A longitudinal study of neutralizing antibodies and disease progression in HIV-1-infected subjects

Sera from human immunodeficiency virus-1-infected participants in the Multicenter AIDS Cohort Study were tested to assess the association between serum neutralizing antibodies (NAbs) and disease progression. Each of 14 pairs, retrospectively matched for age, sex, race, and CD4+ lymphocyte numbers early in the study, consisted of a rapid progressor (RP) who developed AIDS and a long-term nonprogressor (LTNP) who remained asymptomatic. Serum samples were drawn early, when all participants were asymptomatic, and late, when the RPs had developed clinical AIDS. The LTNPs and RPs had similar levels of NAbs against primary isolates at the early time point, indicating that NAb levels are not predictive of disease progression; at the late time point, the LTNPs had significantly higher titers because of an increase in the level of serum NAbs in the LTNPs and/or a decrease in the NAbs in the RPs. The patterns of neutralizing activity over time suggest that changes in effective NAbs against different viruses do not occur in parallel.     

Immunodominant epitopes of HIV-1 p17 and p24.

Immunodominant antibody-binding sites were mapped using overlapping synthetic peptides of the structural proteins p17 and p24 of human immunodeficiency virus type 1 (HIV-1). Using sera from HIV-1-infected individuals at a variety of disease states, three major epitopes were identified within p17 and one within p24. Antibodies which recognized these epitopes were present in all risk groups throughout all stages of HIV infection, regardless of the presence of high levels of serum p24 antigen.     

Cellular and antibody responses directed against the HIV-1 principal neutralizing domain in HIV-1-infected children.

The principal neutralizing domain (PND) for antibody response is located within the V3 variable region of gp120 and can also stimulate T-cell responses. In some adults infected with human immunodeficiency virus (HIV) an HIV-1-specific T-cell response can be detected by demonstrating in vitro proliferation to HIV-1 proteins and peptides. In other HIV-1 infected adults an HIV-1-specific T-cell response can involve interleukin 2 (IL-2) secretion in the absence of T-cell proliferation. To elucidate the T-cell responses to PND in children, we examined the proliferative and the IL-2 secretory responses of peripheral blood lymphocytes from 19 HIV-1-infected children toward a peptide which contained a highly conserved sequence of the principal neutralizing domain of HIVMN (PND-MN). Stimulation with PND-MN induced proliferation of lymphocytes from 2 of the children and IL-2 secretion by lymphocytes from 5 of the children. In a 3-month-old infant, the in vitro cellular response to the PND-MN indicated HIV-1 infection prior to the detection p24 antigen in her serum. Although antibodies directed against PND-MN were detected in all but one of the children examined, the presence of high-affinity/avidity antibodies to the PND-MN correlated with the presence of a cellular response to PND-MN. Thus, in HIV-1-infected children an HIV-1 specific T-cell response in the absence of a proliferative response can be assessed by determination of the IL-2 secretory response and correlates with the generation of high-affinity/avidity antibodies.     

Proliferative responses to human immunodeficiency virus type 1 (HIV-1) antigens in HIV-1-infected patients with immune reconstitution

Cell-mediated immunity is affected early in human immunodeficiency virus type 1 (HIV-1) infection. HIV-1-specific CD4+ T cell proliferative responses are not measurable in most patients but have been reported in long-term nonprogressors and in patients treated with highly active antiretroviral therapy (HAART) during primary infection. However, treatment with HAART generally does not restore HIV-1-specific CD4+ T cell responses in chronically infected patients. In this study, HIV-1-specific CD4+ T cell responses in 10 HIV-1-infected patients who began HAART with low CD4 cell count nadirs and experienced significant immune reconstitution were studied. Surprisingly, 5 of these patients had proliferative responses to > or =1 HIV-1 gene product, compared with 0 of 8 chronically infected patients who started HAART when their CD4 cell counts were still relatively high. These results suggest that, in some patients with advanced HIV-1 infection, treatment with HAART can lead not only to significant increases in CD4 cell counts but also to the restoration of HIV-1-specific responses.     

