Determinants of protection among HIV‐exposed seronegative persons: an overview

Both clinical experience and a growing medical literature indicate that some persons who have been exposed to human immunodeficiency virus (HIV) infection remain uninfected. Although in some instances this may represent good fortune, cohorts of uninfected persons have been reported who are considered at high risk for infection. In these cohorts a variety of characteristics have been proposed as mediating protection, but to date only the 32–base pair deletion in the chemokine (C‐C motif) receptor 5 gene, which results in complete failure of cell surface expression of this coreceptor, has been associated with high‐level protection from HIV infection. With this in mind, there are probably many other factors that may individually or in combination provide some level of protection from acquisition of HIV infection. Because some of these factors are probably incompletely protective or inconsistently active, identifying them with confidence will be difficult. Nonetheless, clarifying the determinants of protection against HIV infection is a high priority that will require careful selection of high‐risk uninfected cohorts, who should undergo targeted studies of plausible mediators and broad screening for unexpected determinants of protection.     

Cathepsin D displays in vitro β-secretase-like specificity

The formation of Aβ and Aβ-containing fragments is likely a key event in the process of neural degeneration in Alzheimer's disease. The N-terminal residue (Asp-1) of Aβ and its C-terminally extended sequences is liberated from the β-amyloid precursor protein (βAPP) by β-secretase(s). This activity appears highly increased by the presence (N-terminally to Asp-1) of a double-mutation (KM→NL) found in several Swedish families affected by early onset Alzheimer's disease. By means of synthetic peptides encompassing the ‘normal' (N peptide) and mutated (ΔNL peptide) sequences targeted by β-secretase(s), we have detected a human brain protease displaying preferred efficiency for the ΔNL peptide than for the non-mutated analog. This activity is sensitive to pepstatin, maximally active at acidic pH and hydrolyses the two peptides at the expected M/D or L/D cleavage sites. Such acidic activity is also detected in rat brain, PC12 cells and primary cultured astrocytes. The pepstatin sensitivity and pH maximum of the brain activity that appeared reminiscent of those displayed by the acidic protease cathepsin D led us to examine this enzyme as a putative β-secretase-like candidate. Purified cathepsin D displays higher catalytic parameters for the ΔNL peptide than for the non-mutated peptide, cleaves these two substrates at the expected M/D or L/D sites, and is maximally active at acidic pH. However, cathepsin D does not cleave peptides bearing mutations that were previously shown to drastically lower or fully block Aβ secretion by transfected cells. Furthermore, cathepsin D hydrolyses recombinant baculoviral ΔNLβAPP₇₅₁ at a 6-fold higher rate than βAPP₇₅₁ and gives rise to a 12-kDa C-terminal product that is recognized by antibodies fully specific of the N-terminus of Aβ. Altogether, our study indicates that cathepsin D displays several in vitro β-secretase-like properties that suggests that this protease could fulfill such a role, at least in the Swedish genetic form of Alzheimer's disease. © 1997 Elsevier Science B.V. All rigths reserved.     

Infection with human herpes virus type 8 in an area at high prevalence for hepatitis C virus infection in southern Italy

The Campania Region is a geographical area of southern Italy characterized by high incidence rates of hepatocellular carcinoma and of classic Kaposi's sarcoma. Epidemiological investigations carried out among different population groups in this region have found high prevalence rates of both hepatitis C virus (HCV) and human herpesvirus type 8 (HHV-8). To assess co-infection rates of HCV and HHV-8, we carried out a cross-sectional seroepidemiological study prevalence in Pomigliano d'Arco, a Health District of Campania located 20 km away from Naples. The overall rate of HCV/HHV-8 co-infection was 3.1%, 3.5% among men and 2.7% among women. No difference emerged in the HCV/HHV-8 co-infection rates according to seropositivity for HCV infection, either overall (Mantel Haenszel odds ratio = 1.2, 95% CI: 0.6-2.6) or when the analysis was stratified by gender. These findings support the hypothesis that in Campania common routes of transmission are rarely shared by HCV and HHV-8 infections. Local factors may result in different epidemiological patterns for these two viral infections. However, our findings have important public health implications, especially in Mediterranean countries where HCV and HHV-8 infections are endemic.     

