fluid and blood were collected for quantification of HHV-8 DNA and antibodies., Results: The presence of HHV-8 DNA in blood was more common (P < 0.001) and the viral load higher (P < 0.001) in men with KS in comparison with men without KS. Mean HHV-8 viral loads in blood and oral fluids were associated with disease status, being highest among patients with progressing KS, intermediate among patients with stable KS, and lowest among patients with regressing KS. Consistent with our previous report high antibody titers to HHV-8 orf 65 were inversely associated with HHV-8 shedding in oral fluid., Conclusions: We observed a significant association between changes in KS disease severity and the presence and viral load of HHV-8. HHV-8 viral load in blood may provide useful information to clinicians for assessment of the risk of further disease progression in patients with KS.

To examine trends in HIV prevalence in the US household population, serum or urine samples from 2 National Health and Nutrition Examinations Surveys (NHANES) (1988-1994 and 1999-2002), were tested for HIV antibody. In the 1999 to 2002 survey, data on risk behaviors, CD4 T lymphocytes, and antiretroviral therapy (ART) were also available. In the 1988 to 1994 survey, there were 59 positive individuals of 11,203 tested. In NHANES 1999 to 2002, there were 32 positive individuals of 5926 tested. The prevalence of HIV infection among those aged 18 to 39 years in NHANES 1988 to 1994 was 0.38% (95% confidence interval [CI]: 0.22-0.68) as compared with 0.37% (95% CI: 0.17 to 0.80) in 1999 to 2002. Prevalence did not change significantly between surveys in any race and/or ethnic or gender group among 18- to 39-year-old participants. HIV prevalence was 3.58% (95% CI: 1.88 to 6.71) among non-Hispanic blacks in the 40- to 49-year-old age group in 1999 to 2002, but the age range available in NHANES 1988 to 1994 was 18 to 59 years and does not allow direct comparison of prevalence. Cocaine use and the presence of herpes simplex virus-2 antibody were the only significant risk factors for HIV infection for non-Hispanic blacks. Fifty-eight percent of infected individuals not reporting ART had CD4 T-lymphocyte counts < 200 cells/mm3 compared with 18.2% on therapy and 12.5% of participants newly informed of their HIV status.

Use of the standard dual-platform flow cytometric method for determination of CD4(+) T-lymphocyte counts, which needs both a flow cytometer (FCM) and hematological analyzer, would inevitably lead to increased variability. The development of new single-platform (SP) FCMs that provide direct CD4(+) T-lymphocyte counts for improved assay precision and accuracy have recently attracted attention. This study evaluated one of those systems, CyFlow(green) (Partec), a single-parameter SP volumetric FCM. The performance of CyFlow(green) was compared with those of two reference standard SP microbead-based technologies of the three-color TruCOUNT tube with the FACScan FCM and a two-color FACSCount system (Becton Dickinson Biosciences). Absolute CD4(+) and CD8(+) T-lymphocyte counts in 200 human immunodeficiency virus type 1-seropositive blood specimens were determined. Statistical analysis for correlation and agreement were performed. A high correlation of absolute CD4 counts was shown when those obtained with CyFlow(green) were compared with those obtained with the bead-based three-color TruCOUNT system (R(2)=0.96; mean bias, -69.1 cells/microl; 95% confidence interval [CI], -225.7 to+87.5 cells/microl) and the FACSCount system (R(2)=0.97; mean bias, -40.0 cells/microl; 95% CI, -165.1 to+85.1 cells/microl). The correlation of the CD4(+) T-lymphocyte counts obtained by the two bead-based systems was high (R(2)=0.98). Interestingly, CyFlow(green) yielded CD4(+) T-lymphocyte counts that were 21.8 and 7.2 cells/microl lower than those obtained with the TruCOUNT and the FACSCount systems, respectively, when CD4(+) T-lymphocyte counts were <250 CD4(+) T-lymphocyte counts/microl range or 17.3 and 5.8 cells/microl less, respectively, when CD4(+) T-lymphocyte counts were <200 cells/microl. The single-parameter CyFlow(green) volumetric technology performed well in comparison with the performance of the standard SP bead-based FCM system. However, a multicenter comparative study is needed before this FCM machine is implemented in resource-limited settings.

The combination of unique single nucleotide polymorphisms in the CCR5 regulatory and in the CCR2 and CCR5 coding regions, defined nine CCR5 human haplogroups (HH): HHA-HHE, HHF*1, HHF*2, HHG*1, and HHG*2. Here we examined the distribution of CCR5 HH and their association with HIV infection and disease progression in 36 HIV-seronegative and 76 HIV-seropositive whites from North America and Spain [28 rapid progressors (RP) and 48 slow progressors (SP)]. Although analyses revealed that HHE frequencies were similar between HIV-seronegative and HIV-seropositive groups (25.0% vs. 32.2%, p > 0.05), HHE frequency in RP was significantly higher than that in SP (48.2% vs. 22.9%, p = 0.002). Survival analysis also showed that HHE heterozygous and homozygous were associated with an accelerated CD4 cell count decline to less than 200 cells/microL (adjusted RH 2.44, p = 0.045; adjusted RH = 3.12, p = 0.037, respectively). These data provide further evidence that CCR5 human haplogroups influence HIV-1 disease progression in HIV-infected persons.