Decline of antibody reactivity to outer viral core protein p17 is an earlier serological marker of disease progression in human immunodeficiency virus infection than anti-p24 decline

Using a modified immunoblot procedure we looked for early serological markers of disease progression in sequential serum samples from 30 initially symptomless HIV-infected homosexual men. Sixteen men who did not progress beyond persistent generalized lymphadenopathy (PGL) and did not develop HIV antigenaemia showed persistent strong immunoglobulin G (IgG) reactivity to all initially recognized HIV proteins. Three out of four men who did not progress beyond PGL but did develop HIV antigenaemia showed declining or absent IgG reactivity to the outer HIV core protein p17, whereas reactivity to other initially recognized HIV proteins persisted in all four; in one of these subjects a striking decline in anti-p17 reactivity occurred 1 1/2 months after HIV antibody seroconversion and 7 1/2 months before HIV antigenaemia developed. In nine out of 10 men who developed constitutional disease [Centers for Disease Control (CDC) group IV A] or AIDS (CDC groups IV C1 and IV D), a decline in anti-p17 reactivity was seen preceding or at disease development; in two of these men a concomitant decline in anti-p24 reactivity was seen. In the only individual without HIV antigenaemia who developed CDC group IV disease, anti-p17 reactivity declined 10 months before disease development, whereas no similar decline in anti-p24 reactivity was seen. Decline in IgG antibody reactivity to HIV core protein p17 appears to be an earlier marker of disease progression than the previously reported decline in anti-p24 reactivity, and may be of value in selecting individuals for secondary prevention of HIV-related disease development.     

Paradoxical responses in a cohort of HIV-1-infected patients with mycobacterial disease.

SETTING: Paradoxical worsening or relapse of opportunistic infections has been described after initiation of highly active anti-retroviral therapy (HAART) in human immunodeficiency virus (HIV) infected patients. DESIGN: Retrospective study of a group of 33 HIV-infected patients with mycobacterial disease analysing the incidence and characteristics of patients with and without paradoxical response after starting HAART and/or mycobacterial treatment. RESULTS: Nine patients in the group had paradoxical response. No significant difference of baseline characteristics was observed in these patients. The decrease in viral load was significantly greater among patients with paradoxical response than in patients without. CONCLUSION: No clinical difference was found in the evolution of HIV-infected patients with mycobacterial disease after the resolution of the episode of paradoxical response.     

Polymorphisms of innate immunity genes influence disease progression in HIV-1-infected children

Toll-like receptors (TLRs) and defensins (DEFs) play a crucial role in the host's innate immunity and may influence HIV-1 disease progression. We investigated the impact of TLR9 +1174G?>?A, 1635A?>?G and DEFβ1 -44C?>?G, -52G?>?A single nucleotide polymorphisms on the clinical outcome of 95 HIV-1-infected children. The TLR9 1635AG genotype and TLR9 [G;G] haplotype were associated with rapid disease progression, whereas the DEFβ1 -44CG genotype and DEFβ1 [G;G] haplotype correlated with a better clinical outcome.     

Homocysteine and cardiovascular disease: a 17-year follow-up study in Busselton.

STUDY OBJECTIVE: Prospective assessment of serum homocysteine level in relation to risk of coronary heart disease (CHD) and stroke. DESIGN: Case-cohort study with 17 years follow up. METHODS: Homocysteine was measured from stored serum. Proportional hazards regression models were used to obtain adjusted hazard ratios. RESULTS: There was no significant overall relationship between homocysteine and cardiovascular disease after controlling for known confounders. For women, removal of creatinine from the multivariate model resulted in a significant relationship. CONCLUSIONS: These results provide little support for a significant independent relationship between level of homocysteine and risk of CHD or stroke in men and women with no evidence of pre-existing cardiovascular disease.     

HLA phenotype is a factor in determining rate of disease progression and outcome in HIV-1-infected individuals.

HLA allele frequencies were examined for possible association(s) with the rate of disease progression and with the disease outcome (AIDS diagnosis) in a population of HIV-1-infected individuals. Certain alleles were associated with the relative rate of CD4+ T-cell decline. Association of particular alleles with several disease outcomes associated with infection was also observed. It is important to keep these two aspects (disease progression, AIDS diagnosis) separate when studying HLA in the HIV-1-infected population. Alleles that may play a role in the rate of virus speed by effecting the immune response may be different from those found to be associated with a particular disease. We feel that the only truly informative data, in this regard, can be generated from a relative precise determination of the time of infection (to study disease progression) and adequate numbers of individuals with specific diseases to study specific disease association. If such data can be generated we will have a much better understanding of the pathogenetic process(es) of HIV-1 infection.     

