Cryptococcus neoformans is a fungal pathogen that, after inhalation, can disseminate to the brain. Host alveolar macrophages (AMs) represent the first defense against the fungus. Once phagocytosed by AMs, fungal cells are killed by a concerted mechanism, involving the host-cellular response. If the cellular response is impaired, phagocytosis of the fungus may be detrimental for the host, since C. neoformans can grow within macrophages. Here, we identified a novel cryptococcal gene encoding antiphagocytic protein 1 (App1). App1 is a cryptococcal cytoplasmic protein that is secreted extracellularly and found in the serum of infected patients. App1 does not affect melanin production, capsule formation, or growth of C. neoformans. Treatment with recombinant App1 inhibited phagocytosis of fungal cells through a complement-mediated mechanism, and Δapp1 mutant is readily phagocytosed by AMs. Interestingly, the Δapp1 mutant strain showed a decreased virulence in mice deficient for complement C5 (A/Jcr), but it was hypervirulent in mice deficient for T and NK cells (Tgε26). This study identifies App1 as a novel regulator of virulence for C. neoformans, and it highlights that internalization of fungal cells by AMs increases the dissemination of C. neoformans when the host cellular response is impaired
CD8(+) cells from healthy HIV-1-infected individuals suppress human immunodeficiency virus (HIV) replication in infected cells by a non-cytotoxic mechanism. This activity is associated with the production of a soluble CD8(+) cell antiviral factor (CAF) that inhibits viral replication at the level of transcription. Strong CD8(+) cell non-cytotoxic anti-HIV responses (CNARs) correlate with an asymptomatic state and long-term survival of HIV-infected individuals. This antiviral activity is lost when the infected individual advances to disease. In attempts to define the gene(s) mediating CNAR we have evaluated differential gene expression between CD8(+) cells from infected subjects with high CNAR and CD8(+) cells from uninfected controls that lack this activity. The expression analysis, using the Affymetrix GeneChip Human Genome U133 Set, indicated that 18% of the genes were differentially expressed (DE) of which 9.2% were up-regulated. A total of 568 genes were up-regulated with a >2.0-fold difference in expression levels and a >50% concordance of difference call. Stringent selection criteria narrowed down the list to 52 up-regulated 'high confidence genes' (> or = 75% concordance). These genes function in a wide variety of cellular processes and include 13 associated with immunologic activity.
In primary HIV infection administering IL-2 concomitant with HAART following 1 year of treatment with HAART gives a significant increase in CD4 cells and a previously unrecognized beneficial effect on the CD8 cell non-cytotoxic anti-HIV response.
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