To address whether human herpesvirus 8 (HHV-8) DNA in peripheral blood mononuclear cells (PBMCs) might be the product of latent or lytic infection and to shed light on sporadic detection of HHV-8 DNA in individuals seropositive for the virus, we studied the frequency of infected cells, total virus load, and virus load per infected cell in PBMCs from men coinfected with HHV-8 and human immunodeficiency virus (HIV), some of whom had Kaposi's sarcoma. The low frequencies of infected cells detected (fewer than one per million cells in some individuals) suggest that the prevalence of the virus in circulating leukocytes was underestimated in previous studies that employed more conventional sampling methods (single, small-volume specimens). Mean virus loads ranged from 3 to 330 copies per infected PBMC; these numbers can represent much higher loads in individual lytically infected cells (>10(3) genomes/cell) in mixtures that consist predominantly of latently (relatively few genomes) infected cells. The presence in some subjects of high HHV-8 mean genome copy numbers per infected cell, together with viral DNA being found in plasma only from subjects with positive PBMCs, supports earlier suggestions that the virus can actively replicate in PBMCs. In some individuals, mean virus loads were less than 10 genomes per infected cell, suggesting a tightly controlled purely latent state. HHV-8 genome copy numbers are substantially higher in latently infected cells derived from primary effusion lymphomas; thus, it appears that HHV-8 is able to adopt more than one latency program, perhaps analogous to the several types of Epstein-Barr virus latency.

Objective: To study the natural history and pathogenesis of human herpesvirus 8 (HHV-8) infection in HHV-8-seropositive, immunosuppressed men., Design: Longitudinal study of 87 HHV-8- and HIV-seropositive men [42 with Kaposi's sarcoma (KS)] during four visits over a 2 month period., Methods: : Patients provided oral fluid and blood. HHV-8 antibody titers were measured with peptide-based enzyme-linked immunosorbent assays (ELISA) for ORF65 and K8.1; HHV-8 DNA was detected with polymerase chain reaction ELISA., Results: HHV-8 DNA was present in oral fluid or peripheral blood mononuclear cells (PBMC) at one or more of the four visits in 71% of men with KS and 56% of men without KS. The strongest correlate of HHV-8 DNA in PBMC was the presence of KS [odds ratio (OR), 8.7; 95% confidence interval (CI), 3.4-22]. Detection of HHV-8 DNA in oral fluid or PBMC was often intermittent, but individuals who shed virus at one time point were more likely to shed at other times. Some men had incomplete epitope recognition in their anti-HHV-8 antibody response. High antibody titers were associated with the absence of circulating HHV-8, particularly for the ORF65 seroassay (OR, 0.16; 95% CI, 0.05-0.51)., Conclusions: Among HHV-8 seropositive men, circulating virus is common even in the absence of disease. The link between KS and HHV-8 DNA in PBMC suggests that anti-herpes drugs may impede KS development or progression. Seroassays should target multiple epitopes to achieve maximal sensitivity. HHV-8 replication may be limited by high antibody titers or other immune function for which antibodies are a marker.

Human herpesvirus 8 (HHV-8) is the etiologic agent of Kaposi's sarcoma (KS). Several studies indicate horizontal HHV-8 transmission among children in areas where KS is endemic, but few studies have assessed acquisition of HHV-8 by children in low seroprevalence areas. Antibody screening was carried out for HHV-8 and Epstein-Barr virus (EBV) on 787 serum specimens from children living in two areas where HHV-8 is not endemic, the United States (US) and Germany, and on 184 specimens from children living in a KS-endemic area (Nigeria). For children in the US and Germany, the results showed low HHV-8 seroprevalence rates (3-4%). However, US children aged 6 months to 5 years had higher HHV-8 antibody titers than did 6-17-year-old children (P < 0.01), a finding consistent with more recent infections being detected in the younger children. Compared with seroprevalence rates and antibody titers in US and German children, those in Nigerian children were significantly higher, and seroprevalence increased with age. There was no evidence of cross-reactivity between assays for HHV-8 and EBV, despite the genetic similarity of these two herpesviruses. The data indicate that HHV-8 transmission among children where HHV-8 is not endemic occurs, but is uncommon. The findings also suggest that HHV-8 antibodies, as measured by current tests, may not persist for long periods in populations at low risk for KS and that vertical transmission is rare, although longitudinal studies are necessary to address directly these issues., (Copyright 2004 Wiley-Liss, Inc.)

Objective: To identify risk factors for Kaposi's sarcoma (KS) among men seropositive for both human herpesvirus 8 (HHV-8) and HIV., Design: Cross-sectional study of 91 HHV-8 seropositive, HIV seropositive men who have sex with men (57 with KS), and 70 controls at lower risk for KS., Methods: Patients received clinical evaluations. Blood, oral fluids, semen, rectal brush, rectal swab, and urine were collected, and tests for HHV-8 were performed., Results: Men with KS were more likely to have HHV-8 DNA in peripheral blood mononuclear cells (PBMC) than men without KS [35.1 versus 5.9%, odds ratio (OR), 8.6, 95% confidence interval (CI), 1.9-39.9]. The prevalence of HHV-8 DNA in oral fluids was similar for the two groups (37.0 versus 32.4%; OR, 1.2; 95% CI, 0.5-3.0). HHV-8 DNA was rarely detected in specimens of other types from these men, or in any specimens from the 70 controls. Among men with KS, HHV-8 DNA in PBMC was associated with new KS lesions (OR, 4.5; 95% CI, 1.4-14.5), and HHV-8 DNA in oral fluids was associated with oropharyngeal KS lesions (OR, 3.1; 95% CI, 1.0-10.1). Men with high HHV-8 antibody titers were more likely to have KS (OR, 9.6; 95% CI, 1.2-78.2), but were less likely to have new KS lesions (OR, 0.2; 95% CI, 0.0-1.1) or HHV-8 DNA in PBMC (OR, 0.2; 95% CI, 0.0-1.6) or oral fluids (OR, undefined; = 0.001)., Conclusions: In HHV-8- and HIV-seropositive men, HHV-8 DNA is associated with KS. Among men without KS, HHV-8 DNA is most commonly found in oral fluids. High HHV-8 antibody titers may protect against circulating HHV-8 and new KS lesions.