Immunologic and virologic responses to HAART in severely immunocompromised HIV-1-infected children

OBJECTIVE: To determine the long-term immunologic and virologic effects of highly active antiretroviral therapy (HAART) in children with AIDS. DESIGN: A prospective observational study. SETTING: Two pediatric HIV clinics. PARTICIPANTS: Twenty-five protease-inhibitor naive HIV-infected children (aged 2-18 years) with advanced disease (CD4 < or =6%). INTERVENTION: HAART (one protease inhibitor and one or more nucleoside analogs). Diphtheria and tetanus immunization in six patients after 18 months of therapy. MAIN OUTCOME MEASURES: Changes in percentage of CD4 cells and plasma HIV-1 RNA levels; post-treatment assays of lymphoproliferative responses to recall antigens; CD4 cell memory phenotype. RESULTS: Median duration of follow-up was 18.8 months (range, 7.5-28 months). At baseline the CD4 cell percentage was 2% (range, 0-6%), this increased significantly to 16% (range, 3-48%) above baseline at 12 months (P = 0.002). The mean maximum CD4 cell increase was 20.7% (range 4-48%) which corresponds to 657x10(6) cells/l (range, 30-2240x10(6) cells/l) above baseline. By contrast, the median viral load was not significantly lower at 12 months than at baseline (P = 0.34), and only 25% of the patients had sustained undetectable viral load. Of the reconstituted CD4 cells 70% were naive, and none of the subjects had lymphoproliferative responses to tetanus and diphtheria although 40% did develop responses to Candida, an environmental antigen. A single immunization with diphtheria and tetanus toxoid produced lymphoproliferative responses to tetanus in three out of six patients. CONCLUSIONS: HAART was associated with sustained increases in CD4 cell counts, despite a high incidence of 'virologic failure'. CD4 counts and the proportion of naive cells were higher than have been reported in adults, which may be a reflection of greater thymic activity in children. Memory cell clones for antigens encountered in the past which are not prevalent before therapy could not be expanded without additional antigenic exposure.     

A 17-year follow-up study of hypertensive and normotensive male university students in Japan.

The aim of the present study was to determine the disease course of hypertensive male university students followed for 8 to 26 years (average, 17 years) after graduation. Subjects were classified into two groups. 1) A hypertensive group (H-group) consisting of 338 conclusively hypertensive male students followed from 1973 to 1990 at the Institute of Health Science, Kyushu University. Their ages ranged from 20 to 27 years, and all had high blood pressure (BP) of 140 mmHg or greater in systole (SBP) and/or 90 mmHg or greater in diastole (DBP) at a regular health check. This was confirmed by BP measurements for 3 days within 1 week. 2) A normotensive control group (N-group) consisting of 732 normotensive students (110-124 SBP/60-74mmHg DBP) for whom faculty, age, sex, height, weight, and examination period were matched to the H-group as closely as possible. In 1997, each subject was sent a questionnaire with items on height, weight, sitting BP, pulse rate, family history of hypertension, lifestyle habits (such as drinking and smoking), stress and personality type. Completing the questionnaire were 177 (52.4%) of the H-group and 206 (28.1%) of the N-group subjects. Hypertension continued in 44.6% of the H-group subjects, whereas 9.2% of the N-group subjects became hypertensive. The rate of hypertension at the end of the investigation was significantly higher in those subjects who had a family history of hypertension than in those who did not. Weight gain (+15.1%) was the highest in H-group subjects who were initially normotensive. These subjects showed a significantly higher incidence of smoking and drinking than the other subjects. These results confirmed lifestyle to be one of the most important factors in keeping BP normal throughout life and also suggested that fundamental health education should be introduced at an early age.     

The influence of lymphocyte counts and disease progression on circulating and inducible anti-HIV-1 cytotoxic T-cell activity in HIV-1-infected subjects.

