Conserved sequence and structural elements in the HIV-1 principal neutralizing determinant.

The principal neutralizing determinant (PND) of human immunodeficiency virus HIV-1 is part of a disulfide bridged loop in the third variable region of the external envelope protein, gp120. Analysis of the amino acid sequences of this domain from 245 different HIV-1 isolates revealed that the PND is less variable than thought originally. Conservation to better than 80 percent of the amino acids in 9 out of 14 positions in the central portion of the PND and the occurrence of particular oligopeptide sequences in a majority of the isolates suggest that there are constraints on PND variability. One constraining influence may be the structural motif (beta strand--type II beta turn--beta strand--alpha helix) predicted for the consensus PND sequence by a neural network approach. Isolates with a PND similar to the commonly investigated human T cell lymphoma virus IIIB (HTLV-IIIB) and LAV-1 (BRU) strains were rare, and only 14 percent of sera from 86 randomly selected HIV-1 seropositive donors contained antibodies that recognized the PND of these virus isolates. In contrast, over 65 percent of these sera reacted with peptides containing more common PND sequences. These results suggest that HIV vaccine immunogens chosen because of their similarity to the consensus PND sequence and structure are likely to induce antibodies that neutralize a majority of HIV-1 isolates.

Common epitope in human immunodeficiency virus (HIV) I-GP41 and HLA class II elicits immunosuppressive autoantibodies capable of contributing to immune dysfunction in HIV I-infected individuals.

We previously reported the identification of highly conserved homologous regions located in the carboxy terminus of the HIV I gp41-envelope (aa 837-844), and the amino-terminal of the beta chain of all human HLA class II antigens (aa 19-25). Murine monoclonal antibodies, raised against synthetic peptides from these homologous regions, bound not only to the isolated peptides, but also to the native gp160 and class II molecules. In this study one-third of sera from HIV I-infected individuals, at different disease stages, were found to react with both the gp41 and class II-derived peptides. These sera also reacted with "native" HLA class II molecules. The potential affects of such autoantibodies on normal immune functions were examined. It was found that in the presence of class II-cross-reactive (but not control) sera, the proliferative responses of normal CD4+ T cells to tetanus toxoid and allogeneic stimuli were markedly decreased. In addition, these sera could eliminate class II-bearing cells by antibody dependent cellular cytotoxicity. Similar affects were seen with affinity-purified IgG antibodies from patients' sera. Thus, the "molecular mimicry" between HIV I and HLA class II antigens, may lead to the generation of autoantibodies in HIV I-infected individuals that may contribute to the early functional impairment of CD4+ T cell observed in many HIV I-infected individuals.

Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging.

We have tested the T helper cell (TH) potential of asymptomatic, HIV seropositive (HIV+) patients, using an in vitro assay for IL-2 production. Peripheral blood leukocytes (PBL) from 74 HIV+ patients and 70 HIV- control donors were tested for TH function when stimulated with influenza A virus (FLU), tetanus toxoid (TET), HLA alloantigens (ALLO), or PHA. Of the HIV+ patients, four different response patterns were observed: (a) patients who responded to all four stimuli (16%); (b) patients who were selectively unresponsive to FLU and TET, but responded to ALLO and PHA (54%); (c) patients who were unresponsive to FLU, TET, or ALLO, but responsive to PHA (16%); and (d) patients who failed to respond to any of these stimuli (14%). Our results indicate a time-dependent progression from a stage responsive to all four stimuli to a stage unresponsive to any of the stimuli tested, progressing in the order outlined above. The earliest TH defect is the loss of responses to FLU and TET, indicating a selective defect in CD4+ MHC self-restricted TH function. The later loss of ALLO and PHA IL-2 responses suggests more severe TH dysfunction involving both CD4+ and CD8+ T cells. None of these patterns of TH unresponsiveness in asymptomatic HIV+ individuals were correlated with CD4+ cell numbers nor with Walter Reed staging criteria. This study indicates that the in vitro TH assay used can detect multiple stages of immune dysregulation early in the course of HIV infection and raises the possibility that staging of HIV+ patients should include in vitro TH functional analyses of the type described here.