The immunodominant region of the human herpesvirus 8 (HHV-8), the antibody-binding site of glycoprotein K8.1A, was mapped to the N-terminal region by using overlapping peptides and a residue replacement method. The main epitope was located within residues 44 to 56 (GQVYQDWL----C). Based on this information, we developed an enzyme immunoassay to detect HHV-8 antibodies in human sera using a four-branch multiple antigenic peptide as the antigen. The sensitivity and specificity of the assay were 96 and 99.4%, respectively. This assay should be useful for population-based, epidemiological studies of HHV-8 infection.

Improvement of serologic assays for detection of antibodies against human herpesvirus 8 (HHV-8) is critical to better understand its epidemiology and biology. We produced the HHV-8 latent (ORF73) and lytic (ORF65, K8.1, and glycoprotein B) antigens in the Semliki Forest virus system and evaluated their performance in immunofluorescence assays (IFAs) and enzyme-linked immunosorbent assays (ELISAs). These assays were compared with other latent antigen-based assays, including an IFA based on primary effusion lymphoma (PEL) cells and an ELISA based on bacterially expressed ORF73 antigen, as well as with other lytic antigen-based assays, including an IFA based on induced PEL cells, a commercial ELISA based on purified virions, and ELISAs based on K8.1- and ORF65-derived oligopeptides. We used a panel of 180 serum specimens obtained from three groups expected to have high, intermediate, and low HHV-8 prevalences. Using three different evaluation methods, we found that (i) the performances of the lytic antigen-based ELISAs were almost equivalent, (ii) the lytic antigen-based assays were more sensitive than the latent antigen-based assays, and (iii) in general, IFAs were more sensitive than ELISAs based on the same open reading frame. We also found that serum specimens from healthy individuals contained antibodies cross-reactive with HHV-8 glycoprotein B that can potentially cause false-positive reactions in lytic PEL-based IFAs. Although this is not a substantial problem in most epidemiologic studies, it may confound the interpretation of data in studies that require high assay specificity. Because the K8.1-based IFA provides sensitivity similar to that of lytic PEL-based IFAs and improved specificity, it can be a useful alternative to the PEL-based IFAs.

A variety of assays for the diagnosis human herpesvirus 8 (HHV-8) infection have been reported. We compared several such assays with a panel of 88 specimens from human immunodeficiency virus (HIV)-infected patients with Kaposi's sarcoma (KS) (current-KS patients; n = 30), HIV-infected patients who later developed KS (later-KS patients; n = 13), HIV-infected patients without KS (no-KS patients; n = 25), and healthy blood donors (n = 20). PCR assays were also performed with purified peripheral blood mononuclear cells (PBMCs) to confirm positive serologic test results. The order of sensitivity of the serologic assays (most to least) in detecting HHV-8 infection in current-KS patients was the mouse monoclonal antibody-enhanced immunofluorescence assay (MIFA) for lytic antigen (97%), the orfK8.1 peptide enzyme immunoassay (EIA) (87%), the orf65 peptide EIA (87%), MIFA for latent antigen (83%), the Advanced Biotechnologies, Inc., EIA (80%), and the orf65 immunoblot assay (80%). Combination of the results of the two peptide EIAs (combined peptide EIAs) increased the sensitivity to 93%. For detection of infection in later-KS patients, the MIFA for lytic antigen (100%), the orfK8.1 peptide EIA (85%), and combined peptide EIAs (92%) were the most sensitive. Smaller percentages of no-KS patients were found to be positive (16 to 56%). Most positive specimens from the current-KS and later-KS groups were positive by multiple assays, while positive specimens from the no-KS group tended to be positive only by a single assay. PCR with PBMCs for portions of the HHV-8 orf65 and gB genes were positive for less than half of current-KS and later-KS patients and even fewer of the no-KS patients. The concordance between serologic assays was high. We propose screening by the combined peptide EIAs. For specimens that test weakly positive, we recommend that MIFA for lytic antigen be done. A positive result with a titer of >/=1:40 would be called HHV-8 positive. A negative or low titer would be called HHV-8 negative. If a population has a high percentage of persons who test positive by the combined peptide EIAs, then a MIFA could be performed with the negative specimens to determine if any positive specimens are being missed. Alternatively, if a population has a low percentage that test positive, then a MIFA could be performed with a subset of the negative specimens for the same reason. As described above, only a titer of >/=1:40 would be considered HHV-8 positive.

