Stefan Lindbäck

Cutting Edge: The Prevalence of Regulatory T Cells in Lymphoid Tissue Is Correlated with Viral Load in HIV-Infected Patients

Inadequate local cell-mediated immunity appears crucial for the establishment of chronic HIV infection. Accumulation of regulatory T cells (Treg) at the site of HIV replication, the lymphoid organs, may influence the outcome of HIV infection. Our data provide the first evidence that chronic HIV infection changes Treg tissue distribution. Several molecules characteristics of Treg (FoxP3, CTLA-4, glucocorticoid-induced TNFR family-related receptor, and CD25) were expressed more in tonsils of untreated patients compared with antiretroviral-treated patients. Importantly, most FoxP3+ cells expressed CTLA-4, but not CD69. Furthermore, a direct correlation between FoxP3 levels and viral load was evident. In contrast, FoxP3 expression was decreased in circulating T cells from untreated patients, but normalized after initiation of treatment. Functional markers of Treg activity (indoleamine 2,3-dioxygenase, TGF-β, and CD80) were markedly increased in the tonsils of untreated patients. Our data could provide a new basis for immune-based therapies that counteract in vivo Treg and thereby reinforce appropriate antiviral immunity.

Viral dynamics in primary HIV-1 infection.

ObjectivesTo study the natural course of viremia during primary HIV infection (PHI). MethodEight patients were followed from a median of 5 days from the onset of PHI illness. Plasma HIV-1 RNA levels were measured frequently and the results were fitted to mathematical models. HIV-1 RNA levels were also monitored in nine patients given two reverse transcriptase inhibitors and a protease inhibitor after a median of 7 days from the onset of PHI illness. ResultsHIV-1 RNA appeared in the blood during the week preceding onset of PHI illness and increased rapidly during the first viremic phase, reaching a peak at a mean of 7 days after onset of illness. This was followed by a phase of rapidly decreasing levels of HIV-1 RNA to an average of 21 days after onset. Viral density continued to decline thereafter but at a 5- to 50-fold lower rate; a steady-state level was reached at a median of 2 months after onset of PHI. Peak viral density levels correlated significantly with levels measured between days 50 and 600. Initiation of antiretroviral treatment during PHI resulted in rapidly declining levels to below 50 copies/ml. ConclusionsThis study demonstrates the kinetic phases of viremia during PHI and indicates two new contributions to the natural history of HIV-1 infection: PHI peak levels correlate with steady-state levels and HIV-1 RNA declines biphasically; an initial rapid decay is usually followed by a slow decay, which is similar to the initial changes seen with antiviral treatment.

Diagnosis of primary HIV-1 infection and duration of follow-up after HIV exposure

ObjectiveTo determine the sensitivity of 33 currently available and seven earlier tests for the detection of HIV or HIV antibody in primary HIV-1 infection, to estimate the duration of the ‘window period’ and the influence of early initiated antiretroviral treatment (ART). DesignA prospective cohort study of 38 patients with primary HIV-1 infection. ART was initiated at a median time of 13 (range 0–23) days after the onset of symptoms in 10 patients. Main outcome measuresThe time from infection to onset of symptoms and from onset of symptoms to the appearance of HIV antibody as measured by 36 different tests, and the start and duration of viraemia, as detected by four different tests. ResultsThe illness appeared 13–15 days after infection in 12 of 15 determinable cases, and seroconversion was detected within 1–2 weeks after the onset of illness by 27 of 30 currently available tests for HIV antibody, in contrast to the 2–7 weeks or more needed by the old tests. HIV RNA appeared during the week preceding the onset of illness and was detected in all subsequent samples, except when ART had been initiated, which also induced a delay of the antibody response. ConclusionMany tests for HIV or HIV antibody can now be employed for an early confirmation of primary HIV infection (PHI). Currently available screening tests proved much more sensitive than older tests, and seroconversion was usually detected within one month after infection. Consequently, in Sweden we now recommend only 3 months of follow-up after most cases of HIV exposure.

Does symptomatic primary HIV-1 infection accelerate progression to CDC stage IV disease, CD4 count below 200 x 10(6)/l, AIDS, and death from AIDS?