Negative correlation between blood cell counts and serum neopterin concentration in patients with HIV-1 infection.

Hematopoietic disturbances are common in patients with HIV-1 infection. Recent studies on immune activation markers such as neopterin demonstrate that HIV-1 infection is associated with chronic immune activation. We investigated a possible association between serum neopterin concentrations and blood cell counts (CD4+ T cells, white blood cells, platelets, red blood cells) and hemoglobin and hematocrit in 94 HIV-1-seropositive individuals [52 Walter Reed (WR) stage 1, 31 WR2, one WR5, and 10 WR6]. There were significant negative correlations between neopterin concentrations and CD4+ T cells, hemoglobin, hematocrit and platelets. These correlations were also significant if either only WR1 and WR2 patients or the entire set of data were considered for calculations. Thus, hematological abnormalities are associated with chronic immune activation in patients with HIV-1 infection. Large amounts of neopterin are released by human macrophages on stimulation with interferon-gamma (IFN gamma), and tumor necrosis factor alpha (TNF alpha) further enhances the effect of IFN gamma. Therefore, our data suggest that activated immune cells and specific cytokines such as IFN gamma and TNF alpha are involved inhibiting hematopoiesis.

Spectrum of cerebrospinal fluid findings in various stages of human immunodeficiency virus infection.

This report summarizes the results of neurologic and cerebrospinal fluid (CSF) study findings in over 400 of the 649 human immunodeficiency virus-infected US Air Force personnel, evaluated as of Dec 31, 1987. Eighty percent of these patients were entirely asymptomatic and immunologically normal, 13% had low T-helper lymphocyte counts and/or cutaneous anergy, and only 7% had opportunistic infection. Sixty-three percent of all patients had some CSF abnormality. Sixty percent of the asymptomatic group had at least one abnormal result, over 25% had three or four CSF abnormalities, and over 7% had five or six abnormal values. When patients with evidence of blood-brain barrier leak were excluded, significant differences were seen between disease groups with regard to CSF glucose, CSF IgG levels, and CSF IgG synthesis. No human immunodeficiency virus-related central nervous system abnormalities were found on neurologic examination in immunologically intact asymptomatic patients regardless of CSF findings. No clear-cut predictor of impending central nervous system complications has, as yet, been identified from the CSF parameters studied.

Neuropsychological and neurological function of human immunodeficiency virus seropositive asymptomatic individuals.

Although individuals with acquired immunodeficiency syndrome (AIDS) are often impaired on a variety of neuropsychological tasks, questions remain as to when neuropsychological decline can be reliably detected during the course of human immunodeficiency virus (HIV) infection. Detailed neuropsychological testing was accomplished on a cohort of 83 immunologically and neurologically intact asymptomatic HIV-infected individuals drawn from a larger pool of 649 US Air Force personnel with HIV antibodies. These asymptomatic subjects were compared with a group of HIV-negative subjects, and no significant differences in neuropsychological functioning were found. No significant neuropsychological differences were found as a function of cerebrospinal fluid abnormalities in these asymptomatic subjects. When data from 13 subjects with immune compromise were included in the analyses, those with abnormal cerebrospinal fluid values performed significantly poorer on a task of verbal memory, suggesting that cognitive dysfunction is antedated by immunological decline. Methodological problems that inhibit specification of the incidence, prevalence, and natural history of HIV-related cognitive impairment are discussed, as are data suggesting that previously published high estimates of the frequency of HIV-related dementia may not be representative of all HIV-infected populations.

Cerebrospinal fluid anti-cardiolipin antibodies in patients with HIV-1 infection.