Objectives: To determine the molecular nature of HIV-1 quasispecies and their evolution, in vivo over time, in an American cohort of 22 homosexual men [four rapid progressors (RP), 15 slow progressors (SP) and three long-term non-progressors (LTNP)], infected with HIV-1 between 1982 and 1983, and to assess the possible role of the HIV-1 V2 region extension in HIV disease progression., Design: Genetic and phylogenetic analyses of the V3 region and the nef gene clones over time from uncultured peripheral blood mononuclear cells (PBMC) of American patients with varying HIV disease progression rates., Methods: Proviral DNA from longitudinally collected uncultured PBMC were subjected to PCR amplification in the nef gene and env V2 and V3 regions, followed by cloning, sequencing and phylogenetic analysis to establish evolutionary relationships between HIV-1 strains over time., Results: Analysis of multiple viral clones showed nef gene deletions/insertions in 10 out of 15 SP, along with the coexistence of intact and defective nef gene lineages in the same individual over time, whereas these nefgene abnormalities were absent from HIV-1 strains from LTNP. Increasing quasispecies diversity in HIV-1 strains, over time, abrogation of a V3 region N-linked glycosylation site in > 60% of the clones, and, importantly, an extended V2 region were unique features of HIV-1 strains from SP and LTNP., Conclusions: The V2 region extension was unique to only SP and LTNP, and so may have a role in slow progression or non-progression of HIV disease. Increasing genetic diversity in HIV-1 strains in SP and LTNP correlated with the immunocompetent status of the host.

Persons who were human immunodeficiency virus type 1 (HIV-1)-infected but who remained persistently seronegative (HIPS) on HIV-1 antibody tests were examined through AIDS case surveillance. Six such individuals (HIPS-1 to -4, -7, and -9) were examined to determine whether their persistent seronegativity was attributable to immune dysfunction or infection with atypical HIV. Of the 6, 4 had antibody titers to at least 1 other common pathogen. In vitro stimulation of peripheral blood mononuclear cells from HIPS-4 and HIPS-7 with pokeweed mitogen or phosphorothioate oligodeoxynucleotide (direct B cell mitogen) did not produce HIV-1-specific antibody. Reconstitution experiments with recombinant interleukin (rIL)-4 and rIL-12 also had no impact on antibody production. Virus isolates from HIPS-4 and -9 were R5X4-tropic, whereas HIPS-7 was CCR5-tropic only. Sequence analysis of long terminal repeat, p24, and env gp41 did not reveal any specific mutation, and phylogenetic analysis confirmed that all 6 virus specimens were HIV-1 subtype B. These data suggest that the lack of a detectable antibody response in these patients may be the result of immune dysfunction.

To study human herpesvirus 8 (HHV-8) transmission between individuals and in populations, we developed a system for genetic fingerprinting of HHV-8 strains based on variation in the HHV-8 K1, glycoprotein B (gB), and glycoprotein H (gH) genes. Using this system, we sequenced nearly the entire K1 gene (840 bp); two segments of the gB gene (open reading frame 8), totaling 813 bp; and a 702-bp segment of the gH gene (open reading frame 22) from blood and tissue samples obtained from 40 human immunodeficiency virus-infected and noninfected individuals, including those with Kaposi's sarcoma, primary effusion lymphoma, or Castleman's disease. The specimen collection was assembled from individuals living in diverse geographical locations, including the United States, Australia, New Zealand, Uganda, and Zambia. As reported by others, K1 was the most variable gene, with up to 16% variation at the nucleotide sequence level and up to 32% variation at the amino acid sequence level. Despite this extensive sequence variation, the K1 amino acid sequence contained 14 conserved cysteine sites, suggesting a conserved tertiary structure. gB and gH sequences were highly conserved, in most cases differing by <0.6% in pairwise comparisons. K1 was the most useful gene for strain discrimination, but the other genes enabled the discrimination of strains with identical K1 sequences. Individuals from diverse geographic locations were infected with four different HHV-8 genotypes; strains did not strictly segregate by continent of origin. The majority of HHV-8 strains from the United States and Europe were relatively closely related, whereas some strains identified from Uganda and Australia were phylogenetically distant. Genotype I strains were the most common and were found on three continents. Identical sequences were found in specimens obtained from different body sites and at different times from the same individual., (Copyright 1999 Academic Press.)

Reported prevalences of human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus) in semen have ranged widely. This is possibly due to differences in assay sensitivity, geographic or population-based differences in the true presence of the virus in semen, and PCR contamination. This study assessed interlaboratory sensitivity and reproducibility in the analysis of blinded experimental panels, each consisting of 48 specimens and being composed of semen specimens from different healthy artificial-insemination donors (n = 30) and human immunodeficiency virus (HIV)-infected patients (n = 7) plus positive (n = 4) and negative (n = 7) controls. The experimental panels analyzed in each laboratory were identical except for being independently coded. Of 10 experiments done in five laboratories, 5 experiments from three laboratories had evidence of PCR contamination; all instances of contamination were in the context of nested PCR procedures. In the experiments with no false-positive results, HHV-8 DNA was detected in three (8%) of the 37 semen specimens (two from artificial-insemination donors and one from an HIV-positive patient) but in only 3 (1.6%) of the 184 PCRs in which these specimens were analyzed. This suggests that HHV-8 DNA is present in semen at concentrations that can be too low to allow its consistent detection. This study emphasizes the importance of performing blinded, multi-institution experiments to provide a coherent basis for comparing results and to motivate standardization of methods.