OBJECTIVE: To evaluate specific anti-HIV cytotoxic T-lymphocyte (CTL) activity in relation to basic clinical and laboratory parameters used to follow HIV infection. METHODS: Lymphocytes from HIV-1-infected subjects with different clinical and immunologic features of HIV infection were tested for circulating and inducible anti-HIV CTL activity using autologous B-lymphoblastoid cells infected with recombinant vaccinia viruses expressing the HIV gag, pol and env genes as targets. Anti-HIV CTL were induced by stimulation with HIV-infected autologous lymphoblasts in vitro. RESULTS: We detected circulating anti-HIV CTL in asymptomatic subjects exclusively and found a significant association (P < 0.01) between CD8+ lymphocyte counts > or = 900/microliters blood and detectable levels of circulating anti-HIV CTL. Subjects with circulating anti-HIV CTL also had a higher mean CD8+ lymphocyte count than those without detectable circulating activity (P < 0.001), but there was no significant difference in mean CD4+ lymphocyte count. CD8+ human histocompatibility leukocyte antigen (HLA) class I-restricted anti-HIV CTL were induced in all HIV-infected subjects tested following stimulation with HIV-infected autologous lymphoblasts in vitro. In subjects without detectable circulating anti-HIV CTL, circulating HLA-DR+ cells contributed to anti-HIV CTL activity induced by stimulation with HIV or concanavalin A in vitro. CONCLUSIONS: Circulating anti-HIV CTL activity is associated with CD8+ lymphocyte counts > or = 900/microliters. Anti-HIV CTL retain proliferative and functional capacity following in vitro stimulation with HIV and interleukin-2 through all stages of HIV infection. Persistent inducible anti-HIV CTL activity in subjects with advanced HIV disease and without circulating CTL suggests impaired activation and/or proliferation of the CTL in vivo.     

Irritable bowel syndrome--prognosis and diagnostic safety. A 5-year follow-up study

The irritable bowel syndrome is the commonest diagnosis in gastroenterological clinics, although diagnostic criteria and investigatory programs vary. To elucidate the diagnostic safety and prognosis of the syndrome, a retrospective study was conducted. One hundred and twelve consecutive patients with irritable bowel syndrome as the final and only abdominal diagnosis in the period 1977-79 were followed up in 1984. Seventeen patients died during the follow-up period; two of these were considered diagnostic failures (chronic pancreatitis and pancreatic cancer). Of the remaining 95 patients, 93 were available for the follow-up study. Three diagnostic failures were found (gallbladder stones, kidney stone, thyrotoxicosis). The diagnostic failure rate was accordingly 4.5% (5/110). Half of the patients had unchanged or aggravated symptoms at the follow-up study, independent of treatment. The only predictor of a poor prognosis was abdominal surgery before the diagnosis.     

Broad spectrum of coreceptor usage and rapid disease progression in HIV-1-infected individuals from Central African Republic

To study the progression of HIV-1 infection and coreceptor usages in Central African Republic, clinical data, plasma viral load, and coreceptor usage of sequential HIV-1 isolates were analyzed in a seroincident prospective cohort (PRIMOCA). Twenty-three HIV-1 infected individuals from the Central African Armed Forces were followed from 1995 to 2000. Viruses were isolated from 17 patients at various time points after seroconversion and their coreceptor usage was examined using GHOST cells expressing CD4 and one of the HIV-1 chemokine coreceptors CCR5, CXCR4, BOB/GPR15, and Bonzo/STRL33/CXCR6. Eleven patients died from AIDS. Eight of them died between 2 and 5 years after seroconversion, after a brief symptomatic stage. Patients who rapidly progressed to AIDS and death displayed the highest viral loads after seroconversion. All isolates obtained soon after seroconversion used CCR5, albeit, in some cases, CXCR4, BOB, or Bonzo were also used. Most isolates remained R5 (59 out of 61 isolates), although viruses using CXCR4 appeared in some cases of progression to AIDS. In several cases, a broad tropism was observed during the course of infection, with a frequent usage of BOB and Bonzo in addition to CCR5. Rapid progression to disease and short survival time among Central African HIV-1 patients appear more frequent than those reported in industrialized countries. Viral coreceptor used was mainly CCR5, but, interestingly, a large part of isolates also used BOB and Bonzo. However, there was no strict correlation between the clinical outcome and extended viral tropism.