Effects of CCR5-Delta32 and CCR2-64I alleles on HIV-1 disease progression: the protection varies with duration of infection

OBJECTIVE: To examine temporal variation in the effects of CCR5-Delta32 and CCR2-64I chemokine receptor gene polymorphisms on HIV-1 disease progression. DESIGN: Pooled analysis of individual patient data from 10 cohorts of HIV-1 seroconverters from the United States, Europe, and Australia. METHODS: We studied HIV-1 seroconverters of European (n = 1635) or African (n = 215) ancestry who had been genotyped for CCR5-Delta32 and CCR2-64I. We used Cox proportional hazards models with time-varying coefficients to determine whether the genetic protection against AIDS (1987 case definition) and death varied with time since seroconversion. RESULTS: Protection against AIDS conferred by CCR5-Delta32 held constant at a 31% (RH 0.69, 95% CI 0.54, 0.88) reduction in risk over the course of HIV-1 infection, whereas protection against death held constant at a 39% reduction in risk (RH 0.61, 95% CI 0.45, 0.88). When the period from AIDS to death was isolated, the survival benefit of CCR5-Delta32 diminished 2 years after AIDS. Protection against AIDS conferred by CCR2-64I was greatest early in the disease course. Compared with individuals without CCR5-Delta32 or CCR2-64I, individuals with one or two copies of CCR2-64I had a 58% lower risk of AIDS during the first 4 years after seroconversion (RH 0.42, 95% CI 0.23, 0.76), a 19% lower risk during the subsequent 4 years (RH 0.81, 95% CI 0.59, 1.12), and no significant protection thereafter. CONCLUSION: The protection against AIDS provided by CCR5-Delta32 is continuous during the course of infection. In contrast, the protection provided by CCR2-64I is greatest early in the course of infection.     

Recombinant human TSH increases the efficacy of a fixed activity of radioiodine for treatment of multinodular goitre

Context: High doses of ¹³¹I are usually needed in the treatment of multinodular goitre (MNG) for effective thyroid volume (TV) reduction. Recombinant human thyroid‐stimulating hormone (rhTSH) is an adjuvant to enhance ¹³¹I uptake, allowing a decrease in radiation activity and enhancing ¹³¹I efficacy. Objective: To evaluate whether rhTSH increases the efficacy of a fixed activity of ¹³¹I for the treatment of MNG. Design:  Two‐year, observational, placebo‐controlled study. Setting: Patients received 0.1 mg rhTSH (A), 0.005 mg rhTSH (B) or placebo (C). A fixed activity of 1.11 GBq of ¹³¹I was administered 24 h after rhTSH or placebo. Patients:  A total of 28 outpatients (26 females and two males) with MNG. Measurements: TSH, free T4, T3, thyroglobulin (Tg) and TV. Results: Basal radioactive iodine uptake and TV values were comparable among all groups. After rhTSH or placebo, peak levels of TSH, free T4, T3 and Tg were higher in A than in B or in C (p < 0.05). Hyperthyroidism was observed in A (n = 2), B (n = 6) and C (n = 4). Thyroid enlargement was reported in A (n = 3) and B (n = 6). After 24 months, 10 patients developed hypothyroidism (four in A, three in B and three in C). TV reduction was similar between A and B (37.2 ± 25.5% vs. 39.3 ± 27.9%, p = 0.88), but different from the non‐significant reduction in C (15.3 ± 28.3%, p = 0.08). Conclusions: Followed by 1.11 GBq, a very low dose of 0.005 mg rhTSH was equally safe and effective as 0.1 mg rhTSH. Both doses increased the efficacy of radioiodine. Adverse events were mild, transient and readily treatable.     

HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy

Hodgkin lymphoma (HL) incidence with HIV infection may have increased with the introduction of combination antiretroviral therapy (cART), suggesting that immune reconstitution may contribute to some cases. We evaluated HL risk with cART during the first months of treatment. With 187 HL cases among 64 368 HIV patients in France, relative rates (RRs) and 95% confidence intervals (CIs) of HL were estimated using Poisson models for duration of cART, CD4 count, and HIV load, with and without adjustment for demographic/clinical covariates. HL risk was unrelated to cART use overall, but it was related to time intervals after cART initiation (P = .006). Risk was especially and significantly elevated in months 1-3 on cART (RR 2.95, CI 1.64-5.31), lower in months 4-6 (RR 1.63), and null with longer use (RR 1.00). CD4 count was strongly associated with HL risk (P < 10??), with the highest HL incidence at 50-99 CD4 cells/mm3. With adjustment for CD4 count and covariates, HL risk was elevated, but not significantly (RR 1.42), in months 1-3 on cART. HIV load had no added effect. HL risk increased significantly soon after cART initiation, which was largely explained by the CD4 count. Further studies of HIV-associated HL are needed.