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Biomedical subjects

H W Sheppard

Publications and source records attributed to H W Sheppard.

At least 55 records · Page 3Linked to original sources
PubMed1993

Risk factors for hepatitis C virus seropositivity in heterosexual couples.

OBJECTIVES: To determine the risk of heterosexual transmission of hepatitis C virus (HCV) and to identify other risk factors for HCV seropositivity in heterosexual couples. DESIGN: Retrospective cross-sectional study comparing HCV-seropositive and HCV-seronegative heterosexual men and women. SETTING: Couples recruited from the community and screened for participation in a study of the heterosexual transmission of human immunodeficiency virus. PARTICIPANTS: A total of 340 subjects, 170 men and 170 women in sexual partnerships, aged 18 through 61 years. MAIN OUTCOME MEASURE: Seropositivity for HCV antibodies. RESULTS: Overall, 31 (18%) of the 170 women and 56 (33%) of the 170 men were positive by a four-antigen HCV immunoblot. Injection drug use and hemophilia were strongly associated with HCV seropositivity. Sixty-four percent of injection drug users were positive (odds ratio [OR], 27.0; 95% confidence interval [CI], 13.4 to 56.1; P < .0001), as were all four hemophiliacs in the study. History of blood transfusion was significantly associated with HCV seropositivity (OR, 2.7; 95% CI, 1.1 to 7.0; P = .02). Positivity for HCV was not associated with measures of sexual behavior within couples or with numbers of other sexual partners, history of sexually transmitted diseases, or human immunodeficiency virus seropositivity. However, two of the 31 women without parenteral risk but with a long-term HCV-positive male partner were HCV seropositive compared with none of 81 women with an HCV-negative male partner (P = .07). CONCLUSIONS: These results provide little evidence of HCV sexual transmission but are consistent with infrequent sexual transmission. They corroborate the importance of injection drug use and transfusion of blood or blood products in transmitting HCV and underscore the importance of ascertaining parenteral exposures when examining sexual transmission of HCV.

Adult↗
PubMed1993

Comparison of risk factors for hepatitis C and hepatitis B virus infection in homosexual men.

Serum samples from 735 homosexual or bisexual men were tested for antibodies to hepatitis C virus (HCV) and serologic markers of hepatitis B virus (HBV), and risk factors for each infection were compared. Thirty-four (4.6%) were confirmed HCV-positive compared with 81% positive for one or more HBV serologic marker(s). History of intravenous drug use (IVDU) and blood transfusion were significantly associated with HCV positivity (odds ratio [OR] = 14.3 and 4.4, respectively), but neither was significantly associated with HBV positivity. Sexual behavior was significantly associated with infection with both viruses. When IVDU and blood transfusion were controlled for, HCV infection was marginally associated with > 50 sex partners/year (OR = 2.1), > 25 oral receptive partners (OR = 2.4), and > 25 anal receptive partners (OR = 1.9). HBV infection was more strongly associated with the same variables. HCV infection is uncommon in homosexual men and IVDU is the primary route of transmission, but sexual transmission also occurs, albeit infrequently.

Adult↗
PubMed1993

The characterization of non-progressors: long-term HIV-1 infection with stable CD4+ T-cell levels.

OBJECTIVE: To identify and characterize individuals with long-term HIV-1 infection who have experienced little or no progressive CD4+ T-cell loss during follow-up. PATIENTS AND METHODS: The rate of CD4+ T-cell loss (CD4 slope) was determined for each of the 290 participants in the San Francisco Men's Health Study who were seropositive at study entry in 1984. The study population was stratified, by CD4 slope, into 10 groups of 29 individuals and each group was characterized using a variety of cross-sectional and longitudinal laboratory measurements. RESULTS: Approximately 10% of the HIV-1-infected men experienced no net CD4+ T-cell loss during 78 months of follow-up. Compared with all other seropositive subjects, these 'non-progressors' were the extreme cases in a relatively continuous distribution of CD4 slopes, rather than a discrete subpopulation. Although they had no net cell loss, their mean CD4+ cell count was approximately 400 x 10(6)/l lower and their mean CD8+ cell count approximately 250 x 10(6)/l higher than seronegative subjects, suggesting early changes followed by stabilization. The CD4 slope was associated with the levels of beta 2-microglobulin, neopterin, p24 antibody, erythrocyte sedimentation rate, viral burden, and the proportion of HIV-1 isolates with tropism for the MT-2 T-cell line. Multivariate cluster analysis of these laboratory markers did not distinguish the non-progressors as a distinct subgroup. CONCLUSIONS: These findings support both a biphasic natural history and the suggestion that the broad range in HIV disease progression rates may be the result of several independent factors interacting in a variety of combinations. Recent changes in laboratory markers, known to predict both CD4+ cell loss and AIDS, suggest that non-progressors are undergoing slow HIV disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1993

HIV-1 PCR and isolation in seroconverting and seronegative homosexual men: absence of long-term immunosilent infection.

