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J. W. Mosley,
E. A. Operskalski,
L. H. Tobler,
Z. J. Buskell,
W. W. Andrews,
B. Phelps,
J. Dockter,
C. Giachetti,
L. B. Seeff,
M. P. Busch,
for the Transfusion-transmitted Viruses Study and Retrovirus Epidemiology Donor Study Groups
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ABSTRACT: Knowing the likely distribution of intervals from hepatitis C infection to first RNA-negativity is important in deciding about therapeutic intervention. Prospectively collected sera and data from the Transfusion-transmitted Viruses Study (1974–1980) provide specific dates of infection and pattern of alanine aminotransferase (ALT) elevations. We examined frequency, timing and correlates of spontaneous resolution for 94 acutely infected transfusion recipients followed for a median of 9.5 months. Later, follow-up sera (>10 years) were available for 27 of the 94 cases from a Veterans Administration (VA) Study (1989–1990). Twenty-five (27%) of the 94 cases were classified as probably resolved during the episode itself. First RNA negativity occurred at 6–50 weeks (median, 19.5 weeks) after infection, and 5–43 weeks (median, 11 weeks) after ALT elevation. Thirteen of the 25 cases remained RNA-negative subsequently; 12 others had 1–6 RNA-positive sera intercalated between first and last RNA-negative results. RNA negativity, therefore, began variably and was interrupted in 12 cases of 25 (48%) by transient RNA-positive sera. Five of these 25 patients who were RNA-negative in the last study specimen had late, Veterans Administration Study follow-up; none showed viraemia. Of the remaining 69 transfusion transmitted virus study recipients, whose last serum was RNA-positive, two cleared viraemia after the last study serum but before late follow-up. Eleven (16%) had 23 intercalated RNA-negative sera before last positivity. RNA status, therefore, needs monitoring for many months before judging the spontaneous outcome as transient negativity may occur. Resolution was significantly more common in women and symptomatic cases; it was not associated with viral load in the infectious donation, HCV genotype, or the recipient’s age.
Journal of Viral Hepatitis 12/2007; 15(2):120 - 128. · 4.09 Impact Factor
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ABSTRACT: Little information is available regarding the risk of human immunodeficiency virus type 1 (HIV-1) infection for patients transfused before routine anti-HIV-1 screening of blood donors was instituted in March 1985. A model was developed for estimating both the proportion and the number of transfusion recipients in the San Francisco Bay area who were infected by HIV-1 during each of the 7 years preceding routine donor screening for anti-HIV-1. The model is based on analysis of 1) donation histories of HIV-1-infected donors identified at the regional blood center; 2) HIV-1 seroprevalence estimates for homosexual and bisexual men in San Francisco; and 3) HIV-1 infection and survival rates for recipients traced by the Transfusion Safety Study and Irwin Memorial Blood Centers’ Look Back Program. The incidence of transfusion- associated HIV-1 infection is estimated to have risen rapidly from the first occurrence in 1978 to a peak in late 1982 of approximately 1.1 percent per transfused unit. The decrease after 1982 coincided with the implementation of high-risk donor deferral measures. It is estimated that, overall, approximately 2135 transfusion recipients were infected with HIV-1 in the San Francisco region alone. This number suggests a higher prevalence of transfusion-associated HIV-1 infection than has been generally recognized and indicates the need for continued tracing of potentially exposed recipients. The data also strongly support the effectiveness of early donor education and self-exclusion measures and emphasize the importance of continued research and development in this area.
Transfusion 03/2003; 31(1):4 - 11. · 3.22 Impact Factor
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PhD Associate Professor M.P. Busch MD,
J.E. Valinsky,
T. Paglieroni,
H.E. Prince,
G.J. Crutcher,
G.F. Gjerset,
E.A. Operskalski,
E. Charlebois,
C. Bianco,
P.V. Holland,
L.R. Petersen,
C.G. Hollingsworth, J.W. Mosley
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ABSTRACT: Background: The recent recognition of idiopathic CD4+ T-lymphocytopenia (ICL) had led to concern that an unknown immunodeficiency virus may be transmissible by transfusion.Study Design and Methods: To evaluate the prevalence and significance of low CD4+ values among blood donors, CD4+ data on 2030 blood donors who were negative for antibody to human immunodeficiency virus type 1 (HIV-1) were compiled. Those with CD4+ values below ICL cutoffs (< 300 CD4+ T cells/μL, or < 20% CD4+ T cells) were recalled for follow-up investigations. Serial CD4+ data on 55 homosexual men who seroconverted during prospective follow-up and data on 139 anti-HIV-1-positive blood donors initially evaluated in 1986 were reviewed as well.Results: Five seronegative donors (0.25%) had absolute CD4+ counts < 300 cells per μL and/or < 20 percent. On follow-up, all five donors had immunologic findings within normal ranges, lacked HIV risk factors, and tested negative for HIV types 1 and 2 and human T-lymphotropic virus type I and II infections by antibody and polymerase chain reaction assays. Four of five donors reported transient illness shortly after their low CD4+ count donations. The median interval from HIV-1 seroconversion to an initial CD4+ value below ICL CD4+ cutoffs was 63 months for infected homosexual men. Of 139 HIV-1-infected blood donors studied 1 to 2 years after seropositive donations, 34 (24%) had CD4+ counts < 300 cells per μL and/or < 20 percent.Conclusion: Low CD4+ counts are rare among anti- HIV-1-negative volunteer blood donors and are generally associated with transient illnesses. If any unknown virus progresses similarly to HIV- 1, CD4+ count donor screening would be a poor surrogate for its detection.