Objective: To study coreceptor usage of sequential primary HIV-1 isolates in a longitudinal follow-up cohort of HIV-1-infected men to understand its contribution to pathogenesis of HIV disease., Design: Viral coreceptor usage of sequential primary isolates from HIV-1-infected individuals was examined at various timepoints and data was compared with CD4 cell counts, rates of disease progression and beta-chemokine production., Methods: Fifty-eight sequential primary isolates were obtained from four rapid progressors, six late progressors, and three long-term nonprogressors (LTNP) and their coreceptor usage was examined by infection of peripheral blood mononuclear cells (PBMC) from donors with wild-type or non-functional CC-chemokine receptor (CCR)-5, and by infection of GHOST4 cells expressing CD4 and various chemokine receptors [CCR-1-CCR-5, CXC-chemokine receptor (CXCR)-4, BOB/GPR15, BONZO/STRL33]. Production of RANTES and macrophage inflammatory protein (MIP)-1beta was examined using unstimulated or phytohemagglutinin (PHA)-stimulated PBMC isolated from these individuals at multiple timepoints during infection., Results: A switch from single CCR-5 coreceptor usage to multiple coreceptor usage occurred in all four rapid progressors and three out of six late progressors. In addition to the commonly used coreceptors CXCR-4, CCR-5, and CCR-3, some of the viruses isolated from patients in the terminal stage of infection also used CCR-1, CCR-2b, CCR-4, and BOB as coreceptors. The emergence of viral variants capable of utilizing multiple coreceptors generally preceded CD4 cell decline to < 200 x 10(6)/l and correlated with the onset of AIDS. In contrast, three LTNP maintained exclusive usage of CCR-5 over a period of 7-12 years post-infection. Endogenous production of RANTES and MIP-1beta by PBMC from LTNP was not significantly different from rapid and late progressors. However, PHA-driven production of both chemokines was significantly higher in LTNP, suggesting that in vivo activating stimuli might curtail HIV replication by inducing these chemokines., Conclusions: Viral variants capable of utilizing a broad range of coreceptors correlated with HIV-1 disease progression. In contrast, LTNP maintain exclusive usage of CCR-5 and produce higher levels of beta-chemokines. Thus, both viral and host determinants leading to the emergence of viral variants capable of using an expanded range of coreceptors may be likely determinants of disease progression.

A dominant epitope within the human herpesvirus 8 (HHV8) ORF 65-encoded protein was mapped to an 8-amino-acid (aa) sequence (RKPPSGKK [aa 162 to 169]) by an amino acid replacement method. Using a 14-aa peptide (P4) encompassing this epitope as the antigen, we developed an enzyme immunoassay for HHV8 antibodies. The presence of P4 antibodies in a panel of 61 human serum specimens was highly correlated with biopsy-confirmed Kaposi's sarcoma. The homologous Epstein-Barr virus peptide derived from BFBR3-encoded protein did not interfere with the assay, suggesting that P4 is specific for HHV8.

The relevance of a TNF-alpha promoter polymorphism, a G-to-A polymorphic sequence at position-308, was examined to test whether variant alleles of TNF-alpha affect susceptibility to infection with HIV-1 and progression to AIDS. Analysis of specimens from cohorts of HIV-1 positive homosexual men demonstrated that 3 of the 32 (9.4%) HIV-1-infected long-term nonprogressors (LTNPs) were homozygous for the uncommon TNF-2 allele compared with 3 of the 196 (1.5%) HIV-1-seronegative blood donors and uninfected homosexual men (p < 0.05). There was no difference in heterozygosity among HIV-1-seropositive or -seronegative groups, although some of the seropositive men heterozygous for the TNF2 genotype were also heterozygous for CCR5delta32. However, no significant association was found between TNF genotypes and time of survival, CD4 slopes, or viral loads when seroincident (n = 109) and seroprevalent cases (n = 442) from the Chicago MACS were analyzed. Functional analysis of lymphocytes from the seronegative group revealed no difference in endogenous or mitogen-induced TNF-alpha production, as well as susceptibility to in vitro HIV-1 infection between different TNF-genotype donors. These data suggest that TNF genotypes do not play a direct role in HIV-1 disease progression; however, they could potentially be part of a multigenic linkage that may be involved in delaying progression to AIDS.

HIV-1 produces more than 20 mRNAs encoding the viral proteins. We have used a sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) approach to determine HIV-1 transcriptional patterns during the course of viral infection in unstimulated peripheral blood mononuclear cells (PBMCs) from different patients. Several sets of PCR primers, used in parallel reactions, allowed the amplification and specific detection of almost all individual HIV-1 transcripts. We investigated the transcriptional profile in two individuals during primary acute and early chronic infection. In these individuals, HIV-1 mRNA expression was elevated at the first time points examined and declined over time. In addition, we performed a detailed study of HIV-1 expression in several individuals over a minimum of 7 years following seroconversion. We found that long-term asymptomatic individuals had undetectable or low levels of the three classes of HIV-1 transcripts (unspliced, singly spliced, and multiply spliced). Individuals who demonstrated disease progression showed either a general increase in the amount of expression of all transcripts or elevated levels of unspliced transcripts in late-stage disease. The splicing pattern in each patient was conserved over the years and differed among the different individuals. No evidence of major changes in the splicing pattern was found during disease progression within the same individual. Thus, HIV-1 transcriptional patterns are viral strain specific rather than disease stage specific. These results indicate that high-level expression of any class of HIV-1 transcripts is associated with clinical progression. Our analysis also demonstrates the importance of using more than one set of primers to evaluate HIV-1 RNA expression, since virus in patient PBMCs showed sequence heterogeneity in conserved regions.

