Viral levels in newborn African infants undergoing primary HIV-1 infection.

We examined weekly changes in viral levels in seven untreated infants infected with HIV at birth. Viral levels spiked immediately but reverted quickly to plateau levels typical of infant HIV infection within 2 weeks of first detected viraemia. We speculated that the depletion of naive, susceptible cells is responsible for the rapid decrease in spike levels and that the rapid replacement of lymphocytes in infants causes the high plateau viral levels (10(5) copies/ml) to be sustained.     

Antibody-dependent enhancement of human immunodeficiency virus type 1 (HIV-1) infection in vitro by serum from HIV-1-infected and passively immunized chimpanzees.

Based on recent reports of antibody-dependent enhancement of human immunodeficiency virus type 1 (HIV-1) infection in vitro by serum from HIV-1-infected humans, sera from HIV-1 antibody-positive chimpanzees (Pan troglodytes) was evaluated for enhancing activity in an in vitro infection assay that uses MT-2 cells (a human lymphoblastoid cell line). Although fresh chimpanzee serum was found to have pronounced infection-enhancing properties in the absence of antibody to HIV-1, this effect was abolished by heat inactivation (57 degrees C, 1 hr) or treatment with cobra venom anticomplementary protein. Heat-inactivated, HIV-1 antibody-positive chimpanzee serum could enhance HIV-1 infection of MT-2 cells in vitro when combined with fresh, normal human serum. By serial serum samples from three HIV-1-infected chimpanzees, HIV-1 antibody-positive chimpanzees are shown to develop enhancing antibodies early in infection (2 mo postchallenge), whereas neutralizing antibodies develop later. Over the course of HIV-1 infection, this enhancing activity decreases while neutralizing activity increases, suggesting a possible role for enhancing and neutralizing activities in HIV-1 pathogenesis. The enhancing activity of an IgG fraction used to passively immunize chimpanzees against HIV-1 infection is shown to be present at dilutions as high as 1:65,000, offering an interesting possible reason for the failure of passive immunization to protect chimpanzees from HIV infection. These results suggest that serum from HIV-1-immunized chimpanzees might be tested to determine whether current HIV-1 candidate vaccines induce production of antibodies that mediate antibody-dependent enhancement of HIV-1 infection in this in vitro assay.     

Low antibody response in infants with measles and children with subclinical measles virus infection

During a measles epidemic (December 1979-March 1980) in two adjacent villages in Tamil Nadu, 78 of 143 under-fives were affected, eight of whom died, giving an attack rate of 54% and case-fatality rate of 10%. Seven months later 72 children (41 with measles, seven with history of measles in prior epidemics and 24 with no history of measles) were bled to measure measles virus haemagglutination-inhibition antibody. Of the 48 with measles history, 46 had measurable antibody. Surprisingly, of the 24 without a history, 16 had measurable antibody indicating the frequency of subclinical measles during epidemics. The geometric mean antibody titre was lower in infants with measles than in older children (P less than 0.05). The mean titre was lower in those with subclinical measles than in those with clinical measles (P less than 0.01).     

Immunogenicity of standard-titer measles vaccine in HIV-1-infected and uninfected Zambian children: an observational study

BACKGROUND: Achieving the level of population immunity required for measles elimination may be difficult in regions of high human immunodeficiency virus type 1 (HIV-1) prevalence, because HIV-1-infected children may be less likely to respond to or maintain protective antibody levels after vaccination. METHODS: We conducted a prospective study of the immunogenicity of standard-titer measles vaccine administered at 9 months of age to HIV-1-infected and uninfected children in Lusaka, Zambia. RESULTS: From May 2000 to November 2002, 696 children aged 2-8 months were enrolled. Within 6 months of vaccination, 88% of 50 HIV-1-infected children developed antibody levels of >or=120 mIU/mL, compared with 94% of 98 HIV-seronegative children and 94% of 211 HIV-seropositive but uninfected children (P=.3). By 27 months after vaccination, however, only half of the 18 HIV-1-infected children who survived and returned for follow-up maintained measles antibody levels >or=120 mIU/mL, compared with 89% of 71 uninfected children (P=.001) and in contrast with 92% of 12 HIV-1-infected children revaccinated during a supplemental measles immunization activity. CONCLUSIONS: Although HIV-1-infected children showed good primary antibody responses to measles vaccine, their rapid waning of antibody suggests that measles vaccination campaigns may need to be repeated more frequently in areas of high HIV-1 prevalence.     