The presence of detectable HIV-1 prior to the appearance of HIV-1-specific antibody was assessed in 41 incident infections that occurred during a 6-year prospective cohort study. All available antibody-negative samples (n = 138) and the first antibody positive sample (n = 41) were tested, under code, by the polymerase chain reaction (PCR) in two laboratories and by HIV-1 isolation in a third laboratory. Samples were available as long as 66 months and at least 18 months before seroconversion for 24/41 subjects. An equal number of time-matched control specimens from persistently seronegative homosexual men and 103 samples from normal blood donors were also tested under code. Samples with discordant results were subjected to coded repeat analysis along with appropriate controls. All but one of the 41 first antibody-positive specimens (97.6%) were PCR positive and 65% were isolation positive. Two control specimens from seronegative homosexual men were PCR positive and one was culture positive, but HLA typing provided clear evidence of specimen mix-up in the specimen archive. For 37/41 seroconvertors, all available antibody negative specimens were negative by both PCR and virus isolation. In three cases, the specimen obtained 6 months before seroconversion was PCR and isolation positive. One specimen, obtained 12 months before SC, was PCR positive and isolation negative but was determined to be the result of sample contamination. Both PCR and isolation were negative in this subject 6 months before SC. In conclusion, we were unable to detect immunosilent infection > 6 months before seroconversion in high-risk homosexual men.

Adult↗
PubMed1993

Use of T lymphocyte subset analysis in the case definition for AIDS.

Infection with HIV-1 and < 200 CD4+ lymphocytes/mm3 has been proposed as an AIDS-defining condition. We have evaluated the effects of using this and other T-cell subset measurements, in the diagnosis of AIDS in two cohorts of homosexual/bisexual men in San Francisco. Among 762 HIV-1 infected men, 200 CD4+ lymphocytes/mm3 corresponded to 13 percent CD4+ lymphocytes and a CD4+/CD8+ ratio of 0.23. If these AIDS-defining criteria had been implemented in mid-1991, the number of living AIDS cases would have increased by 106 (212%), 133 (266%), and 136 (272%), respectively. When these criteria were first met, either before or in the absence of a clinical AIDS diagnosis, about half of the subjects were asymptomatic and the median clinically AIDS-free interval was approximately 2 years. Using two consecutive tests or pair-wise combinations of criteria reduced the number of cases identified by testing error or transient biological variation, but the number of living AIDS cases would still be increased more than twofold. Finally, any AIDS case definition using a specific T-cell subset value will be compromised by the inherent variability in these measurements and the substantial overlap in the results for those with and without clinical manifestations of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1992

The natural history and pathogenesis of HIV infection.

Infection with human immunodeficiency virus (HIV) results in progressive deterioration of the cell-mediated immune system characterized by T-helper-cell dysfunction and loss in the face of signs of generalized immune-system activation. The final stage of HIV disease, AIDS, has a myriad of opportunistic infections and malignancies as its hallmarks. The causal relationship between HIV and this complex disease pattern is clear but the mechanisms by which it occurs are not well understood. There are a number of new developments in our understanding of the natural history of HIV infection from a laboratory standpoint. Our review of this information raises further questions as to the validity of the conventional "cytopathic" model and all its direct descendants. In response to these conflicts, we have developed and present an alternative hypothesis in which AIDS pathogenesis, in all its manifestations, is seen as the outcome of one central process, excess immune activation generated by the interaction of virus with the CD4 receptor. The implications of this hypothesis on therapy of HIV infections are discussed.

HIV Infections↗
PubMed1992

The relationship between AIDS and immunologic tolerance.