An assay for the neutralization of human immunodeficiency virus type 1 (HIV-1) is described in which the reduction in infectious titer of HIV-1 after preincubation at 37 degrees C with antibody-positive serum is the measure of neutralization. The assay format and its controls allow several experimental manipulations that, taken together, indicate an effect of antibody on HIV-1 infectivity that occurs before or independently of HIV-1 attachment. The direct inactivation of HIV-1 infectivity by antibody is irreversible and temperature dependent, requires a bivalent antibody directed against accessible envelope determinants, and does not require a heat-labile or (Ca2+)- or (Mg2+)-dependent cofactor. The mechanism of inactivation cannot be explained by agglutination of virus, nor is it associated with disruption or dissociation of envelope protein from virions. Rather, the antibody is likely to perturb some metastable property of the envelope that is required for entry. Laboratory-adapted HIV-1 isolates were more sensitive to the inactivating effects of sera than were primary patient isolates. The latter were particularly resistant to inactivation by contemporary autologous sera, a feature not explained by blocking antibodies. Additional studies showed a weak relationship between disease course and serum inactivation of the reference LAI laboratory strain of HIV-1. Heteroduplex analysis and autologous inactivation assays of sequential specimens from individual patients indicate that over time, the viral quasispecies that emerge and dominate are resistant to the inactivating effects of earlier sera.

Background: If Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma, serologic evidence of infection should be present in patients before the disease develops., Methods: Using an immunoblot assay for two latent nuclear antigens of KSHV, we tested serum samples from homosexual male patients with the acquired immunodeficiency syndrome (AIDS) with and without Kaposi's sarcoma (HIV-infected men with hemophilia), HIV-seronegative blood donors, and HIV-seronegative patients with high titers of antibodies against Epstein-Barr virus (EBV). Serial serum samples obtained from patients with Kaposi's sarcoma before the diagnosis of the disease were tested for evidence of seroconversion., Results: Of 40 patients with Kaposi's sarcoma, 32 (80 percent) were positive for antibodies against KSHV antigens by the immunoblot assay, as compared with only 7 of 40 homosexual men (18 percent) without Kaposi's sarcoma immediately before the onset of AIDS. Of 122 blood donors, 22 EBV-infected patients, and 20 HIV-infected men with hemophilia, none were seropositive. When studied by the immunoblot assay over a period of 13 to 103 months, 21 of the 40 patients with Kaposi's sarcoma (52 percent) seroconverted 6 to 75 months before the clinical appearance of Kaposi's sarcoma. The median duration of antibody seropositivity for KSHV-related latent nuclear antigens before the diagnosis of Kaposi's sarcoma was 33 months., Conclusions: In most patients with kaposi's sarcoma and AIDS, seroconversion to positivity for antibodies against KSHV-related nuclear antigens occurs before the clinical appearance of Kaposi's sarcoma. This supports the hypothesis that Kaposi's sarcoma results from infection with KSHV.

We explored a possible route of transmission of Kaposi's-sarcoma-associated herpes virus (KSHV) with nested and unnested PCR techniques. We looked for KSHV DNA sequences in semen of HIV-positive homosexual men and HIV-negative healthy semen donors. With unnested primers we found KSHV sequences in 21 of 33 (64%) homosexual men and in none of 30 healthy donors. With a nested PCR assay, 30 of 33 (91%) specimens from the homosexual men and 7 of 30 (23%) specimens from healthy donors had detectable KSHV sequences. Over 5 years of follow-up, 13 of 30 KSHV-positive homosexual men (43%) developed KS compared with none of the 3 KSHV-negative homosexual men.

We investigated children with CD4+ T lymphocytopenia to determine the magnitude and public health impact of this condition and to investigate possible causes. Children < 13 years old with CD4+ T lymphocyte counts below age-adjusted cutoffs (age < 24 months, 1000 cells/microliters; age > or = 24 months, 300 cells/microliters) or < 20% on 2 separate measurements were considered to have CD4+ T lymphocytopenia. We solicited information from clinicians and public health departments on these children and their families and collected blood for immunologic and retroviral testing. We identified 18 children (10 boys; 14 African-Americans) with a median age of 10 months at their first low CD4+ T lymphocyte measurement. Three children had had opportunistic infections and two still had low CD4+ T lymphocyte counts 5 and 7 years later. Of the 11 children born to human immunodeficiency virus (HIV)-infected mothers 7 were asymptomatic. Specimens from all children were negative for HIV and human T lymphotropic virus antibodies and negative for HIV by culture or polymerase chain reaction. Among 12 families interviewed no other HIV-seronegative family or household member had illnesses suggestive of immunosuppression. We conclude that negative retroviral tests and lack of illness among their family members do not support the hypothesis that a retrovirus causes CD4+ T lymphocytopenia among these children.(ABSTRACT TRUNCATED AT 250 WORDS)

In an ultrasensitive assay for reverse transcriptase (RT), an in vitro-transcribed heteropolymeric RNA sequence was used as a template and polymerase chain reaction (PCR) amplification with Southern blot hybridization served as a detection system for the cDNA reaction product. The assay, called Amp-RT, detected 9 tested retroviruses in unconcentrated culture supernatants diluted 10(2)- to 10(5)-fold. A comparative analysis using human immunodeficiency virus type 1 (HIV-1) revealed that Amp-RT was 100,000 times more sensitive than the standard RT assay, 10,000 times more sensitive than p24 antigen capture and branched DNA assays, and 100 times more sensitive than RT-PCR or TCID50 assays. Analysis of serum specimens from 42 HIV-1-infected persons by Amp-RT showed that 36 samples (85.7%) were RT-positive. In contrast, 41 serum specimens from persons seronegative for HIV-1 and human T lymphotropic virus types I and II were all Amp-RT-negative.