Newborn rats in the murine typhus enzootic infection cycle: studies on transplacental infection and passively acquired maternal antirickettsial antibodies

This study focused attention on the newborn rat as a possible significant participant in the highly successful enzootic cycle of murine typhus. We examined the influence of maternal Rickettsia typhi (R. mooseri) infection in rats on the offspring with respect to the possible vertical transmission of R. typhi and the passive transfer of maternal antirickettsial antibodies. Transmission of R. typhi by rickettsemic pregnant rats did not occur either transplacentally during gestation to their fetuses or postnatally through colostrum and milk to their newborn. The rickettsial burden of the placenta was sometimes greater than 10(6) plaque forming units per g tissue and undetectable in colostrum or milk. However, newborn rats were highly susceptible to infection per os. Transplacental passage of antirickettsial antibody to offspring was detectable only when the mother's antibody titer was high. Passive postpartum acquisition of antirickettsial antibodies by newborn rats from colostrum and milk of immune mothers occurred regardless of the height of the maternal antibody titer, rose to a maximum at about 3 weeks of age, and then declined rapidly, becoming undetectable 4 weeks after birth.     

Detection of salivary immunoglobulin A antibodies to HIV-1 in infants and children

Secretory immunoglobulin A (slgA) antibodies of non-maternal origin are present in newborns and slgA to HIV-1 antigens has been detected in infected adults. In this study we investigated the presence of HIV-1-specific IgA in saliva from 41 children (aged 1 day-46 months) born to women at risk for HIV-1 infection. Saliva samples were assayed for HIV-1 antibodies with IgA-specific Western blot. The samples from 10 out of 11 children with subsequently proven infection, including one aged 6 months, demonstrated IgA antibodies to HIV-1 envelope antigens. Samples from infants under 15 months, who were born to infected mothers and subsequently shown to be uninfected, were slgA negative. Of the 12 children with continued indeterminate HIV-1 status, eight showed neither slgA nor serologic evidence of infection and four showed slgA antibodies. HIV-1-specific slgA was detectable before the age of 15 months and may prove to be valuable in the diagnosis of HIV-1 infection in infants.     

HIV type 1 infection is a risk factor for mortality in hospitalized Zambian children with measles.

BACKGROUND: Measles remains a significant cause of vaccine-preventable mortality in sub-Saharan Africa, yet few studies have investigated risk factors for measles mortality in regions of high human immunodeficiency virus type 1 (HIV-1) prevalence. METHODS: Between January 1998 and July 2003, children with clinically diagnosed measles who were hospitalized at the University Teaching Hospital in Lusaka, Zambia, were enrolled in an observational study. Demographic and clinical information was recorded at enrollment and at discharge or death. Measles was confirmed by detection of antimeasles virus immunoglobulin M antibodies, and HIV-1 infection was confirmed by detection of HIV-1 RNA. RESULTS: Of 1474 enrolled children, 1227 (83%) had confirmed measles and known HIV-1 infection status. Almost one-third of the HIV-1-infected children with measles were <9 months of age, the age of routine measles vaccination, compared with one-fourth of the uninfected children (P = .07). Death occurred during hospitalization in 23 (12.2%) of the HIV-1-infected children and 45 (4.3%) of the HIV-1-uninfected children (p < .001) with measles. After adjusting for age, sex, and measles vaccination status, HIV-1 infection (odds ratio, 2.5; 95% confidence interval, 1.4-4.6), < or =8 years of maternal education (odds ratio, 2.4; 95% confidence interval, 1.2-4.8), and the presence of a desquamating rash (odds ratio, 2.2, 95% confidence interval, 1.3-3.6) were significant predictors of mortality due to measles. CONCLUSIONS: In a region of high HIV-1 prevalence, coinfection with HIV-1 more than doubled the odds of death in hospitalized children with measles. Increased mortality among HIV-1-infected children is further evidence that greater efforts are necessary to reduce transmission of the measles virus in regions of high HIV-1 prevalence.     

