Methylation of theSDHgene explains the loss ofSDHgene expression in SDH wild-type gastrointestinal stromal tumors.

Objectives: Reduced dendritic cell (DC) frequencies and functions in individuals with longstanding HIV-1 infection are predictive of opportunistic infections and AIDS. To investigate possible early alterations in DC levels after HIV infection, we prospectively examined plasmacytoid dendritic cell (pDC) and myeloid dendritic cell (mDC) frequencies and plasma IFN-α levels in patients undergoing primary HIV-1 infection (PHI). Methods: Peripheral blood DC frequencies and absolute counts were determined by flow cytometry. Plasma IFN-α levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: In comparison to uninfected subjects, pDC, but not mDC, levels were reduced (P < 0.001) in subjects with PHI, especially in those with high viral loads or low CD4 T-cell counts. During 24–48 weeks of observation, untreated subjects experienced slight declines in pDC and CD4 T-cell levels. In contrast, subjects initiating early antiretroviral therapy (ART) exhibited increases (P < 0.001) in pDC and CD4 T-cell counts. No effect of treatment on mDC counts was observed. Circulating plasma IFN-α was undetectable by ELISA regardless of the duration of HIV-1 infection. Conclusion: PHI is characterized by a reduction in pDC and CD4 T-cell counts that correlates with the magnitude of virus replication and is not evidenced by the mDC count or plasma IFN-α level. Early ART appears to have similar restorative effects on pDC and CD4 T-cell counts.

To investigate possible mechanisms behind HIV-1 escape from CTL, we performed detailed longitudinal analysis of Gag (SLYNTVATL)- and RT (ILKEPVHGV)-specific CTL responses and plasma epitope sequences in five individuals. Among those with CTL against consensus epitope sequences, epitope mutations developed over several years, invariably followed by decay of the CTL targeting the consensus epitopes. The maturation state of the CTL varied among individuals and appeared to affect the rate of epitope mutation and CTL decay, despite similar IFN-γ production. Escape mutations were oligoclonal, suggesting fitness constraints. The timing of escape indicated that the net selective advantage of escape mutants was slight, further underscoring the importance of understanding factors determining selective pressure and viral fitness in vivo. Our data show surprisingly consistent decay of CTL responses after epitope escape mutation and provide insight into potential mechanisms for both immune failure and shifting CTL specificities.

Autophagy, the major mechanism for degrading long-lived intracellular proteins and organelles, is essential for eukaryotic cell homeostasis. Autophagy also defends the cell against invasion by microorganisms and has important roles in innate and adaptive immunity. Increasingly evident is that HIV-1 replication is dependent on select components of autophagy. Fittingly, HIV-1 proteins are able to modulate autophagy to maximize virus production. At the same time, HIV-1 proteins appear to disrupt autophagy in uninfected cells, thereby contributing to CD4+ cell death and HIV-1 pathogenesis. These observations allow for new approaches for the treatment and possibly the prevention of HIV-1 infection. This review focuses on the relationship between autophagy and HIV-1 infection. Discussed is how autophagy plays dual roles in HIV-1 replication and HIV-1 disease progression.

HIV-specific antibodies become detectable and continue to increase in frequency during primary infection. The effects of early antiretroviral treatment (ART) and its discontinuation on the evolution of this immune response have not been systematically analyzed. To investigate the associations between antibody titer, viral load, and ART, we used a less-sensitive enzyme-linked immunosorbant assay (LS-EIA) to measure changes in HIV-1-specific antibody levels in treated and untreated subjects undergoing primary infection. In this longitudinal study, antibody levels gradually increased in therapy-naive subjects, reaching a plateau approximately 40 weeks postinfection. In contrast, antibody titers remained low among subjects receiving ART. Subjects who discontinued ART exhibited a more rapid rise in antibody titers than therapy-naive subjects, suggesting the presence of an enhanced B cell response. These results demonstrate that early ART prevents the typical evolution of the HIV-1-specific antibody response and can alter the expected kinetics of this response in subjects discontinuing therapy.