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Biomedical subjects

J W Mosley

Publications and source records attributed to J W Mosley.

At least 19 recordsLinked to original sources

Role of viral load in heterosexual transmission of human immunodeficiency virus type 1 by blood transfusion recipients. Transfusion Safety Study Group.

Eighteen transfusion recipients infected with human immunodeficiency virus type 1 (HIV-1) were followed prospectively with their 19 long-term sexual partners from 1986 to 1993 in California, Florida, and New York. Follow-up included clinical, behavioral, immunologic, serologic, and virologic evaluations. Two partners were already infected when seen 18 and 34 months after sexual contact began following the infectious transfusion. Four of 17 initially seronegative partners seroconverted during 23 person-years of observation. The recipient's clinical status, mononuclear cell subset variations, and time trend in CD4+ counts had no association with transmission. Individual plasma HIV-1 ribonucleic acid (RNA) loads were stable during observation, and sexual transmission was not attributable to an upward trend or transient burst in viremia. However, recipients who transmitted HIV-1 to their sexual partners had higher mean viral RNA levels than did nontransmitting recipients (4.3 vs. 3.6 log10 copies/ml; p = 0.05). Although this series was small, the prospective observations suggest that viral load was the only characteristic in the recipient that contributed to heterosexual infectiousness.

Acquired Immunodeficiency Syndrome

Comparative rates of disease progression among persons infected with the same or different HIV-1 strains. The Transfusion Safety Study Group.

Rates of HIV-1 progression vary widely. To investigate the relative effects of viral and host characteristics on course, we compared persons infected by the same and different subtype B strains. Forty-three infection chain clusters were identified, each defined by an infected blood donor, that donor's recipients, and the recipients' sexual partners, representing second and third generations of infection. Analysis of levels and rates of change in CD4 lymphocyte counts and viral load showed that members within a cluster were no more alike in their rates of change in CD4+ lymphocyte counts or viral RNA levels than among clusters. Differences in entry viral RNA levels by cluster were marginal and markedly smaller than interindividual differences. These results argue that, in general, host factors outweigh differences in viral strain in determining HIV-1 disease progression.

Blood Donors

Divergence of HIV-1 quasispecies in an epidemiologic cluster.

BACKGROUND: During treatment with blood components prepared from an HIV-infected donation, two recipients became infected in 1985. One recipient infected her sexual partner. OBJECTIVE: To evaluate the evolution of the originally-shared HIV-1 quasispecies in different human hosts over time, sequence data were obtained from serum from the actual donation sample of blood, and from plasma samples collected from the four members of the epidemiologic cluster over a period extending from 1986 to 1993. METHODS: The V3 hypervariable region of env and the gag p17 gene were analysed. CD4 and CD8 counts, as well as HIV RNA burden data, were collected. RESULTS: One patient died from AIDS during the study. This patient showed a greater degree of diversity in the V3 region, with a higher positive charge over time, than the other individuals. Phylogenetic analysis revealed that the V3 sequences from each of the four individuals occupied separate branches of a phylogenetic reconstruction (tree). Two distinct subgroups evolved in the donor, one with GPGR and the other with GSGR/GSGK at the tip of the V3 loop. This latter group was not detected in the other individuals. The sequences in the sexual partner were no more related to those in the infecting transfusion recipient than to sequences from the other members of the cluster, consistent with sexual transmission having occurred at a time shortly after the recipient was infected. CONCLUSION: The shared HIV-1 quasispecies in this epidemiologic cluster diverged in an individual-specific manner.

Amino Acid Sequence

An ELISA for detection of antibodies to the E2 protein of GB virus C.

An ELISA was developed for detection of antibodies to GB virus C (GBV-C) using a recombinant E2 protein expressed in CHO cells. Seroconversion to anti-E2 positivity was noted among several persons infected with GBV-C RNA-positive blood through transfusion. Of 6 blood recipients infected by GBV-C RNA-positive donors, 4 (67%) became anti-E2 positive and cleared their viremia. Thus, anti-E2 seroconversion is associated with viral clearance. The prevalence of antibodies to E2 was relatively low (3.0%-8.1%) in volunteer blood donors but was higher in several other groups, including plasmapheresis donors (34.0%), intravenous drug users (85.2%), and West African subjects (13.3%), all of whom tested negative by GBV-C reverse-transcription polymerase chain reaction (RT-PCR). These data demonstrate that testing for anti-E2 should greatly extend the ability of RT-PCR to define the epidemiology and clinical significance of GBV-C.