Characterization of HIV-1-specific antibodies and HIV-1-crossreactive antibodies to platelets in HIV-1-infected haemophiliac patients

Sera from HIV-1-infected haemophiliacs were examined for human immunodeficiency virus (HIV) specific antibodies and for platelet crossreactive antibodies. Using HIV sepharose 4B affinity columns for serum absorption, antibodies against various HIV antigens, including HIV lysate, HIV-p24 and HIV-gp120, were eluted either by low or by high pH buffer. The eluates were examined by ELISA for HIV specificity and by flow cytometry for platelet crossreactivity. Two types of HIV antibodies could be eluted, i.e. acid-sensitive and alkaline-sensitive antibodies. HIV antibodies were obtained in 26/29 acid eluates and in 25/29 of the alkaline eluates from HIV-lysate columns; 96% (25/26) of the acid-eluted antibodies were HIV-specific but 48% (12/25) of the alkaline-eluted antibodies also showed crossreactivity to platelets. Of the 20 alkaline-eluted HIV-p24 antibodies, 40% (8/20) reacted specifically with HIV-p24 and 60% (12/20) were platelet crossreactive. In contrast, of the alkaline-eluted HIV-gpl20 antibodies ( n =17), 88% (15/17) were HIV gpl20-specific and only 12% (2/17) were platelet crossreactive. Western blot analysis of platelets demonstrated that the anti-p24 antibodies recognized three bands with approximate molecular weights of 72 000 to 95 000. 69% of the serum antiplatelet antibodies showed platelet glycoprotein IIbIIIa specificity. Anti-HIV antibodies could be eluted from platelets. Hence, platelet crossreactive antibodies in HIV infection are primarily alkaline-sensitive and are associated predominantly with HIV p24 antibody; these antibodies may play a role in the immune thrombocytopenia of HIV-infected haemophiliacs.     

CCR5 genotype and HIV-1 infection in perinatally-exposed infants

The CCR5 chemokine receptor is required by non-syncytium HIV-1 strains to infect target cells. A 32 base pair deletion (delta32) in the CCR5 gene causes a structural CCR5 modification that does not permit HIV-1 entry into cells. The rate of the CCR5 delta32 was investigated in 137 children born from HIV-infected mothers. Overall, five (10.6%) of 47 HIV-infected infants showed the defect in heterozygosis vs. eight (8.9%) of 90 uninfected children. No CCR5 delta32 homozygotes were found. Interestingly, among infected children, five (21.7%) of 23 showing a slow disease progression were heterozygous for the CCR5 delta32, meanwhile none of the 24 infants with rapid disease course had the deletion (P = 0.022). In conclusion, the CCR5 delta32 defect does not protect against vertical HIV-1 transmission, but is associated with a delayed disease progression in HIV-infected children.     

