Clinical research in HIV/AIDS最新文献

Macrophages are one of the main cellular targets of human immunodeficiency virus type 1 (HIV-1). Macrophage infection by HIV-1 is inefficient due to the presence of the viral restriction factor sterile alpha motif and histidine aspartic acid domain containing protein 1 (SAMHD1). Ex vivo human monocyte-derived macrophages (MDMs) express SAMHD1 in an equilibrium between active (unphosphorylated) and inactive (phosphorylated) states. We and others have shown that treatment of MDMs with the FDA-approved tyrosine kinase inhibitor, dasatinib, ablates SAMHD1 phosphorylation, thus skewing the balance towards a cellular state that is refractory to HIV-1 infection. We hypothesized that dasatinib inhibits a putative tyrosine kinase that is upstream of SAMHD1. In search for this tyrosine kinase, we probed several candidates and were unable to identify a single target that, when inhibited, was sufficient to explain the dephosphorylation of SAMHD1 we observe upon treatment with dasatinib. On the other hand, we probed the ability of dasatinib to directly inhibit the serine/threonine cyclin dependent kinases 1, 2, 4 and 6 and confirmed that dasatinib directly inhibits these kinases. Therefore, our results show that inhibition of the proximal CDKs 1, 2, 4 and 6 by dasatinib is clearly detectable, leads to blockade of infection by HIV-1, and may be sufficient to explain the activity of dasatinib against SAMHD1 phosphorylation.

Background: South Africa has the highest global burden of human immunodefciency virus [HIV]. The study compared the cost-effectiveness of individual and combination HIV preventive strategies against the current rollout of ART and possible ART scale-up.

Methods: Adolescents attending South African schools in 2012 were included in the semi-Markov running annual cycles. The ART and HIV counseling and testing program [comparator] was weighed against the interventions [viz. HIV vaccine, a dual vaccine strategy [HIV and HPV vaccines], oral pre-exposure prophylaxis [PrEP] and voluntary medical male circumcision [VMMC]; and various combinations thereof. Quality-adjusted life years [QALY] determined changes in HIV associated mortality and infections averted. One-way and probabilistic sensitivity analysis determined parameter uncertainty. Discount rates of 3% with a lifetime horizon [70 years] were applied.

Results: Dual vaccination was highly cost-effective strategy [US$ 7 per QALY gained] and averted 29% of new HIV infections. VMMC [US$ 30 per QALY gained] proved more cost-effective than HIV vaccination alone [US$ 93 per QALY gained], though VMMC averted 6% more new infections than the HIV vaccine when considered among male participants. PrEP interventions were the least cost-effective with pharmaceutical and human resource spending driving the costs. Combined dual vaccination and VMMC strategies were a dominant intervention. Strategies involving PrEP were the least cost-effective.

Conclusion: VMMC, HIV vaccination and dual vaccination strategies were more cost-effective than any PrEP strategies. A multi-intervention biomedical approach could avert considerable new HIV infections and present a cost-effective use of resources; particularly where large scale multi-interventional randomized controlled trials are absent.

The long-term survival of HIV-1 infected individuals credited to the availability and use of effective antiretroviral therapy (ART) is unfortunately now accompanied by an almost 50% prevalence of HIV-1 associated neurocognitive disorder (HAND). Increasingly, it has been realized that HIV-1 infected people on ART have clinical and pathological observations of Alzheimer's disease (AD)-like manifestations including neurocognitive problems, intraneuronal accumulation of amyloid beta (Aβ) protein, and disturbed synaptic integrity. Part of the current challenge facing the medical community and people living with HIV-1 infection is that the pathogenesis of HAND remains unclear, and little is known about how AD-like pathology is developed as a result of HIV-1 infection and/or long-term ART treatment. Here we discuss the potential role of altered plasma cholesterol homeostasis, a prominent feature of HIV-1 infection, on the development of intraneuronal Aβ accumulation in HIV-1 infected brain. We speculate that elevated plasma LDL cholesterol, once it enters brain parenchyma via an increasingly leaky BBB, can be internalized by neurons via receptor-mediated endocytosis, a process that could promote internalization of amyloid beta precursor protein (AβPP). Unlike brain in situ synthesized apoE-cholesterol, apoB-containing LDL-cholesterol could lead to cholesterol accumulation thus disturbing neuronal endolysosome function and ultimately the accumulation of intraneuronal Aβ in HIV-1 infected brain.