Africa

Host-specific driving force in human immunodeficiency virus type 1 evolution in vivo.

To investigate the process of human immunodeficiency virus type 1 (HIV-1) evolution in vivo, a total of 179 HIV-1 V3 sequences derived from cell-free plasma were determined from serial samples in three epidemiologically linked individuals (one infected blood donor and two transfusion recipients) over a maximum period of 8 years. A systematic analysis of pairwise comparisons of intrapatient sequences, both within and between each sample time point, revealed a preponderance and accumulation of nonsynonymous rather than synonymous substitutions in the V3 loop and flanking regions as they diverged over time. This strongly argues for the dominant role that positive selection for amino acid change plays in governing the pattern and process of HIV-1 env V3 evolution in vivo and nullifies hypotheses of purely neutral or mutation-driven evolution or completely chance events. In addition, different rates of evolution of HIV-1 were observed in these three different individuals infected with the same viral strain, suggesting that the degree of positive pressure for HIV-1 amino acid change is host dependent. Finally, the observed similar rate of accumulation in divergence within and between infected individuals suggests that the process of genetic divergence in the HIV epidemic proceeds regardless of host-to-host transmission events, i.e., that transmission does not reset the evolutionary clock.

Amino Acid Sequence

Hematologic profile and lymphocyte subpopulations in hemoglobin SC disease: comparison with hemoglobin SS and black controls. The Transfusion Safety Study Group.

Compared with subjects with homozygous SS disease (Hb SS), persons with hemoglobin SC (Hb SC) are known to have a more gradual loss of splenic function, a lower incidence of bacterial infections, and fewer end-organ failures. We studied hematological indices and lymphocyte subpopulations of 27 Hb SC subjects and compared them with 173 Hb SS patients and 131 black controls. Hb SC patients had higher hemoglobin levels than Hb SS subjects, lower total leukocyte, granulocyte, monocyte, and lymphocyte counts. Platelets decreased with age but not significantly, instead of increasing as among Hb SS patients. Mononuclear cells were generally similar to controls with the exception of CD8+HLA-DR+ counts resembling Hb SS. Hematologic changes in Hb SC are limited to moderate granulocytosis in children and adults, mild monocytosis in adults, and increased activation of just one lymphocyte subset among those measured.

Adolescent

Donor levels of serum alanine aminotransferase activity and antibody to hepatitis B core antigen associated with recipient hepatitis C and non-B, non-C outcomes.

BACKGROUND: Hepatitis virus(es) that are neither hepatitis B (HBV) nor hepatitis C (HCV) (non-B, non-C [NBNC]) may be transmitted by transfusion. The present study assessed donor values for alanine aminotransferase (ALT) and antibody to hepatitis B core antigen (anti-HBc) for their association with HCV and NBNC hepatitis outcomes among allogeneic blood recipients. STUDY DESIGN AND METHODS: Data on blood donors and recipients enrolled in the Transfusion- Transmitted Viruses Study in four United States cities from 1974 through 1980 were supplemented by anti-HBc testing of donors and anti-HCV evaluation of recipients. Two statistical approaches estimated the value of these indirect tests in detecting donors associated with HCV seroconversion and NBNC hepatitis in recipients. RESULTS: For HCV cases, donor ALT alone (at > or = 60 IU/L) had a sensitivity and a specificity of 30 and 96 percent, respectively, and anti-HBc alone (at > or = 60% inhibition) had a sensitivity and specificity of 53 and 86 percent, respectively. The two markers combined had a sensitivity and a specificity of 69 and 83 percent. For NBNC hepatitis cases, each measure had low sensitivity (20%) that was not improved by using both (28%) [corrected]. CONCLUSION: The indirect tests proved to be equal in sensitivity to the first-generation anti-HCV tests. The positive predictive power of these indirect tests in the 1980s was sufficient to affect HCV incidence in studies during that period. Improved anti-HCV assays, however, replaced the need for indirect tests. The sensitivity of indirect tests for NBNC hepatitis contributed little.

Alanine Transaminase

Factors influencing human immunodeficiency virus type 1 transmission by blood transfusion. Transfusion Safety Study Group.