Behavioral risk exposure and host genetics of susceptibility to HIV-1 infection

BACKGROUND: Some individuals are readily infected with low human immunodeficiency virus type 1 (HIV-1) exposure, whereas others appear less susceptible, suggesting that host genetics plays a role in the viral entry pathway. The matched case-control study design with measured risk exposures provides an avenue for discovering genes involved in susceptibility to infection. METHODS: We conducted a nested case-control study of African Americans (266 HIV-1 seroconverter cases and 532 seronegative controls from the AIDS Link to Intravenous Experience cohort), to examine the association between 50 single-nucleotide polymorphisms (SNPs) in 9 candidate genes (CCR5, CCR2, RANTES, MIP1A, MCP2, IL10, IFNG, MCSF, and IL2) and susceptibility to HIV-1 infection. To account for differential exposure propensities, risk behavior self-reported during semiannual visits was used to estimate a standardized cumulative risk exposure (SCRE). Individual SNPs were evaluated using conditional logistic-regression models, and the inferred haplotypes were assessed in the haplotype trend regression analyses after adjusting for age and SCRE. RESULTS: Four SNPs (CCR2-V64I, CCR5-2459, MIP1A+954, and IL2+3896) and specific haplotypes in the IL2 and CCR2/CCR5 regions were significantly associated with HIV-1 infection susceptibility in different genetic models. CONCLUSIONS: Our results suggest that genetic variants in associated host genes may play an important role in susceptibility to HIV-1 infection.     

Serum thrombopoietin levels in thrombocytopenic and non-thrombocytopenic patients with human immunodeficiency virus (HIV-1) infection.

HIV-1 seropositive patients often exhibit thrombocytopenia, considered of multifactorial aetiology. Thrombopoietin (TPO), a recently isolated cytokine, is the main regulator of megakaryocyte and platelet production. The objective of this study was to analyse serum TPO levels in thrombocytopenic and non-thrombocytopenic HIV-1 infected patients. Serum TPO levels were measured by ELISA in 43 healthy individuals and in 88 HIV-1 infected patients: 68 thrombocytopenics and 20 non-thrombocytopenics. Thrombocytopenic HIV-1 infected patients showed higher TPO concentrations (263 +/- 342 pg/ml) than non-thrombocytopenics (191 +/- 86 pg/ml); levels in both groups were significantly higher than those of healthy controls (121 +/- 58 pg/ml). Two subgroups of thrombocytopenic patients, the autoimmune thrombocytopenic purpura (AITP) group and the mild thrombocytopenic group, presented TPO levels similar to those of non-thrombocytopenics. Patients exhibiting pancytopenia showed the highest TPO concentrations. However, there was no correlation between TPO levels and platelet counts in any group of HIV-1 infected patients. TPO levels in HIV-1 seropositive patients were slightly increased and the differences in TPO levels between thrombocytopenic and non-thrombocytopenic patients were generally small. The finding of mildly increased TPO levels along with the recently described recovery of thrombocytopenia following recombinant TPO administration confirms the implication of ineffective platelet production in the origin of HIV-associated thrombocytopenia.     

Influence of HIV infection on changes in circulating leukocyte counts during measles in Zambian children

Measles remains an important problem in Africa, where human immunodeficiency virus type 1 (HIV-1) infection is prevalent. To identify the consequences of coinfection, Zambian children hospitalized with measles were studied at entry, discharge, and 1 month after discharge. All children had low lymphocyte and eosinophil counts at entry and high leukocyte and monocyte counts during recovery. The death of cultured lymphocytes was more prolonged for HIV-positive children. CD38 and Fas were increased on CD4+ and CD8+ lymphocytes, and CD28 was decreased on CD8+ lymphocytes in all children. Abnormalities in CD4+ and CD8+ lymphocyte percentages and CD28 expression associated with HIV infection were preserved during measles. Therefore, the patterns of changes in leukocyte counts were similar, with little evidence that measles exacerbated HIV-associated lymphocyte abnormalities.     

The immunologic response to infection with respiratory syncytial virus in infants.

Fifty infants younger than six months, hospitalized for infection with respiratory syncytial virus (RSV), were studied by examination of serial samples of nasal secretion. Secretory neutralizing activity was measured by plaque reduction and secretory antibody by indirect fluorescence using conjugated antiserum to human IgA, IgG, or IgM. Secretory neutralizing activity during infection rose or fell fourfold with approximately equal frequency (20% and 26%, respectively). In contrast, levels of IgA antibody to RSV in secretions rose fourfold in 56%--65% of the infants and fell in none. The frequency of such rises in titer of antibody was directly related to age. In individual secretions the correlation between neutralizing activity and IgA antibody to RSV was poor: neutralizing activity was often found in the absence of detectable antibody, and IgA antibody to RSV was often nonneutralizing. Nevertheless, the development of IgA antibody to RSV correlated in time with the disappearance of virus from the respiratory tract. The timing of this secretory response is consistent with the hypothesis that antibody contributes significantly to cure of infection.     