Abstract Objective: To investigate the prognostic significance of symptomatic primary HIV-1 infection. Design: Prospective study of homosexual men seroconverting to HIV in 1985 and 1986. Patients were followed up at least three times yearly with clinical examinations and T cell subset determinations for an average of 7.2 years. Setting: Research project centred on attenders for treatment and screening for HIV at the Karolinska Institute, Stockholm. Subjects—19 patients presenting with a glandularfever-like illness associated with seroconversion to HIV and 29 asymptomatic seroconverters. Main outcome measures: Progression to Centers for Disease Control and Prevention stage IV disease, CD4 cell count below 200 × 106/l, AIDS, and death from AIDS. Results: Symptomatic seroconverters were significantly more likely to develop Centers for Disease Control and Prevention stage IV disease (95% (upsilon) 66%), CD4 cell counts below 200 × 106/l (84% (upsilon) 55%), and AIDS (58% (upsilon) 28%) and die of AIDS (53% (upsilon) 7%). Conclusion: A glandular-fever-like illness associated with seroconversion to HIV-1 predicts accelerated progression to AIDS and other HIV related diseases.

Evaluation of 14 commercial HIV-1/HIV-2 antibody assays using serum panels of different geographical origin and clinical stage including a unique seroconversion panel.

The performance of 14 commercially available HIV-1/2 antibody assays were compared using well-characterized serum panels containing in total 1500 1800 sera. The panels included consecutive HIV-negative blood donor sera from Sweden, unselected blood donor and patient sera from Tanzania and unselected sera from outpatient clinics in Guinea-Bissau. Furthermore selected HIV-1 antibody positive sera from Sweden and Tanzania and HIV-2 antibody positive sera from Guinea-Bissau were included in the panels. The HIV-1 antibody positive sera were from individuals at various stages of HIV infection, from primary infection, to asymptomatic phase and late stage disease. 12 of the 14 assays identified correctly all HIV-1 and HIV-2 antibody positive sera. One Tanzanian HIV-1 antibody positive sample with complete banding pattern on Western blot was not detected by two of the ELISAs employing synthetic peptides. There were small differences in sensitivity between the assays when used for analysis of seroconversion panels. The most sensitive assay, Abbott IMx HIV-1/HIV-2 III Plus detected antibodies in all nine samples collected from four individuals during the first week after onset of symptoms of primary HIV-1 infection. Most of the assays became reactive during the second week after onset of symptoms and the least sensitive assays were reactive from the third week. The assays showed a high specificity ranging from 99.2 to 100% when used for analysis of Swedish blood donor sera, while most of the assays showed a significantly lower specificity, 91.9-99.6%, when used for testing African specimens.

Longer survival after HIV infection for injecting drug users than for homosexual men: implications for immunology.

Background: Comparisons of progression in HIV‐1 infection between injecting drug users (IDU) and homosexual men have been inconclusive due to short follow‐up periods, often with less well‐defined starting points and endpoints. In addition, comparisons of survival after infection have been to some extent obscured by higher non‐AIDS mortality in IDU. Methods: In a retrospective cohort study, homo‐/bisexual men and IDU were followed, with dates of seroconversion defined within ± 1 year by a previously negative HIV antibody test. Endpoints were CD4 cell count below 200 × 106/l, AIDS, and death from AIDS. Results: Sixty‐three homo‐/bisexual men and 125 IDU fulfilled the entry criteria, with no significant differences in age at or date for seroconversion. Mean follow‐up times were 6.7 and 7.0 years, respectively. The homo‐/bisexual group had a significantly accelerated progression rate to all three endpoints: time to CD4 cell count below 200 × 106/l (P= 0.002), to AIDS (P = 0.0003), and to death from AIDS (P < 0.0001). Adjusting for age and sex only made marginal alterations. Ten years after infection, 54% of homosexual men had developed an AIDS‐defining condition and 51% had died from AIDS, whereas the corresponding percentages in the IDU group were 26 and 15%, respectively. There was, however, no difference in overall mortality due to an almost constant, non HIV‐related, yearly mortality of some 4% in IDU. Conclusions: In our cohort there was a highly significant difference in disease progression and death from AIDS between homo‐/bisexual men and IDU. This difference was proposed to be due to the transmission route determining the initial immune response and suggested that this route may have played a more important role than virus variability on the subsequent prognosis.

