Incidence of herpes simplex virus type 2 infection in the United States.

Between the time that two large, national surveys were conducted, the Second National Health and Nutrition Examination Survey (1976-1980) and the Third National Health and Nutrition Examination Survey (1988-1994), prevalence of herpes simplex virus type 2 (HSV-2) infection in the United States increased by 30%. From these survey data, the authors estimated the incidence of HSV-2 infection in the civilian, noninstitutionalized population aged > or = 12 years by means of a mathematical model that allowed overall incidence to increase linearly with time but required the shape of the age-specific incidence curve to remain constant. From 1970 to 1985, annual incidence of HSV-2 infection in HSV-2-seronegative persons increased by 82%, from 4.6 per 1,000 (95% confidence interval: 4.2, 5.0) to 8.4 per 1,000 (95% confidence interval: 7.7, 9.1). Incidence in 1985 was higher in women than in men (9.9 vs. 6.9 per 1,000), higher in Blacks than in Whites (20.4 vs. 6.3 per 1,000), and highest in the group aged 20-29 years (14.6 and 22.5 per 1,000 in men and women, respectively). Thus, by 1985, approximately 1,640,000+/-150,000 persons (730,000 men and 910,000 women) were being infected annually with HSV-2.

Use of human CD3 monoclonal antibody for accurate CD4+ and CD8+ lymphocyte determinations in macaques: phenotypic characterization of the CD3- CD8+ cell subset.

Macaque monkeys are frequently used in models for studies of infectious diseases, immunity, transplantation and vaccine development. Such use is largely due to the conservation of functionally important cell surface molecules and the phylogenetic proximity of their immune systems to that of humans. Some monoclonal antibodies (mAb) raised against human leukocyte antigens can be utilized in the monkey. Until recently, many primate centers have utilized the CD2 monoclonal antibody to enumerate T lymphocytes. We have evaluated the anti-human CD3 mAb in macaques and sooty mangabeys. Using this monoclonal antibody, pigtailed macaques were found to have a much higher proportion of CD2+ CD3- CD8+ cells as compared with rhesus macaques and sooty mangabeys. Such cells comprised approximately one-half of all CD8+ cells in the pigtailed macaque, but only one-quarter of CD8+ cells in the rhesus, and one-fifth in the sooty mangabey. Use of the CD2 monoclonal antibody as the T-cell marker resulted in underestimating CD4/CD8 ratios compared with using the CD3 mAb in pigtailed macaques. Phenotypic characterization of this subset of CD3- CD8+ cells indicated that they are CD16+, CD45RA+, CD11b+, CD69+ and CD28-. This would indicate that these cells represent an activated natural killer cell subset.

Risk factors for cervical intraepithelial neoplasia in southwestern American Indian women.

The authors assessed risk factors for cervical intraepithelial neoplasia (CIN) among southwestern American Indian women using case-control methods. Cases were New Mexico American Indian women with biopsy-proven grade I (n = 190), grade II (n = 70), or grade III (n = 42) cervical lesions diagnosed between November 1994 and October 1997. Controls were American Indian women from the same Indian Health Service clinics with normal cervical epithelium (n = 326). All subjects underwent interviews and laboratory evaluations. Interviews focused on history of sexually transmitted diseases, sexual behavior, and cigarette smoking. Laboratory assays included polymerase chain reaction-based tests for cervical human papillomavirus infection, tests for gonorrhea and chlamydia, wet mounts, and serologic assays for antibodies to Treponema pallidum, herpes simplex virus, and hepatitis B and C viruses. In multiple logistic regression analysis, the strongest risk factors for CIN II/III among American Indian women were human papillomavirus type 16 infection (adjusted odds ratio (OR) = 7.6; 95% confidence interval (CI): 2.4, 23.2), any human papillomavirus infection (OR = 5.8; 95% CI: 3.3, 10.0), low income (OR = 3.3; 95% CI: 1.7, 6.2), and history of any sexually transmitted disease (OR = 2.0; 95% CI: 1.1, 3.5). Unlike previous research, this study found no strong associations between CIN and sexual activity or cigarette smoking.

Prolonged dominance of clonally restricted CD4(+) T cells in macaques infected with simian immunodeficiency viruses.