A hypothesis is presented in which the immunodeficiency and cell loss leading to acquired immune deficiency syndrome and the clonal deletion associated with immunologic tolerance occur through a common mechanism. In a previous publication we proposed that the interaction of human immunodeficiency virus (HIV) with CD4 delivers activation signals that disrupt immune system regulation. In this article, we compare the biology of HIV infection with recent discoveries concerning the "two-signal" molecular mechanism for thymic selection. We propose that two-signal activation is normally followed by clonal expansion and the programmed death of most or all daughter cells through mechanisms that are proportional to the strength and duration of the activation signals. In the thymus, self-reactive cells are trapped in the continuous presence of both antigen signals (signal 1) and costimulatory signals (signal 2), leading to clonal deletion. In mature lymphocytes, we propose that HIV infection contributes a chronic high-affinity signal 2, which shifts the equilibrium of antigen-activated T-cell populations further toward programmed death. This leads to incremental memory cell deficits and gradual clonal deletion at a rate dependent on the frequency of antigen exposure and the ability of an HIV quasispecies to induce signal 2.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Production of site-selected neutralizing human monoclonal antibodies against the third variable domain of the human immunodeficiency virus type 1 envelope glycoprotein.

Cell lines secreting IgG1 human monoclonal antibodies (mAb) to the envelope glycoprotein, gp120, of human immunodeficiency virus (HIV) have been produced by transformation of peripheral blood cells from HIV-infected individuals and by fusion of transformed cells to a human-mouse heteromyeloma cell line (SHM-D33). Two human mAbs were site-selected by means of a 23-mer synthetic peptide spanning a portion of the third variable domain of gp120 from the MN strain of HIV. The two heterohybridomas produce three times more IgG than do their parent lymphoblastoid cell lines. The specificities of these mAbs have been mapped to sequences near the tip of the disulfide loop of the gp120 third variable domain, Lys-Arg-Ile-His-Ile and His-Ile-Gly-Pro-Gly-Arg, respectively. The mAbs have dissociation constants of 3.7 x 10(-6) M and 8.3 x 10(-7) M, neutralize HIVMN in vitro at nanogram levels, and bear the characteristics of antibodies associated with protective immunity in vivo.

Antibodies, Monoclonal↗
PubMed1991

Immune response to HIV p24 core protein during the early phases of human immunodeficiency virus infection.

The immune response to the p24 core antigen of human immunodeficiency virus type 1 (HIV-1) was studied in serial samples collected prospectively from 52 homosexual males in two separate cohorts from Amsterdam and San Francisco. p24 antibody levels were quantified with an antigen sandwich immunoassay using p24 recombinant antigen as capture and probe. Titers and slopes of dilution curves reflecting antibody affinity were analyzed. Only 45 of 52 men developed a measurable primary immune response to p24. In 17 (33%) patients there was a low response with maximum antibody titer below 66, shallow (low affinity) dilution curve, and 10 of the 17 became HIV antigen positive over a 2 year period. In 24 (46%) of the 52 patients titers ranged from 100-4000, steeper dilution curves were noted, and none became HIV antigen positive. Four (8%) men developed a strong immune response with high titers (greater than 12,000) and high affinity type dilution curve. Over time, after the peak immune response, antibody titer declined in some individuals related in part to the formation of immune complexes between HIV-1 p24 antigen and antibody which were dissociable. In vitro, the addition of increasing amounts of purified p24 antigen corresponded to decreasing antibody titer and a shallower dilution curve suggesting a preferential consumption of high affinity antibodies for complex formation. The magnitude of immune response to HIV-1 p24 antigen varies widely in infected homosexual men. Both the intrinsic ability to mount an immune response and immune complex formation contribute to the measurable antibody level.

Bisexuality↗
PubMed1991

Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics.

From a prospective cohort study, 24 asymptomatic men were identified who had been antibody positive for human immunodeficiency virus (HIV) for at least 5 years (median = 9.1) with CD4+ lymphocyte counts greater than or equal to 400 cells/mm3. Of these "nonprogressors", 23 (96%) had evidence of HIV infection by either HIV culture or the polymerase chain reaction (PCR) for HIV DNA, although only 1 (4%) had a positive assay for HIV RNA (by PCR) and no one was positive for p24 antigen. Compared with 24 antibody-negative men and 14 men with AIDS, nonprogressors had higher CD8+ counts and lower natural killer cell activity. Nonprogressors had higher beta 2-microglobulin levels than did seronegative controls, suggesting some degree of immune system activation. Compared with men with AIDS, nonprogressors seemed to have a stronger antibody response to six different HIV-related proteins but did not differ significantly in neutralizing antibody or antibody-dependent cellular cytotoxic activity.