Both cerebrospinal fluid (CSF) immunologic abnormalities and serum anti-cardiolipin antibodies (aCL) have been reported in patients with HIV-1 infection. The antibody specificity of only a small amount of the total CSF IgG in these patients is known, and is directed against a variety of HIV-1 antigens. The specificity of the remaining CSF IgG is unknown. We report the results of the first study of CSF aCL in an HIV-1-infected population. We measured aCL IgG and IgM in the CSF of 21 HIV-1-infected patients without nervous system symptoms or AIDS, and in four HIV-1-negative controls. Twelve HIV-1-infected patients had an abnormal serum aCL value and CSF immunologic abnormalities and 9 HIV-1-infected patients had either abnormal serum aCL or CSF immunologic abnormalities but not both, or were normal in both regards. There was no difference between any HIV-1-infected patient and controls for CSF aCL IgM. Nine of 12 patients with an abnormal serum aCL and CSF immunologic abnormalities had CSF aCL IgG values that were at least 5 SD above normal control values, whereas none of the remaining patients had abnormal CSF aCL IgG values. All patients with abnormal CSF aCL IgG values had an intact blood-brain barrier as evidenced by an albumin index of less than 9, and all had nonreactive CSF VDRL tests. These data demonstrate that aCL IgG is produced intrathecally in some HIV-1-infected patients.

CD4+ monocyte counts in persons with HIV-1 infection: an early increase is followed by a progressive decline.

In this study, we asked whether there is a difference in the number of CD4+ and CD4- peripheral blood monocytes as CD4+ T cells decrease during HIV-mediated immunodeficiency. Monocytes and T cells from 90 HIV-positive and 43 HIV-negative persons were analyzed by flow cytometry. The 90 HIV-positive patients represented the entire spectrum of CD4+ T-cell counts. We report that as CD4+ T cells decrease, the number of CD4+ monocytes decrease in parallel. Moreover, significantly higher CD4+ monocyte counts were observed in persons with early stage HIV disease, i.e., greater than 800 CD4+ T cells/mm3, than in HIV-negative persons with greater than 800 CD4+ T cells/mm3. Potential implications of these findings are discussed.

The natural history of human immunodeficiency virus infection in screened HIV positive U.S. Air Force personnel: a preliminary report.

We prospectively studied 157 HIV antibody-positive U.S. Air Force personnel identified by universal ELISA screening and confirmed by Western blot. They were initially evaluated and then re-evaluated at least once at approximately 1 year intervals. In order to determine which if any demographic and serologic cofactors were significantly related to progression of immunodeficiency early in the course of disease, we compared these variables with the mean change in CD4 cells per month and with progression in Walter Reed stage. Upon entry into the study, the subjects were classified as follows: sex: 153 (97.5%) male, 4 (2.5%) female; race: 84 (53.5%) white, 63 (40.1%) black, 8 (5.1%) Hispanic, and 2 (1.3%) Oriental; age: mean of 28.6 years (63.0% between 20 and 32 years); and Walter Reed stage: 108 (68.8%) Walter Reed 1, 26 (16.6%) Walter Reed 2, 9 (5.7%) Walter Reed 3, 6 (3.8%) Walter Reed 4, 5 (3.2%) Walter Reed 5, and 3 (1.9%) Walter Reed 6. The mean follow-up period was 12.2 months (range of 2 to 35 months). The mean change in CD4 cells per month was -0.072 (range of -94.75 to +67.58). Factors at entry that are significantly related to loss of CD4 cells included serum IgA over 300 mg/dl (p = 0.0450) and anergy (p = 0.0093). Factors at entry significantly related to progression in Walter Reed stage included serum IgA over 300 mg/dl (p = 0.0001), low absolute CD4 count (p = 0.0001), and low CD4/CD8 ratio (p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

CSF changes in a longitudinal study of 124 neurologically normal HIV-1-infected U.S. Air Force personnel.

Over a 2 year period, 124 neurologically normal HIV-1-infected patients had three successive cerebrospinal fluid (CSF) examinations approximately 1 year apart. Immunological status as measured by absolute CD4 counts in the blood identified two groups of patients over time: (a) a group with progressive CD4 decline (66 patients), and (b) a group with stable CD4 counts (58 patients). These two study groups provided us the opportunity to compare CSF changes (cells, protein, albumin index, IgG, IgG index, and IgG synthesis rate) in neurologically normal individuals with respect to immunological status over time. We found significantly increased intrathecal cellular response and IgG production over time independent of CD4 group. We conclude that any clinical study comparing CSF findings in neurologically symptomatic HIV-infected individuals must recognize and control for these CSF changes in neurologically asymptomatic patients.