The repertoire of functional CD4(+) T lymphocytes in human immunodeficiency virus type 1-infected individuals remains poorly understood. To explore this issue, we have examined the clonality of CD4(+) T cells in simian immunodeficiency virus (SIV)-infected macaques by assessing T-cell receptor complementarity-determining region 3 (CDR3) profiles and sequences. A dominance of CD4(+) T cells expressing particular CDR3 sequences was identified within certain Vbeta-expressing peripheral blood lymphocyte subpopulations in the infected monkeys. Studies were then done to explore whether these dominant CD4(+) T cells represented expanded antigen-specific cell subpopulations or residual cells remaining in the course of virus-induced CD4(+) T-cell depletion. Sequence analysis revealed that these selected CDR3-bearing CD4(+) T-cell clones emerged soon after infection and dominated the CD4(+) T-cell repertoire for up to 14 months. Moreover, inoculation of chronically infected macaques with autologous SIV-infected cell lines to transiently increase plasma viral loads in the monkeys resulted in the dominance of these selected CDR3-bearing CD4(+) T cells. Both the temporal association of the detection of these clonal cell populations with infection and the dominance of these cell populations following superinfection with SIV suggest that these cells may be SIV specific. Finally, the inoculation of staphylococcal enterotoxin B superantigen into SIV-infected macaques uncovered a polyclonal background underlying the few dominant CDR3-bearing CD4(+) T cells, demonstrating that expandable polyclonal CD4(+) T-cell subpopulations persist in these animals. These results support the notions that a chronic AIDS virus infection can induce clonal expansion, in addition to depletion of CD4(+) T cells, and that some of these clones may be SIV specific.

Correlation of virus load and soluble L-selectin, a marker of immune activation, in pediatric HIV-1 infection.

OBJECTIVE: HIV infections in children are characterized by high viral load and, in some perinatally infected newborns, delayed appearance of viral markers. Both phenomena may be related to different levels of immune activation affecting viral replication. This study was designed to investigate the relationship between immune activation and viral replication in pediatric HIV infection, and the role of pre-existent immune activation in facilitating HIV transmission to the fetus/newborn. DESIGN: Plasma levels of soluble L-selectin (s-LS), an immune activation marker, were determined in 100 infants with perinatally transmitted HIV infection, compared with 106 age-matched HIV-exposed uninfected controls. Included in the analysis were samples from 31 HIV-infected (10 PCR+ and 21 PCR-) and 35 uninfected newborns aged < 2 days. METHODS: To determine s-LS levels, a solid phase ELISA was performed on plasma samples of patients and controls. RESULTS: s-LS levels in uninfected children were higher than those in normal adults. HIV-infected patients had more rapidly increasing values in the first 6 months of life compared with uninfected infants. Plasma s-LS levels correlated with HIV viral loads (r, 0.50). Among newborns in the first 2 days of life, s-LS levels were lowest in those with negative PCR tests, compared with PCR-positive or uninfected infants. CONCLUSIONS: These results suggest that higher immune activation in children contributes to higher viral loads, and that the level of pre-existent immune activation may have a role in determining which infants have detectable virus in peripheral blood at birth.

The disruption of macaque CD4+ T-cell repertoires during the early simian immunodeficiency virus infection.

T-cell receptor (TCR) complementarily determining region 3 (CDR3) spetratyping analysis was employed to assess the ability of an AIDS virus to disrupt CD4 + T-cell repertoires during the primary infection. Rhesus and pig-tailed macaques infected with simian immunodeficiency virus (SIV)mac 251 and SIVsmmFGb, respectively, were evaluated. Following SIV infection, the macaques exhibited an apparent decline of CD4 + peripheral blood lymphocyte (PBL) counts, which was associated with a change in CDR3 profiles from multiple-length distribution to one- or two-length dominance in the selected TCR Vbeta-expressing CD4 + PBL subpopulations. Molecular analysis of the perturbed cell subpopulations suggested that the CD4 + T cells bearing the dominant CDR3 length were clonally expanded. These results indicate that SIV infection can induce a disruption of macaque CD4 + T-cell repertoires during the primary infection. The finding in this study, therefore, suggests that the virus-induced clonal dominance can contribute to the disruption of CD4 + T-cell repertoires.

Enzyme-linked immunospot assay for the diagnosis of active Treponema pallidum infection during the various stages of syphilis.

BACKGROUND: Specific serologic assays for syphilis cannot differentiate current infections from past infections and are inefficient to monitor efficacy of antibiotic therapy. GOAL: To develop a new immunologic assay for the identification of active Treponema pallidum infection during the various stages of syphilis. STUDY DESIGN: Peripheral blood mononuclear cells obtained from patients with syphilis in an STD clinic were tested for T. pallidum-specific circulating antibody-secreting cells (ASC) by an enzyme-linked immunospot assay (ELISPOT). RESULTS: Specific ASC were demonstrated in all six patients with primary syphilis and in 14 of 16 patients diagnosed with secondary syphilis. ASCs were undetectable in five patients 8 to 16 days after appropriate therapy, but persisted in one case that was considered treatment failure. Among the 13 patients diagnosed with latent syphilis, six (46%) demonstrated ASC, reflecting antigenic stimulation. CONCLUSION: The ELISPOT assay is effective for the diagnosis of primary and secondary syphilis. The presence of circulating ASC suggests persistent active infection in some patients during the latent disease stage.