Adult↗
PubMed1991

Lack of detection of human immunodeficiency virus in persistently seronegative homosexual men with high or medium risks for infection.

Some studies have suggested that seronegative homosexual men who have practiced high-risk sexual behavior can carry the human immunodeficiency virus (HIV) in a silent state, detectable only by polymerase chain reaction (PCR) or selective viral culture. To assess this concept, blood specimens were studied from 59 homosexual men with recognized risk behaviors: unprotected anal receptive intercourse at least once and many lifetime sex partners. After extensive virologic studies and PCR analysis, only one virus-positive, antibody-negative individual was identified. These findings indicate that HIV virus-positive, seronegative individuals are rare.

Adult↗
PubMed1991

The initial immune response to HIV and immune system activation determine the outcome of HIV disease.

A study was conducted to assess the relative contribution of the HIV-1-specific immune response and -nonspecific immune activation to HIV disease progression. The titer of antibody to the p24 core protein and the concentration of serum neopterin were measured in 238 HIV-1-seropositive subjects in a prospective cohort study of homosexual men. Antibody titers were extremely variable among cohort participants but relatively stable over time, suggesting inherent differences in the initial immune response capacity. Neopterin concentrations were also variable at cohort entry but generally increased over time. These two markers, measured at cohort entry, had powerful and independent predictive value for the development of AIDS up to 54 months before diagnosis. Subjects with low antibody titers and high levels of neopterin, had the highest incidence of AIDS (60% over 54 months). Patients with low antibody or high neopterin alone had an intermediate risk (34% incidence) and less than 10% of those with high antibody and low neopterin developed AIDS. We propose that the initial immune response to HIV and virus-mediated immune system activation are independent and innately variable components of an individual's response to HIV infection that interact to determine the clinical outcome.

Acquired Immunodeficiency Syndrome↗
PubMed1991

An evaluation of the polymerase chain reaction in HIV-1 seronegative men.

The apparent detection of human immunodeficiency virus (HIV-1) DNA by the polymerase chain reaction (PCR) in seronegative individuals has been the subject of great concern. In this study, 324 seronegative participants in the San Francisco Men's Health Study were evaluated for evidence of infection using a PCR testing algorithm with multiple amplifications targeting different regions of the HIV-1 genome. While most PCR reactions were negative, 8.6% of the specimens showed weak reactivity with one or more primer sets. However, all were negative with at least one primer set and no definitively positive specimens were identified. This study addressed the possibility that some of these PCR reactions might represent latent infection or abortive exposure, leaving residual integrated DNA, rather than false-positive reactions. The frequency of such reactions was determined in homosexual men who have been at risk for HIV-1 infection and in exclusively heterosexual men who have little or no past exposure. The results demonstrate an identical frequency and distribution of equivocal PCR reactions in both populations. Assuming that there is minimal HIV-1 infection among seronegative heterosexual men in San Francisco, we conclude that PCR testing does not provide evidence for a reservoir of occult HIV-1 infection in seronegative homosexual men.

Adult↗
PubMed1991

A multicenter proficiency trial of gene amplification (PCR) for the detection of HIV-1.

The sensitivity and specificity of the polymerase chain reaction (PCR) for the detection of HIV-1 proviral DNA was determined in five laboratories with extensive experience in PCR testing. Five panels consisting of 105 HIV-1-seronegative specimens from regularly repeating blood donors with no risk factors for HIV infection and 99 HIV-1-seropositive and culture-positive specimens from a cohort of homosexual/bisexual men were sent under code to each laboratory. Amplification procedures and testing algorithms by which specimens were judged positive, negative, or indeterminate varied between laboratories. The average sensitivity for the five laboratories was 99.0%, with two laboratories achieving 100%. The average specificity was 94.7%, varying between 90.5 and 100%. The overall false-positive rate was 1.8%, the false-negative rate was 0.8%, and the indeterminate rate was 1.9%. Of 1,005 determinations made by the five laboratories, 32 (3.2%) were misclassifications. Most of the classification errors occurred in specimens from uninfected individuals and were distributed among the laboratories in such a way as to indicate laboratory error rather than the inherent reactivity of some samples. This emphasizes the need for standardization of PCR testing and caution in interpreting positive PCR reactions in HIV-1-seronegative persons.

DNA, Viral↗