Human immunodeficiency virus type 1 (HIV-1) genomic sequences and distinct changes in CD8+ lymphocytes precede detectable levels of HIV-1 antibodies in high-risk homosexuals.

Polymerase chain reaction (PCR) identified regions of the gag, LTR, and env genes of human immunodeficiency virus type 1 (HIV-1) in 5 (13%) of 38 high-risk homosexual men who were negative for HIV-1 antibodies by Western blot (WB). Significant increases in CD8+ cells, particularly those bearing activation CD8+CD38+ and CD8+Ia+ antigens, and marked reductions in CD4+ cells were detected in WB-PCR+ subjects compared with 33 WB-PCR- homosexuals. WB-PCR+ subjects had impaired B cell but not T cell functions. Immunologic characteristics of WB-PCR+ homosexuals were indistinguishable from those of 17 WB+PCR+ subjects. Subjects progressing from WB-PCR- to WB-PCR+ to WB+PCR+ showed sequential phenotypic and functional alterations in their B and T cell compartments. These changes and the presence of HIV-1 genomic sequences were the first indications of HIV-1 infection and together with p24 antigenemia signified an inevitable progression to AIDS.     

Roles of clinical and subclinical reactivated herpes simplex virus type 2 infection and human immunodeficiency virus type 1 (HIV-1)-induced immunosuppression on genital and plasma HIV-1 levels

BACKGROUND: Few longitudinal studies have described the interactions between reactivation of herpes simplex virus type 2 (HSV-2) infection (hereafter, "HSV-2 reactivation") and genital and systemic replication of human immunodeficiency virus type 1 (HIV-1). METHODS: Women in Burkina Faso who were seropositive for both HIV-1 and HSV-2 were enrolled in a randomized placebo-controlled trial of therapy to suppress reactivation of HSV-2 infection (hereafter, "HSV suppressive therapy"). During the baseline phase, 6 enriched cervicovaginal lavage specimens were obtained over 12 weeks to detect and quantify the HIV-1 RNA and HSV-2 DNA loads. RESULTS: Women with genital ulcer disease (GUD) detected at least once were more likely than women in whom GUD was not detected (risk ratio [RR], 1.23; 95% confidence interval [CI], 1.09-1.37) to have genital HIV-1 RNA detected during >or=1 visit. Similarly, women with genital HSV-2 DNA detected during >or=1 clinic visit were more likely than women in whom genital HSV-2 DNA was not detected (RR, 1.17; 95% CI, 1.01-1.34) to have genital HIV-1 RNA detected at least once. In addition, the mean genital HIV-1 RNA loads for women with GUD detected during >or=1 visit and women with HSV-2 genital shedding detected during >or=1 visit were greater than that for women in whom genital HSV-2 DNA or GUD was never detected. The plasma HIV-1 RNA load was increased among women for whom >or=1 visit revealed GUD (+0.25 log(10) copies/mL; 95% CI, -0.05-0.55) or genital HSV-2 DNA (+0.40 log(10) copies/mL; 95% CI, 0.15-0.66), compared with women who did not experience GUD or HSV-2 genital shedding, respectively. The association of HSV-2 reactivations on HIV-1 replication tended to be stronger in patients with a higher CD4(+) cell count (i.e., >500 cells/microL). The contribution of HSV-2 to HIV-1 replication among women with CD4(+) cell count of 500 cells/microL deserves further investigation. CLINICAL TRIALS REGISTRATION: The ANRS 1285 Study is registered with the National Institutes of Health (registration number NCT00158509).