Correlates of herpes simplex virus seroprevalence among women attending a sexually transmitted disease clinic.

BACKGROUND: Infections by herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are common in the United States. Herpes simplex virus type 2 is transmitted sexually, and the prevalence of antibodies to HSV-2 has increased in recent years. GOALS OF THIS STUDY: The objective of the present study was to estimate the seroprevalence of HSV-1 and HSV-2 antibodies among women attending a sexually transmitted disease (STD) clinic and to evaluate factors associated with HSV-1 and HSV-2 seropositivity. STUDY DESIGN: The report describes a cross-sectional study conducted at an STD clinic. This study included 1,103 women between the ages of 18 and 35. Eighty-nine percent of the subjects were African Americans. The remaining subjects were white. RESULTS: The overall prevalence of HSV-1 and HSV-2 antibodies among study subjects was 72% and 64%, respectively. Both HSV-1 and HSV-2 seropositivity were related directly to age and were higher among African Americans than whites. The prevalence of HSV-2 antibodies also increased with the number of lifetime sexual partners, an early age at first coitus, a history of syphilis, and the absence of HSV-1 antibodies. Drug use and recent use of barrier contraception were unrelated to either HSV-1 or HSV-2. COMMENT: Despite efforts by the public health community to prevent AIDS by promoting safe sexual practices, the prevalence of HSV-2 seropositivity has increased in recent years. Increased numbers of partners and an early age at first coitus are important correlates of HSV-2 infection. Public health interventions to prevent HSV-2 infection should target teenagers. Women of reproductive age attending STD clinics may also comprise an important target for interventions to prevent perinatal herpes.

Herpes simplex type II and Mycoplasma genitalium as risk factors for heterosexual HIV transmission: report from the heterosexual HIV transmission study.

OBJECTIVES: Two hundred twenty-four human immunodeficiency virus (HIV) discordant couples (one HIV negative, one HIV positive) were compared with 78 seroconcordant heterosexually infected couples with HIV with regard to sexually transmitted diseases. METHODS: Serologic testing and cultures were used to determine exposure of participants to sexually transmitted pathogens. These data were compared with HIV concordance of partners to investigate possible risk factors for HIV transmission. RESULTS: Syphilis, chlamydia, and hepatitis B virus (HBV) serologies did not distinguish between concordant and discordant couples nor did cultures for Neisseria gonorrhoeae and Trichomonas or Chlamydia enzyme immunoassay (EIA). Risk of transmission increased with positive serologies for herpes simplex virus (HSV)-2 (P = 0.002), cytomegalovirus (CMV) (P = 0.04), and Mycoplasma genitalium (P = 0.01), but not with Mycoplasma fermentans or Mycoplasma penetrans. Cytomegalovirus was not a significant risk factor when controlled for HSV-2 status. Examination by partner status showed increased risk of concordance with: HSV-2 positive serology in both partners (odds ratio [OR] = 3.14; confidence interval [CI] = 1.62-6.09; P = 0.007); HSV-2 in female secondary partner (OR = 2.10; CI = 1.12-3.93; P = 0.02) or the male primary partner (OR = 2.15; CI = 1.15-4.02; P = 0.017); M. genitalium antibody in both partners (OR = 3.44; CI = 1.68-7.04; P < 0.001); M. genitalium antibody in the primary male partner (OR = 2.51, CI = 1. 27-4.91; P = 0.008) and M. genitalium antibody in the secondary female partner (OR = 2.52; CI = 1.21-5.23; P = 0.01). CONCLUSIONS: These data support the role of HSV-2 in transmission of HIV and, for the first time, suggest a role for M. genitalium as an independent risk factor.

Thymic dysfunction and time of infection predict mortality in human immunodeficiency virus-infected infants. CDC Perinatal AIDS Collaborative Transmission Study Group.