Idiopathic CD4+ T lymphocytopenia should be considered in HIV-negative patients with skin lesions commonly associated with HIV infection. Patients with idiopathic CD4+ T lymphocytopenia are presumably rare, often have dermatologic lesions, always have low CD4+ T lymphocyte counts, and lack all evidence of HIV-1 infection. We describe a young man with verrucae, basal cell carcinomas, chronic tinea corporis, and laboratory evidence supporting a diagnosis of idiopathic CD4+ T lymphocytopenia.

Peripheral blood mononuclear cells were quantified for the subsets of CD4, CD8, and CD19 lymphocytes by using CD45RA (2H4), CD29(4B4), CD57, CD5, CD10, Leu8, HLA-DR, and TCR gamma delta-1 monoclonal antibodies and dual color immunofluorescence. A comparative analysis of lymphocyte subpopulations was made among 52 HIV-infected and 50 age-matched control children and 30 HIV-seropositive and 27 negative control adults. A significant decrease in the CD4+CD45RA+ "naive" cells was much more marked in HIV-infected children than in HIV-infected adults. A significant percentage increase in the CD4+CD29+ "memory" cells was observed in HIV-infected children but not in infected adults; however, the absolute numbers were usually decreased in all age groups. The mean percentage and absolute numbers of CD4+CD7+ and CD4+Leu8+ cells were decreased in HIV-infected children, although usually not significantly. The CD3+TCR gamma delta-1+ did not show any change in the infected children tested. The mean percentage and absolute number of the CD8+HLA-DR+ cells increased significantly in HIV-infected persons of all ages. The CD8+CD57+ cells were increased in percentage and absolute number in HIV-infected children ages 1-4 and 4-8 years. In the adults, no change was noted in either the percentage or absolute number of CD19+CD5+ B cells, a finding similar to that noted in HIV-infected children above 1 year of age. Although adults showed a significant decrease in both percentage and numbers of CD5- B cells, an increase was noted in the 7- to 12-month-old HIV-infected children. The CD19+CD10+ cells showed a slight but significant decrease in the youngest age group and a significant increase in the older age groups of HIV-infected children. These findings indicate that several lymphocyte subpopulations are altered differentially during HIV infection in children of varying ages and in adults.

Background: Although patients with idiopathic CD4+ T-lymphocytopenia and serious opportunistic infections have been described previously, the clinical and immunologic features of this condition have not been well defined., Methods: We studied in detail five patients with idiopathic CD4+ T-lymphocytopenia. The studies included serologic testing, culture, and polymerase chain reaction for the human immunodeficiency virus (HIV) types 1 and 2, serologic testing for the human T-cell lymphotropic virus (HTLV) types I and II, lymphocyte phenotyping, immunoglobulin quantitation, and lymphocyte-transformation assays, as well as attempts to isolate a retroviral agent. The results were compared with those in HIV-infected persons matched for CD4+ T-cell counts and with those in normal controls. We also studied the spouses of patients and the blood donors for one patient., Results: In these five patients, there was no evidence of either HIV or HTLV infection. All the patients had both low percentages and low counts of CD4+ T cells, with relative increases in percentages, but not counts, of CD8+ cells. Numbers of B cells and natural killer cells were generally normal. As compared with HIV-infected persons, our patients had lower percentages and counts of CD8+ cells and more lymphopenia. CD4+ counts were relatively stable over time. Instead of the high immunoglobulin levels seen in HIV infection, these patients had normal or slightly low levels of immunoglobulins. The lymphocyte-transformation response to mitogens and antigens was depressed. Results in spouses and blood donors were normal., Conclusions: Idiopathic CD4+ T-lymphocytopenia differs from HIV infection in its immunologic characteristics and in its apparent lack of progression over time. Nothing about the immunologic or viral-culture studies performed in these patients or about their family members or blood donors suggests that a transmissible agent causes this condition.

Seventy-five homosexual men with lymphadenopathy syndrome (LAS), subsequently shown to be seropositive for the human immunodeficiency virus (HIV), were enrolled in a prospective study in Atlanta in 1982 and 1983. Subjects have been followed up at 3- to 6-month intervals with clinical and immunologic evaluations, including analysis of T-cell subsets. As of February 28, 1991, AIDS had developed in 36 (48%) of the 75 men. The AIDS cases continued to occur through the 10th year after onset of LAS; the 10-year cumulative incidence of AIDS was 56.6% (Kaplan-Meier survival analysis). Six-year incidence rates following the first observation of a T-helper cell count greater than or equal to 500/mm3, 400-499/mm3, 300-399/mm3, 200-299/mm3, and less than 200/mm3 were 29, 35, 50, 58, and 88%, respectively. Among individual symptoms and signs, only thrush conferred a poorer prognosis (odds ratio = 5.80; 95% confidence interval, 2.93, 11.39, p less than 0.001, Mantel-Byar analysis). The risk of AIDS persists 10 years after the onset of LAS. The AIDS incidence is related directly to T-helper cell depletion; with the exception of thrush, the presence or absence of symptoms and signs appears to be of lesser prognostic significance.