Transfusion 02/2003; 34(3):192 - 197. · 3.22 Impact Factor
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C F de Oliveira,
R S Diaz,
D M Machado,
M T Sullivan,
T Finlayson,
M Gwinn,
E M Lackritz,
A E Williams,
D Kessler,
E A Operskalski, J W Mosley,
M P Busch
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ABSTRACT: Recent reports of variant (non-subtype B) HIV infections in US populations have raised concerns about the sensitivity of subtype B virus-based donor screening and diagnostic assays. This study was designed to determine the prevalence and genetic diversity of HIV subtypes in US blood donors over the last two decades.
Three groups were studied: hemophiliacs infected by clotting factor concentrates in the early 1980s (n = 49), blood donors retrospectively identified as being seropositive in 1985 (n = 97), and blood donors identified as seropositive between 1993 and 1996 (n = 405). Subtype assignment was based primarily on heteroduplex mobility analysis (HMA) of HIV-1 env, with DNA sequence confirmation of selected specimens. HIV peptide-based EIA serotyping was used to rule out HIV-2 and group O infections and to serotype HMA-refractory specimens.
Of 551 specimens, 535 (97%) were assigned subtypes; 532 (99%) of these were subtype B. Three postscreening donations (1%) were assigned non-B subtypes (2 A, 1 C). Two of these three donors were born in Africa; the third was born in the United States and reported no risk factors other than heterosexual activity. HMA distribution plots showed an increase in env diversity among HIV-1 group B strains over time.
The results support the need for continued surveillance of HIV subtype diversity and ongoing validation of the sensitivity of HIV diagnostic assays to non-B subtype infections.
Transfusion 12/2000; 40(11):1399-406. · 3.22 Impact Factor
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Developments in biologicals 02/2000; 102:93-6.
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ABSTRACT: The beta-chemokine receptor CCR5 is required as a coreceptor by non-syncytium-inducing (NSI) strains of human immunodeficiency virus type 1 (HIV-1). NSI viruses predominate early during an infection and are thought to be important for the transmission of HIV-1. The importance of CCR5 during parenteral transmission of HIV-1 was investigated. The distribution of the homozygous deleted CCR5 genotype among 566 exposed persons with hemophilia and 97 exposed transfusion recipients indicated that the lack of CCR5 expression protected persons from infection. This suggests that the initial predominance of NSI viruses during an infection does not result from limited availability of CXCR4-expressing cells within the mucosa but rather implies a more fundamental requisite for CCR5-expressing cells early during an infection regardless of the route of transmission. In addition, no difference in the rate of progression to AIDS (CDC 1987 definition) of infected heterozygous compared with homozygous wild type subjects was observed.
The Journal of Infectious Diseases 11/1998; 178(4):1163-6. · 6.41 Impact Factor
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ABSTRACT: 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.
American Journal of Epidemiology 11/1997; 146(8):655-61. · 5.22 Impact Factor
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Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 08/1997; 15(3):243-4.
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ABSTRACT: 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.
Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 07/1997; 15(2):145-50.
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The Lancet 06/1997; 349(9061):1327. · 38.28 Impact Factor
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ABSTRACT: 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.
Journal of Virology 04/1997; 71(3):2555-61. · 5.40 Impact Factor
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ABSTRACT: During treatment with blood components prepared from an HIV-infected donation, two recipients became infected in 1985. One recipient infected her sexual partner.
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.
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.
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.
The shared HIV-1 quasispecies in this epidemiologic cluster diverged in an individual-specific manner.
AIDS 04/1997; 11(4):415-22. · 6.24 Impact Factor
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B J Dille,
T K Surowy,
R A Gutierrez,
P F Coleman,
M F Knigge,
R J Carrick,
R D Aach,
F B Hollinger,
C E Stevens,
L H Barbosa,
G J Nemo, J W Mosley,
G J Dawson,
I K Mushahwar
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ABSTRACT: 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.
The Journal of Infectious Diseases 03/1997; 175(2):458-61. · 6.41 Impact Factor
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AIDS Research and Human Retroviruses 10/1996; 12(13):1291-5. · 2.25 Impact Factor
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ABSTRACT: 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.
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.
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].
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.
Transfusion 10/1996; 36(9):776-81. · 3.22 Impact Factor
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ABSTRACT: 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.
American Journal of Hematology 08/1996; 52(3):150-4. · 4.67 Impact Factor
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ABSTRACT: 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.
The Journal of Infectious Diseases 08/1996; 174(1):26-33. · 6.41 Impact Factor
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The Lancet 12/1995; 346(8984):1224. · 38.28 Impact Factor
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ABSTRACT: 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.
The Journal of Infectious Diseases 10/1995; 172(3):648-55. · 6.41 Impact Factor
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ABSTRACT: We studied a case in which a 2-month-old premature infant was concurrently transfused with packed erythrocytes from two different human immunodeficiency virus type 1 (HIV-1)-seropositive donors in late 1984. The two donors also each singly infected a second infant. Inspection of sequences from portions of the HIV-1 genomes in each of the two donors showed a close relationship to the strain in their respective singly exposed recipients. Inspection of sequences from the dually exposed recipient provided evidence of an individual simultaneously infected with two distinct HIV-1 strains, as well as recombination of the two strains in vivo.
Journal of Virology 07/1995; 69(6):3273-81. · 5.40 Impact Factor