The effect of human immunodeficiency virus (HIV)-induced thymic dysfunction (TD) on mortality was studied in 265 infected infants in the CDC Perinatal AIDS Collaborative Transmission Study. TD was defined as both CD4 and CD8 T cell counts below the 5th percentile of joint distribution for uninfected infants within 6 months of life. The 40 HIV-infected infants with TD (15%) had a significantly greater mortality than did the 225 children without TD (44% vs. 9% within 2 years). Infants with TD infected in utero had higher mortality than did those infected intrapartum (70% vs. 37% within 2 years), while no significant difference was noted between infants without TD with either mode of transmission. The TD profile was independent of plasma virus load. Virus-induced TD by particular HIV strains and the time of transmission are likely to explain the variation in pathogenesis and patterns of disease progression and suggest the need for early aggressive therapies for HIV-infected infants with TD.

Human immunodeficiency virus infection alters antigen-induced cytokine responses in patients with active mycobacterial diseases.

Peripheral blood cells from 29 patients with active Mycobacterium avium (MAC) or Mycobacterium tuberculosis diseases were tested for mycobacterial antigen-induced interferon (IFN)-gamma and interleukin (IL)-4 production. Among MAC patients, human immunodeficiency virus (HIV) infection was associated with an 80% decrease in those who produced IFN-gamma, resulting in a predominantly type 2 cytokine profile. HIV infection in patients with tuberculosis correlates with a 37% increase in those producing IL-4 and a type 1 to type 0 profile shift. These qualitative changes were independent of CD4+ or CD8+ cell numbers. The amounts of both IFN-gamma and IL-4 were decreased in the HIV-infected population. Quantitative reduction of IFN-gamma was the result of fewer secreting cells rather than a down-regulation at the single-cell level. Disseminated disease was restricted to 2 of 5 HIV-infected MAC patients with a type 2 cytokine profile and 4 of 5 HIV-infected tuberculosis patients with a type 0 profile. These results demonstrated a shift in mycobacterial antigen-specific cytokine profiles from type 1 to type 0 and to type 2, in parallel with AIDS progression.

An epidemiologic study of herpes simplex virus type 1 and 2 infection in Japan based on type-specific serological assays.

A seroepidemiologic study of herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) was performed on Japanese adults. Serum samples collected between 1985-9 from a total of 536 healthy adults, female prostitutes, males with sexually transmitted diseases (STD), homosexual men, and pregnant women were studied by immunodot assays using HSV type-specific antigens, glycoproteins G (gG1 and gG2). HSV-1 infections correlated mostly with age and was widely prevalent among subjects < 40 years. HSV-2 prevalence varied greatly among subgroups defined by sexual activity and was associated with risk behaviours for prostitution, infection with STD, and homosexual activity. HSV-2 seroprevalence was highest among prostitutes (80%), lowest among pregnant women (7%), and intermediate in STD patients (23%) and homosexuals (24%). Because HSV-1 infection during childhood has been decreasing, primary genital HSV-2 infection, with its higher frequency of clinical manifestations, will become a greater burden to the public health in Japan.

An African HIV-1 sequence from 1959 and implications for the origin of the epidemic.

There is considerable genetic diversity among viruses of different subtypes (designated A to J) in the major group of human immunodeficiency virus type 1 (HIV-1), the form of HIV that is dominant in the global epidemic. If available, HIV-1 sequences pre-dating the recognition of AIDS could be crucial in defining the time of origin and the subsequent evolution of these viruses in humans. The oldest known case of HIV-1 infection was reported to be that of a sailor from Manchester who died of an AIDS-like illness in 1959; however, the authenticity of this case has not been confirmed. Genetic analysis of sequences from clinical materials obtained from 1971 to 1976 from members of a Norwegian family infected earlier than 1971 showed that they carried viruses of the HIV-1 outlier group, a variant form that is mainly restricted to West Africa. Here we report the amplification and characterization of viral sequences from a 1959 African plasma sample that was previously found to be HIV-1 seropositive. Multiple phylogenetic analyses not only authenticate this case as the oldest known HIV-1 infection, but also place its viral sequence near the ancestral node of subtypes B and D in the major group, indicating that these HIV-1 subtypes, and perhaps all major-group viruses, may have evolved from a single introduction into the African population not long before 1959.

Emerging and reemerging infectious diseases: a multidisciplinary perspective.

Predictions that infectious diseases would be eliminated as a major threat to human health have been shattered by emerging and reemerging infections, among them acquired immunodeficiency syndrome (AIDS), hemorrhagic fevers, marked increases in infections caused by antimicrobial-resistant bacteria, and the resurgence of tuberculosis and malaria. Understanding the dynamics of emerging and reemerging infections is critical to efforts to reduce the morbidity and mortality of such infections, to establish policy related to preparedness for infectious threats, and for decisions on where to use limited resources in the fight against infections. In order to offer a multidisciplinary perspective, 23 infectious disease specialists, epidemiologists, geneticists, microbiologists, and population biologists participated in an open forum at Emory University on emerging and reemerging infectious diseases. As summarized below, the group addressed questions about the definition, the identification, the factors responsible for, and multidisciplinary approaches to emerging and reemerging infections.