Subjects were 21 men with persistent generalized lymphadenopathy (PGL, n = 13) or AIDS-related complex (ARC, n = 8), who were not receiving anti-retroviral medication, and 21 controls. At baseline, mild cognitive impairment was detected in language, memory, attention, and visual and auditory processing, primarily in patients with ARC. On follow-up, the ARC group showed continued impairment and abnormalities on new measures of distractibility and activities of daily living. Although mild decline in verbal memory was noted for some patients, overall neuropsychological profiles did not show deterioration. Nomenclature for the pattern of mild, stable neuropsychological changes in patients with cognitive symptoms is discussed. Two interdisciplinary panels have recommended the term HIV-1-associated minor cognitive/motor disorder. Unlike the term AIDS dementia, it does not imply progression or a diagnosis of AIDS.

Increased concentrations of neopterin, a marker for cell-mediated immune activation, and decreased numbers of CD4+ T cells, are predictors for progression of disease after infection with human immunodeficiency virus type 1. Previous studies have demonstrated different rates of onset of full-blown acquired immunodeficiency syndrome (AIDS) for groups of patients, defined by laboratory marker values, who were initially symptom-free. By re-analysis of one such study, we demonstrate how for an individual patient, the individual marker values, together with a prior risk estimate, can be converted into current or accumulated post-test probability of onset of AIDS at a certain time. We used a statistical technique suggested by Albert et al. (Clin Chem 1984;30:69-76), which allows incorporation of fixed and time-dependent covariates. Besides allowing individual projections, the method shows that the predictive abilities of CD4+ T cell numbers and of neopterin concentrations do not vary greatly with regard to time of observation; both laboratory markers independently modulate the underlying prior probability of AIDS onset, which is significantly increased with the passage of time.

Human herpesvirus-6 (HHV-6) and human immunodeficiency virus (HIV) are both tropic for CD4+ lymphocytes. To determine whether HHV-6 infection affects the susceptibility to or the course of HIV infection, HHV-6 titers were measured by an anticomplement immunofluorescence assay in serum of three groups of homosexual or bisexual men: (1) those with AIDS (n = 78), (2) those with HIV-associated lymphadenopathy (LAS; n = 81), and (3) those who were HIV-seronegative (n = 55). Early and late serum samples were available for 45 men with LAS (median interval 49 months). Men with early LAS did not differ from HIV-seronegative men in either the percentage that were HHV-6-seropositive or in the distribution of titers. There was a significantly lower percentage of seropositives in AIDS patients than in the other two groups (P less than .01). LAS patients who progressed to AIDS did not differ in percentage seropositivity or distribution of titers from nonprogressors. HHV-6 titers tended to decrease over time. HHV-6 titers late in LAS were similar to those in AIDS patients. These findings suggest that it is unlikely that previous exposure to HHV-6 either predisposes to or affects the course of HIV infection.

To establish whether the syndrome of unexplained generalized lymphadenopathy in homosexual men was new and related epidemiologically to the acquired immune deficiency syndrome (AIDS), we reviewed 3,139 pathology reports of lymph node biopsies performed at seven hospitals in New York City during the years 1977 through 1981. Three hundred twenty-nine patients (10%) were categorized as having unexplained lymph node hyperplasia; a detailed medical record review of 30% of these patients revealed three, two, six, eight, and 16 cases of unexplained generalized lymphadenopathy in the five years studied, respectively. Of these 35 cases, 26 (74%) occurred in males aged 16 to 44. A record review of 68 additional male patients aged 16 to 44 years with unexplained lymph node hyperplasia in two of the hospitals showed a similar increase in cases of unexplained generalized lymphadenopathy during the five-year period. Twenty-one of 25 cases in males with known sexual orientation were homosexual or bisexual. The increase in the syndrome of unexplained generalized lymphadenopathy from 1978 to 1981 and the characteristics of the population affected are similar to those observed for AIDS.

Persons with hemophilia are at risk of the acquired immunodeficiency syndrome (AIDS), and clinically asymptomatic hemophiliacs have shown a high incidence of AIDS-like immune abnormalities, facts leading to speculation that many hemophiliacs have been exposed to the AIDS agent through their blood products. We therefore evaluated the immune status of three groups of blood product recipients without AIDS in New York City, including 47 persons with hemophilia A receiving factor VIII concentrate, 50 persons with homozygous beta-thalassemia, and 27 persons with sickle cell anemia receiving frozen-packed RBCs and 20 healthy persons who had not received a transfusion. Hemophiliac participants had significantly lower lymphocyte counts (median, 1,826/cu mm) than did the thalassemic (6,110/cu mm) or anemic (4,443/cu mm) participants, had lower numbers of T-helper lymphocytes (median, 533 cells/cu mm v 1,733 cells/cu mm and 1,554 cells/cu mm), and had a lower T-helper/suppressor ratio (median, 0.8 v 1.8 and 2.1). These differences remained after adjustment for age and sex. Thus, AIDS-like immune abnormalities were found in patients receiving factor concentrate, but not in those receiving RBCs. These defects could be due to both an immunosuppressive effect of the lyophilized factor itself and to contact with the AIDS agent.