Comparison by race of total serum IgG, IgA, and IgM with CD4+ T-cell counts in North American persons infected with the human immunodeficiency virus type 1.

European patients with human immunodeficiency virus type 1 (HIV-1) infection have been reported to have lower titers of anti-p24 antibody than Central African HIV seropositive patients. Recently, black HIV positive patients in the United States were reported to be more likely to have detectable anti-p24 antibodies, less p24 antigenemia, and higher combined serum immunoglobulins than white HIV positive patients. We measured individual total serum immunoglobulins in 853 HIV positive patients (94% male; 58% white and 42% black) on their initial medical evaluation and compared them with CD4+ T-cell counts. Blacks had notably higher IgG levels (p = 0.001) across the entire spectrum of CD4+ T-cell counts. Serum IgM levels were slightly higher in blacks. IgA levels were not significantly different between the races, although the trend (p = 0.006) was toward higher levels in whites. We also measured these three serum immunoglobulins in 60 HIV seronegative, healthy blood donors (30 black and 30 white). In this control group, blacks had statistically higher IgG and IgA levels than whites. A review of the literature prior to the HIV/acquired immune deficiency syndrome epidemic also supports the view that racial differences in IgG levels are not specific for HIV infection. We speculate that racial differences in humoral immunity, independent of geography or strain of HIV, may account for differences in anti-HIV antibody levels and HIV antigenemia.

Hepatitis C antibody in a non-hemophiliac cohort infected with the human immunodeficiency virus.

Development of a serologic test which detects antibody to hepatitis C virus (anti-HCV) allowed us to compare the seroprevalence of hepatitis C and hepatitis B in 493 persons infected with the human immunodeficiency virus (HIV). These persons, none of whom are hemophiliacs, are part of the US Air Force HIV Natural History Study. We found that Hepatitis B core antibody (anti-HBc) was far more prevalent (59%) than anti-HCV (8%). Anti-HBc prevalence was not different between those with and those without anti-HCV, being present in the majority of persons in both groups. In addition, we compared anti-HCV+ and anti-HCV negative persons in terms of syphilis serologies (Reactive Plasma Reagent [RPR] and Fluorescent Treponemal Antibody Absorption [FTA-ABS]), hepatic transaminase levels, and racial composition. In this cohort, we found that anti-HCV+ persons are significantly more likely to have a positive RPR but not FTA-ABS, increased hepatic transaminase levels, and to be Black rather than Caucasian.

In vivo and in vitro comparison of fire ant venom and fire ant whole body extract.

Thirty-four patients with a history of immediate hypersensitivity to the sting of the imported fire ant were evaluated in a study designed to compare the diagnostic usefulness of fire ant whole body extract (WBE) preparations with that of fire ant venom (IFAV). Ninety-one percent (31/34) of the hypersensitive patients skin tested with IFAV at a maximal concentration of 1:5 X 10(3), v/v, demonstrated a wheal equal to or greater than the histamine control. Fifty-three percent (18/34) of the group were skin test positive to a WBE preparation. When the criteria for a positive skin test were relaxed, 82% of the hypersensitive group could be identified with the IFAWBE. A comparison of skin test results in sensitive patients revealed variability in the sensitivity of the WBE preparations utilized in the study. Leukocyte histamine release demonstrated a dose-response release of histamine with both IFAV and SIWBEa preparations. Specific venom antisera produced in rabbits identified a precipitin line of common identity in a gel-diffusion system containing IFAWBE and IFAV. This finding was verified by the competitive inhibition of IFAWBE with IFAV in a solid-phase radioimmunoassay system. Fire ant WBEs contain venom constituents and are effective diagnostic agents in up to 82% of patients with hypersensitivity to the sting of the imported fire ant. Marked variability in the responsiveness of sensitive patients to different WBE preparations mandates standardization of these diagnostic preparations.