Decreases in CD5+ B lymphocytes in children with the DiGeorge anomaly.

The authors evaluated the lymphocyte subsets in eight children with the DiGeorge anomaly, compared with 48 age-matched control infants. Of particular interest was the finding that the percentage and number of CD5+ B lymphocytes were decreased in seven of the eight cases. This observation may provide insight into thymic function and the interaction of the B and T cell systems in some forms of congenital and acquired immunodeficiencies.

Herpes simplex virus type 2 in the United States, 1976 to 1994.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) infection is usually transmitted sexually and can cause recurrent, painful genital ulcers. In neonates the infection is potentially lethal. We investigated the seroprevalence and correlates of HSV-2 infection in the United States and identified changes in HSV-2 seroprevalence since the late 1970s. METHODS: Serum samples and questionnaire data were collected during the National Health and Nutrition Examination Surveys (NHANES) II (1976 to 1980) and III (1988 to 1994). HSV-2 antibody was assessed with an immunodot assay specific for glycoprotein gG-2 of HSV-2. RESULTS: From 1988 to 1994, the seroprevalence of HSV-2 in persons 12 years of age or older in the United States was 21.9 percent (95 percent confidence interval, 20.2 to 23.6 percent), corresponding to 45 million infected people in the noninstitutionalized civilian population. The seroprevalence was higher among women (25.6 percent) than men (17.8 percent) and higher among blacks (45.9 percent) than whites (17.6 percent). Less than 10 percent of all those who were seropositive reported a history of genital herpes infection. In a multivariate model, the independent predictors of HSV-2 seropositivity were female sex, black race or Mexican-American ethnic background, older age, less education, poverty, cocaine use, and a greater lifetime number of sexual partners. As compared with the period from 1976 to 1980, the age-adjusted seroprevalence of HSV-2 rose 30 percent (95 percent confidence interval, 15.8 to 45.8 percent). The seroprevalence quintupled among white teenagers and doubled among whites in their twenties. Among blacks and older whites, the increases were smaller. CONCLUSIONS: Since the late 1970s, the prevalence of HSV-2 infection has increased by 30 percent, and HSV-2 is now detectable in roughly one of five persons 12 years of age or older nationwide. Improvements in the prevention of HSV-2 infection are needed, particularly since genital ulcers may facilitate the transmission of the human immunodeficiency virus.

The great balancing acts. The pregnant woman, placenta, fetus, and infectious agents.

This article conceptualizes the various balancing acts between the pregnant woman, the placenta, the fetus, and the infectious agents. Despite the very large number of infectious insults during pregnancy, the outcome of most interactions usually is a normal newborn. We have identified only one general immune defect of the fetus and neonate: The inability to respond to polysaccharide antigens; yet, a similar defect also is found with certain polysaccharides in older children and adults. The capacity of the neonate to control severe life-threatening diseases with most infectious agents and the ability of the fetus, when infected in utero, to mount sophisticated, immune responses make it conceptually advantageous to consider the older fetus and the newborn infant as "immunodelayed" rather than as immunodeficient or immature.

Diagnosis of perinatal human immunodeficiency virus infection by polymerase chain reaction and p24 antigen detection after immune complex dissociation in an urban community hospital.

Results of polymerase chain reaction (PCR) and p24 antigen detection after immune complex dissociation (p24-ICD) were compared with antibody results after 18 months of age for human immunodeficiency virus (HIV) diagnosis in 345 prospectively followed, perinatally exposed infants. Of 59 infected and 286 uninfected infants tested at 1-6 months of age, sensitivity and specificity were, respectively, 100% and > 97% for PCR and 90% and > 97% for p24-ICD. Testing was done on > or = 2 occasions in the first 6 months of life in 43 infected infants; 77% had > or = 2 positive results with the same test. Of these infants, 68% had 2 positive p24-ICD tests. In uninfected infants, 96% had only negative tests; none had > 1 positive. By 6 months, all uninfected infants with > or = 2 PCR results could have been diagnosed. HIV status can be determined by PCR by age 6 months in most HIV-exposed infants. p24-ICD should not be used alone, because of its lower sensitivity, but may be useful in areas without advanced laboratory support.