Poor immunological recovery despite virological successful HAART is associated with a higher risk for overall morbidity and mortality and CVEs in particular. This study underlines the importance of starting HAART at higher CD4 cell counts, particularly in older patients.

The proteasome has been shown to make the proper C-terminal cleavage for the generation of several immunodominant class I-presented peptides whereas aminopeptidases generate their proper N termini. In this study, we show that these two distinct proteolytic processes are also involved in generating a subdominant OVA peptide KVVRFDKL (K-L). Moreover, proteasome inhibitors did not enhance the presentation of any K-L construct, suggesting that destruction of this peptide by proteasomes, if any, does not limit its presentation. We have further examined in intact cells the influence of residues flanking this epitope on these proteolytic processes. When the N-terminal flanking residues of K-L are fused to an immunodominant OVA peptide SIINFEKL (S-L), the presentation of S-L is reduced as compared with a construct with its natural flanking sequence and was not inhibited (or enhanced) by proteasome inhibitors. Similarly, a reduction in presentation was observed when the C-terminal flanking residues of the subdominant epitope were attached to S-L. A detailed analysis revealed that the Pro at the P1′ position of K-L was responsible for this reduction, and presentation of these C-terminally extended constructs was sensitive to proteasome inhibitor. The study suggests that both the N- and C-terminal flanks of the subdominant peptide are suboptimal for Ag presentation. Moreover, three of four C-terminal residues that flank other subdominant or cryptic epitopes in OVA reduced the presentation of S-L. Therefore, the residues that flank the C termini of several subdominant and cryptic epitopes are often suboptimal for cleavage and may contribute to the phenomenon of immunodominance.

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log 10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.

The purpose of this investigation was to analyse the impact of the availability of highly active antiretroviral therapy (HAART) on the long-term outcome of human immunodeficiency virus (HIV)-infected patients admitted to the intensive care unit (ICU). A retrospective cohort study of HIV-infected patients admitted to the ICU was undertaken. Outcomes in the pre-HAART era (1990-June 1996), early- (July 1996-2002), and recent-HAART (2003-2008) periods and total HAART era (July 1996-2008) were analysed and compared with those reported of the general population. A total of 127 ICU admissions were included. The 1-year mortality decreased from 71% in the pre-HAART era to 50% in the recent-HAART period (p = 0.06). The 5-year mortality decreased from 87% in the pre-HAART era to 59% in the early-HAART period (p = 0.005). Independent predictors of 1-year mortality in the HAART era were age (odds ratio [OR] = 1.16 [95% confidence interval [CI] = 1.06-1.27]), APACHE II score > 20 (6.04 [1.25-29.22]) and mechanical ventilation (40.01 [3.01-532.65]). The 5-year survival after hospitalisation was 80% and in the range of the reported survival of non-HIV-infected patients (83.7%). Predictors of 1-year mortality for HIV patients admitted to the ICU in the HAART era were all non-HIV-related. Short- and long-term outcome has improved since the introduction of HAART and is comparable to the outcome data in non-HIV-infected ICU patients.

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