R P Brettle

Identification of shared populations of human immunodeficiency virus type 1 infecting microglia and tissue macrophages outside the central nervous system.

ABSTRACT Infection of microglia and other cells of the macrophage/monocyte lineage in the central nervous system (CNS) by human immunodeficiency virus type I (HIV-1) underlies the development of giant cell encephalitis (GCE). It is currently unknown whether GCE depends on the emergence of virus populations specifically adapted to replicate in cells of the monocyte/macrophage lineage and whether this also leads to the specific targeting of macrophages in other nonlymphoid tissues. Autopsy samples from lymph node, brain (frontal region), lung, and full-thickness colon sections were obtained from nine study subjects with GCE and from nine without. The two groups showed no significant differences in CD4 counts, disease progression, or treatment history before death. Genetic relatedness between variants recovered from lymph node and nonlymphoid tissues was assessed by sequence comparison of V3 and p17 gag regions using a newly developed method that scores the sample composition at successive nodes in a neighbor-joining tree. The association index enabled objective, numerical comparisons on the degree of tissue compartmentalization to be made. High proviral loads and p24 antigen expression in the brain were confined to the nine individuals with GCE. GCE was also associated with significantly higher proviral loads in colon samples (median of the GCE+ group: 1,010 copies/106 cells; median of GCE− group, 10/106 cells;P = 0.006). In contrast, there were no significant differences in proviral load between the GCE+and GCE− groups in lymph node or lung samples, where HIV infection was manifested predominantly by infiltrates of lymphoid cells. V3 sequences from brain samples of individuals with GCE showed the greatest compartmentalization from those of lymph node, although samples from other tissues, particularly the colon, frequently contained variants phylogenetically related to those found in brain. The existence of shared, distinct populations of HIV specifically distributed in cells of the monocyte/macrophage lineage was further indicated by immunocytochemical detection of CD68+, multinucleated giant cells expressing p24 antigen in samples of lung and colon in two individuals with GCE. This study provides the basis for future investigation of possible phenotypic similarities that underline the shared distributions of HIV variants infecting microglia and tissue macrophages outside the CNS.

Absence of hepatitis C virus transmission but frequent transmission of HIV-1 from sexual contact with doubly-infected individuals

Hepatitis C virus (HCV) is transmitted through infected blood and blood products, but evidence of other routes of transmission is less clearly understood. In a study designed to examine human immunodeficiency virus (HIV) transmission, the prevalence of HCV has also been measured. Sixty-one couples were analysed, 30 in which partners were at risk through sexual contact alone, of whom 12 (40%) became infected with HIV and none with HCV. Thirty-one partners were exposed sexually and additionally through intravenous drug use. Of these, 16 (52%) became infected with HIV and 25 (80%) contracted HCV infection. These findings support the evidence of others that HCV is only rarely transmitted by sexual intercourse in heterosexual relationships and that HIV is not a co-factor for HCV transmission.

Influence of risk group and zidovudine therapy on the development of HIV encephalitis and cognitive impairment in AIDS patients

Objective:To determine the associations between HIV encephalitis and other central nervous system (CNS) pathology, viral burden, cognitive impairment, zidovudine therapy and risk group in AIDS patients. Design:Planned autopsy study in AIDS patients evaluated prospectively for numerous clinical parameters. Setting:Regional academic centre for clinical care and pathology examination of patients with HIV infection. Patients:Edinburgh cohort of HIV-positive patients prospectively assessed for cognitive impairment, immunosuppression and clinical course. Unbiased series of consecutive autopsies in 27 homosexual men and 39 drug-using patients with AIDS. Interventions:Zidovudine therapy monitored in all patients. Main outcome measures:Determination of CNS viral burden and pathology including immunocytochemically confirmed HIV encephalitis in injecting drug users (IDU) versus homosexual AIDS patients with known CD4 counts and cognitive function. Results:HIV encephalitis was present in 59% of IDU and 15% of homosexuals: 88% of patients with encephalitis had displayed cognitive impairment. HIV encephalitis was strongly associated with a high viral load and HIV p24 immunopositivity. Opportunistic infections and lymphomas were more common in homosexuals (63%) than in IDU (31%) and were associated with the degree of immunosuppression before death. Within both groups, prolonged zidovudine treatment was associated with a lower incidence of HIV encephalitis. Conclusions:This study documents two separate CNS outcomes in AIDS patients in that HIV encephalitis occurs independently of opportunistic infections and lymphomas and shows different associations with risk group, immunosuppression and antiviral treatment before death.

