The impact of highly active antiretroviral therapy on the incidence and outcomes of AIDS-defining cancers in Southern Alberta.

OBJECTIVES: To determine the impact of highly active antiretroviral therapy (HAART) on the incidence and outcomes of Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL) and invasive cervical cancer/dysplasia in a well-defined geographical HIV-infected population between 1984 and 2005. METHODS: A clinic database search, chart review and verification with public health records were undertaken for all AIDS-defining cancers diagnosed in Southern Alberta before and after the introduction of HAART. RESULTS: A total of 2,137 patients with 9,265 person-years of HIV follow-up care were reviewed. One hundred and forty-three cases of KS, 64 cases of NHL and 11 cases of invasive cervical cancer/dysplasia were identified. KS and NHL together accounted for 15% of clinical presentations with an AIDS-defining illness that led to the HIV diagnosis. Following the introduction of HAART, the reduced number of severely immunocompromised patients was associated with 92 and 84% reductions in new diagnoses of KS and NHL, respectively, which were seen mainly in clinic patients declining or failing HAART. Crude reductions of 94 and 65% in mortality from KS and NHL, respectively, were also seen. The prevalences of KS, NHL and invasive cervical cancer/dysplasia have recently stabilized at 3, 1 and 5% of the population, respectively. CONCLUSIONS: The introduction of HAART has dramatically reduced the incidence of KS and NHL and improved survival from these cancers for most patients in HIV care. However, patients still present with KS and NHL leading to their HIV diagnosis.

Distribution and expression of the ZmpA metalloprotease in the Burkholderia cepacia complex.

The distribution of the metalloprotease gene zmpA was determined among strains of the Burkholderia cepacia complex (Bcc). The zmpA gene was present in B. cepacia, B. cenocepacia, B. stabilis, B. ambifaria and B. pyrrocinia but absent from B. multivorans, B. vietnamiensis, B. dolosa, and B. anthina. The presence of zmpA generally correlated with extracellular proteolytic activity with the exception of five strains, which had zmpA but had no detectable proteolytic activity when skim milk agar was used as a substrate (zmpA protease deficient). Western immunoblot experiments with anti-ZmpA antibodies suggest that the zmpA protease-deficient strains do not secrete or accumulate detectable ZmpA. Transcriptional zmpA::lacZ fusions were introduced in selected strains of the Bcc. zmpA::lacZ was expressed in all strains, but expression was generally lower in the zmpA protease-deficient strains than in the zmpA protease-proficient strains. Quantitative reverse transcriptase real-time PCR demonstrated that zmpA protease-deficient strains did express zmpA mRNA, although at various levels. ZmpA has previously been shown to be positively regulated by the CepIR quorum-sensing system. Addition of exogenous AHLs did not restore extracellular protease production to any of the zmpA protease-deficient strains; however, introduction of cepR in trans complemented protease activity in two of five strains. Extracellular proteolytic activity was restored by the presence of zmpA in trans in two of the five strains. These studies suggest that although some strains of the Bcc contain the zmpA gene, multiple factors may influence its expression.

The CepIR quorum-sensing system contributes to the virulence of Burkholderia cenocepacia respiratory infections.

The cepIR genes encode an N-acyl homoserine lactone (AHL)-dependent quorum-sensing system consisting of an AHL synthase that directs the synthesis of N-octanoyl-L-homoserine lactone (ohl) and n-hexanoyl-L-homoserine lactone and a transcriptional regulator. The virulence of cepIR mutants was examined in two animal models. Rats were infected with agar beads containing Burkholderia cenocepacia K56-2, K56-I2 (cepI : : Tp(r)) or K56-R2 (cepR : : Tn5-OT182). At 10 days post-infection, the extent of lung histopathological changes was significantly lower in lungs infected with K56-I2 or K56-R2 compared to the parent strain. Intranasal infections were performed in Cftr((-/-)) mice and their wild-type siblings. K56-2 was more virulent in both groups of mice. K56-I2 was the least virulent strain and was not invasive in the Cftr((-/-)) mice. OHL was readily detected in lung homogenates from Cftr((-/-)) mice infected with K56-2 but was only detected at levels slightly above background in a few mice infected with K56-I2. Lung homogenates from mice infected with K56-2 had significantly higher levels of the inflammatory mediators murine macrophage inflammatory protein-2, KC/N51, interleukin-1beta and interleukin-6 than those from K56-I2-infected animals. These studies indicate that a functional CepIR quorum-sensing system contributes to the severity of B. cenocepacia infections. A zinc metalloprotease gene (zmpA) was shown to be regulated by CepR and may be one of the factors that accounts for the difference in virulence between the cepI mutant and the parent strain.