The PD1/PD-L1 pathway plays a critical role in balancing immunity and host immunopathology. During chronic SIV infection in non-human primates or HIV infection in humans there is persistent immune activation accompanied by an accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. The ligand for PD-1, PDL-1, was observed in cells with myloid/macrophage morphology (M) in lymph nodes. Administration of an anti-PD-L1 antibody to SIV infected animals led to a modest decrease in viremia compared to control animals after discontinuation of antiretroviral therapy. Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. We have identified the presence of defective proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection. Although these novel usHIV-RNA transcripts had exon structures that were different from those of the known spliced HIV-RNA variants, they maintained translationally competent ORFs, involving elements of gag, pol, env, rev, and nef to encode a series of novel HIV-1 chimeric proteins. These novel usHIV-RNAs were detected in five of five patients, including four of four patients with prolonged viral suppression of HIV-RNA levels <40 copies per milliliter for more than 6 years. Our findings suggest that the persistent defective proviruses of HIV-1 are not silent, but rather may contribute to HIV-1 pathogenesis by stimulating host-defense pathways that target foreign nucleic acids and proteins. As part of the leadership of a large, international study group we participated in the randomization of 4685 subjects with early stage HIV infection (CD4+ count of more than 500 cells per cubic millimeter) to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). Study subjects were followed for a mean of 3.0 years. Prior to scheduled completion of the study, the data and safety monitoring board overseeing the study determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval CI, 0.30 to 0.62; P<0.001). The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions. Thus, this study demonstrated that the initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter.
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