Pre-AIDS mortality from natural causes associated with HIV disease progression: Evidence from the European seroconverter study among injecting drug users

Objectives:To study differences in pre-AIDS mortality between European cohorts of injecting drug users (IDU) and to evaluate whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count. Methods:The study population consisted of 664 IDU with documented intervals of HIV seroconversion from eight cohort studies. Differences in pre-AIDS mortality were studied between European sites; an evaluation of whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count was carried out using Poisson regression. Results:One hundred and seven IDU died, of whom 57 did not have AIDS. Pre-AIDS causes of death were overdose/suicide (49%), natural causes such as bacterial infections/cirrhosis (40%), and unintentional injuries/unknown (11%). Considering pre-AIDS death and AIDS as competing risks, 14.7% were expected to have died without AIDS and 17.3% to have developed AIDS at 7 years from seroconversion. No statistically significant differences in pre-AIDS mortality were found between European regions, men and women, age categories and calendar time periods. Overall pre-AIDS mortality did not increase with time since seroconversion, but did increase with decreasing CD4 count. Evaluating cause-specific mortality, only pre-AIDS mortality from natural causes appeared to be associated with time since seroconversion as well as immunosuppression. For natural causes, the death rate per 100 person-years was 0.13 the first 2 years after seroconversion, 0.73 in years 2–4 [risk relative (RR) to years 0–2, 5.6], 1.83 in years 4–6 (RR, 14.0) and 1.54 for ≥ 6 years (RR, 11.7). This rate was 0 for a CD4 cell count ≥ 500 × 106/l, 1.06 for 200–500 × 106/l and 4.06 for < 200 × 106/l (RR versus ≥ 200 × 106/l, 7.0). In multivariate analysis, both CD4 count and time since seroconversion appeared to be independently associated with death from natural causes; CD4 count appeared to be the strongest predictor (adjusted RR, 5.9). Conclusions:A high pre-AIDS mortality rate was observed among IDU. No significant differences were observed across European sites. Pre-AIDS mortality from natural causes but not from overdose and suicide was associated with HIV disease progression.

HIV infection in women : immunological markers and the influence of pregnancy

ObjectiveTo describe the influence of pregnancy on immunological marker paths and progression of HIV-infected women. DesignAnalysis of prospectively collected immunological and clinical data collected on 145 women reviewed at the City Hospital, Edinburgh, between 1985 and 1992 using a two-level random-effects model that allows for within- and between-patient variance. ResultsThere were differences between the marker paths of women according to risk activity; women who had acquired HIV via injecting drug use (in addition to heterosexual intercourse) had a higher level of absolute CD4 cells, CD4% and total lymphocytes at seroconversion than those who had acquired HIV via heterosexual intercourse alone; however, immunological markers declined more steeply after seroconversion. There was no evidence that pregnancy, either before or after HIV seroconversion had an adverse effect on marker paths of HIV disease. There was a significant association between pregnancy after HIV seroconversion and post-pregnancy changes in immunological markers: an increase in the CD4% and a decrease in CD8%. However, causality cannot be implied as pregnancy itself may be associated with considerable lifestyle changes. During pregnancy the total white blood count rose due to an increase in the number of granulocytes, whereas the total lymphocyte numbers fell. The absolute CD4 lymphocyte subset counts fell progressively but the effect was due to the fall in the total lymphocyte counts, there being no influence of pregnancy on either CD4% or CD8%. ConclusionsIn asymptomatic HIV infection, changes in the absolute levels of CD4 and CD8 lymphocyte counts are primarily related to changes in the other components of the white cell count because there were no changes in CD4% and CD8%. Pregnancy itself has no adverse effect on immunological markers of HIV.

Venous thrombosis in HIV infection

Previous reports indicate that venous thrombosis is an infrequent problem in patients with HIV infection. Despite this, various HIV-related factors have been proposed as potentially thrombogenic and an HIV-related hypercoagulability has been suggested. At the present time, there exists no consensus of opinion regarding prophylaxis against venous thrombosis for hospitalized patients with HIV. This article aims to provide an overview of venous thrombosis in HIV infection with particular reference to published and personal evidence for possible risk factors and their implications for prophylaxis.