One hundred thirty-two recipients of blood components that retrospectively tested positive for antibody to human immunodeficiency virus type 1 (anti-HIV-1) were identified. Fourteen (11%) remained seronegative throughout follow-up. Donor and recipient characteristics that could have influenced transmission were examined. Attributes did not differ for infected and uninfected recipients. Peripheral blood mononuclear cells (PBMC) from uninfected recipients were HIV-1-negative by DNA amplification and culture but were susceptible to in vitro infection. Transmitting and nontransmitting donors at donation differed only for HIV-1 RNA positivity. By immunocapture reverse transcriptase-polymerase chain reaction, 6 of 11 transmitters and 0 of 11 nontransmitters tested RNA-positive (P = .02). A more sensitive quantitative RNA assay detected RNA in all donation sera, but median levels were higher in transmitting than nontransmitting sera (P = .01). Median CD4 cell counts were lower for transmitting than nontransmitting donors at enrollment (P = .02). Level of viremia is an important determinant of HIV infection by blood transfusion.

Acquired Immunodeficiency Syndrome

Donor screening for antibody to hepatitis B core antigen and hepatitis B virus infection in transfusion recipients.

BACKGROUND: Testing for antibody to hepatitis B core antigen (anti-HBc) as a surrogate for hepatitis C viremia is no longer needed for blood donor screening. Currently, the important question is how much its use supplements hepatitis B surface antigen (HBsAg) donor screening in preventing transfusion-transmitted hepatitis B virus (HBV) infection. STUDY DESIGN AND METHODS: In a study conducted in the 1970s, 64 blood donors were associated with 15 cases of HBV (1.0%) in 1533 transfusion recipients. Sera from 61 donors at donation and 29 follow-up visits were available for present-day assays for HBsAg, HBV DNA, anti-HBc, and antibody to HBsAg (anti-HBs). RESULTS: HBsAg was found in four previously negative blood donors; HBV DNA was limited to three of these four. Anti-HBc was detected in six HBsAg-negative donors. Two other donors were negative in all assays at donation, but positive for anti-HBc and anti-HBs 2 to 4 months later. The remaining donors were negative for all HBV markers, which left five recipient cases unexplained. No HBV transmission was observed when anti-HBs sample-to-negative control values were > or = 10. CONCLUSION: Some 33 to 50 percent of cases of hepatitis B that could be transmitted by transfusion of blood from HBsAg-negative donors are prevented by anti-HBc screening. Anti-HBc-positive donors unequivocally positive for anti-HBs should be considered noninfectious for HBV and should be allowed to donate. Anti-HBc screening of paid plasmapheresis donors, supplemented by anti-HBs testing, would reduce the amount of HBV to be processed by virus inactivation and increase the content of anti-HBs in plasma pools.

Blood Donors

Rapid molecular epidemiology of human immunodeficiency virus transmission.

Close sequence homology between strains of HIV-1 have been used to corroborate cases of epidemiologically identified transmission. As an alternative to extensive DNA sequence analysis, genetic relateness between pairs of HIV quasispecies was estimated using the reduced electrophoretic mobilities of HIV-1 envelope DNA heteroduplexes through polyacrylamide gels. All six infections acquired in a dental practice in the late 1980s and four of six infections acquired through blood product transfusions and sexual contact in 1984-1985 could be rapidly identified. A rising level of genetic diversity within HIV-1 subtype B facilitated the detection of later transmission events. Transmission linkages could be detected up to 4 years following infection. The simple and rapid technique of DNA heteroduplex tracking can therefore assist epidemiological investigations of HIV transmission and potentially of other genetically variable infectious agents.

Base Sequence

Human immunodeficiency virus type 1 infection: relationship of risk group and age to rate of progression to AIDS. Transfusion Safety Study Group.

Age differences among risk groups may account for rate differences in progression of human immunodeficiency virus type 1 (HIV-1) infection to AIDS. Institutions in 6 US cities used a common protocol to study infected homosexual blood donors, recipients of blood components, and factor VIII-treated hemophiliacs. Follow-up was every 6 months. Actuarial risk for AIDS 8 years after infection was 51% among blood recipients, 36% among homosexual donors, and 24% among hemophiliacs. Significant risk group differences were explained by age differences among cohorts (medians of 61, 29, and 22 years, respectively). When age was adjusted for and both CD4 cell value and zidovudine treatment were used as time-dependent covariates, homosexual donors had more rapid progression than the other groups. Omitting Kaposi's sarcoma as an AIDS-defining condition removed any significant differences among risk groups except CD4 cell count and age. Thus, major factors in AIDS progression are age-related.

Acquired Immunodeficiency Syndrome