Characterization of the viral population during primary HIV-1 infection.

Objective:To study viral heterogeneity at a very early phase of primary HIV-1 infection. Design:Samples were drawn very early during primary HIV-1 infection. A virus population-based approach was used to study the viral heterogeneity in the C2–V3 and p17 regions. Methods:Plasma samples (n = 33) were obtained before or shortly after onset of acute symptoms in 15 patients. In all subjects, the first sample was drawn within 10 days after onset of symptoms. Peripheral blood mononuclear cells (PBMC) were available in two patients. The number of polymorphic sites in the C2–V3 (15 patients) and p17 regions (eight patients) were determined by direct sequencing. Results:The sequence heterogeneity was restricted in most patients, although only two out of 15 patients had a completely homogeneous C2–V3 sequence. However, pronounced individual differences were seen. Rapid sequence changes occurred during the first month in two patients. In one patient, the major DNA species at day 12 later became the major species in plasma. Conclusions:The viral population is seldom completely homogeneous during primary HIV-1 infection, although the heterogeneity is restricted in most, but not all, patients. These individual differences do not seem to be due to sex or viral subtype. Rapid changes of the virus population may occur during primary HIV-1 infection. The DNA species detected in PBMC do not only represent earlier viral quasispecies but are also a potential source of future viral RNA species.

Zidovudine in the management of primary Hiv-1 infection

Eleven subjects who presented with a clinical illness characteristic of primary HIV-1 infection were treated with 1 g zidovudine daily for a median period of 56 days (range, 28–111 days). Primary HIV-1 infection was confirmed in each subject by seroconversion and virus isolation. The acute phase of the illness resolved a median of 4 days (range, 3–14 days) from commencement of zidovudine. Six subjects reported symptoms that may have been side-effects of zidovudine, the most common being nausea in four subjects and headache in two. Treatment was discontinued in one subject who had persistent headache and nausea. Haemoglobin, haematocrit and erythrocyte counts decreased and mean corpuscular volume increased significantly during the treatment. None of the subjects developed anaemia and none required dose modification or blood transfusion as a result of haematological side-effects. There were no significant differences in the granulocyte count or the lymphocyte count during any week of treatment when compared with baseline levels. There were no significant differences in T-cell subset numbers of the subjects during treatment compared with a group of historical controls. HIV-1 was isolated from several subjects during and after termination of zidovudine treatment. The results of this investigation indicate that zidovudine is a safe drug to administer to people with primary HIV-1 infection. There was no clear evidence, however, of any clinical benefit in terms of resolution of the acute illness and no indication that the treatment would prevent development of persistent infection. Nevertheless, the results urge the establishment of a placebo-controlled trial to further evaluate this treatment and its effect on long-term outcome in people with primary HIV-1 infection.

Adherence to treatment in Swedish HIV-infected patients

Objectives:  The objectives were to assess the prevalence of adherence to antiretroviral treatment in Swedish human immunodeficiency virus (HIV)‐infected patients and to evaluate factors associated with adherence.

The Value of C-reactive Protein as a Marker of Bacterial Infection in Patients with Septicaemia/Endocarditis and Influenza

In order to evaluate the capacity of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell count (WBC) and polymorphonuclear neutrophils (PMNs) to differentiate between bacterial and viral infection we studied 176 patients with septicaemia/endocarditis (SE), 59 patients with uncomplicated influenza (UI) and 22 patients with complicated influenza (CI) retrospectively. All 4 parameters were significantly more elevated in SE and CI than in UI. Among patients with SE 10 176 had a CRP value less than 50 mg/l and in patients with UI 5/56 had a CRP value greater than 100 mg/l. Patients with SE caused by pneumococci had the highest CRP levels and patients with alfa-haemolytic streptococci the lowest. The sensitivity and specificity favours the use of CRP as an indicator of bacterial superinfection in influenza.