The Epidemiology of HIV Infection in Edinburgh Related to the Injecting of Drugs: An Historical Perspective and New Insight Regarding the Past Incidence of HIV Infection Derived from Retrospective HIV Antibody Testing of Stored Samples of Serum

The pattern of sudden explosive outbreaks of HIV infection among drug users has been seen in several countries but is as yet incompletely understood. The epidemic of injecting drugs in Edinburgh was associated with at least four overlapping epidemics of blood-borne viruses (hepatitis B, C, D and HIV). Only hepatitis B was initially recognized, being followed by HIV and latterly hepatitis C. Retrospective HIV testing of stored samples of serum from clinically diagnosed patients with HIV has allowed the HIV epidemic to be delineated and more accurate seroconversion dates identified for most of the patients. There is evidence to suggest that the explosive drug-related Edinburgh HIV epidemic may have been self-terminating and that the epidemic in male drug users preceded that in female drug users by around 3 months. We suggest that the self-terminating nature of this epidemic may have been related to changes in drug injecting behaviour or to varying infectivity of the virus. This latter possibility should be explored in future studies of HIV transmission.

Reduced concentrations of IgG antibodies to Pneumocystis carinii in HIV-infected patients during active Pneumocystis carinii infection and the possibility of passive immunisation

The relationship between Pneumocystis carinii antibody concentrations and acute Pneumocystis infection was investigated by testing sequential samples of serum from HIV antibody-positive patients with respiratory symptoms and HIV-negative immunocompromised patients by means of an indirect immunofluorescence assay for specific IgG antibodies to P. carinii. Loss of circulating antibody at the time of active Pneumocystis infection was observed in five patients with proven infection. Three others showed recovery of antibody coinciding with treatment and clinical recovery from infection. Concentrations of specific IgG antibody against P. carinii were measured in 40 blood donors and in six different batches of an intravenous immunoglobulin (IV Ig) preparation. Titres greater than 128 were found in the IV Ig batches examined. The use of IV Ig, either alone or in conjunction with other therapeutic agents, should therefore be considered in patients suffering from acute infection with P. carinii.

Has the rate of progression to AIDS changed in recent years

Objectives:To investigate whether the rate of progression to AIDS has changed over time by testing an effect of the year of seroconversion on AIDS onset (Centers for Disease Control and Prevention 1987 revised classification), next to an effect of the calendar period of follow-up. Design:French multicentre prospective study of 385 homosexual and heterosexual subjects and 231 subjects from a multicentre study of European injecting drug users (IDU), all with a documented date of HIV-1 seroconversion. Method:The effect of the year of seroconversion was compared by the log-rank test. Crude and adjusted relative hazard (ARH) were quantified using the Cox model. Calendar period of follow-up was studied separately for sexual exposure group and IDU and treated as a time-dependent variable in a Cox model. Results:In the 616 study subjects the year of seroconversion was not significantly related to AIDS occurrence (n = 108); the ARH was 0.88 [95% confidence interval (CI), 0.56–1.38] for those who seroconverted in 1988–1989, and 1.17 (95% CI, 0.61–2.25) for those who seroconverted after 1989, compared with those who seroconverted before 1988. In the sexual exposure group, a clear trend towards less rapid progression to AIDS was observed in subjects followed in 1991–1992 (ARH, 0.49; 95% CI, 0.24–0.99) and after 1992 (ARH, 0.54; 95% CI; 0.24–1.21), compared with those followed before 1991. This favorable trend was not observed in IDU despite a significant decrease over time of Pneumocystis carinii pneumonia as AIDS-defining illness. Conversely to sexual exposure groups, the frequency of antiretroviral treatment (mainly zidovudine) prescription was still low during the most recent calendar periods in IDU when the CD4 count threshold of 200 × 106/l was reached. Conclusions:No evidence was found of a change in the rate of progression to AIDS in subjects who seroconverted in recent years. Furthermore, conversely to sexual exposure groups, the lack of favorable trends in IDU users followed in recent years suggest that health-care systems are not always adapted to their lifestyles.

β2-microglobulin levels in drug users : the influence of risk behaviour

beta 2-microglobulin (beta 2M) levels were measured in 217 Edinburgh drug users to assess their usefulness as a marker for HIV-related disease. Eighty HIV-seronegative drug injectors had significantly higher levels than 100 HIV-seronegative blood-donor controls. Amongst 137 asymptomatic HIV-seropositive drug users, those who were defined as continued drug users had significantly higher beta 2M levels and percentages of CD3+ T lymphocytes with DR Class II expression than non-injecting drug users. beta 2M levels correlated with the percentage of activated DR+ CD3+ T lymphocytes. These findings indicate that changes in beta 2M levels may reflect differences in drug-injecting behaviour and are not influenced solely by HIV status or progression. These changes in beta 2M probably represent differing degrees of immunostimulation resulting from the antigenic challenges afforded by continued or frequent drug injection. It is important to establish normal ranges for beta 2M from HIV-seronegative controls who are matched with respect to risk group and behaviour. All these factors should be taken into account if beta 2M is to be used as a marker of HIV progression.