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author:("schizo, Marco")
1.  Aligning New Tuberculosis Drug Regimens and Drug Susceptibility Testing: A Needs Assessment and Roadmap for Action 
The Lancet infectious diseases  2013;13(5):449-458.
New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease.
doi:10.1016/S1473-3099(13)70025-2
PMCID: PMC4012744  PMID: 23531393
Tuberculosis; drug susceptibility testing; diagnostics; drug regimens; modeling; surveillance; implementation; operational
2.  Pilot Studies for Development of an HIV Subtype Panel for Surveillance of Global Diversity 
Abstract
The continued global spread and evolution of HIV diversity pose significant challenges to diagnostics and vaccine strategies. NIAID partnered with the FDA, WRAIR, academia, and industry to form a Viral Panel Working Group to design and prepare a panel of well-characterized current and diverse HIV isolates. Plasma samples that had screened positive for HIV infection and had evidence of recently acquired infection were donated by blood centers in North and South America, Europe, and Africa. A total of 80 plasma samples were tested by quantitative nucleic acid tests, p24 antigen, EIA, and Western blot to assign a Fiebig stage indicative of approximate time from initial infection. Evaluation of viral load using FDA-cleared assays showed excellent concordance when subtype B virus was tested, but lower correlations for subtype C. Plasma samples were cocultivated with phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from normal donors to generate 30 viral isolates (50–80% success rate for samples with viral load >10,000 copies/ml), which were then expanded to 107–109 virus copies per ml. Analysis of env sequences showed that sequences derived from cultured PBMCs were not distinguishable from those obtained from the original plasma. The pilot collection includes 30 isolates representing subtypes B, C, B/F, CRF04_cpx, and CRF02_AG. These studies will serve as a basis for the development of a comprehensive panel of highly characterized viral isolates that reflects the current dynamic and complex HIV epidemic, and will be made available through the External Quality Assurance Program Oversight Laboratory (EQAPOL).
doi:10.1089/aid.2011.0271
PMCID: PMC3358106  PMID: 22149143
4.  Opportunities and Challenges for Cost-Efficient Implementation of New Point-of-Care Diagnostics for HIV and Tuberculosis 
The Journal of Infectious Diseases  2012;205(Suppl 2):S169-S180.
Stakeholders agree that supporting high-quality diagnostics is essential if we are to continue to make strides in the fight against human immunodeficiency virus (HIV) and tuberculosis. Despite the need to strengthen existing laboratory infrastructure, which includes expanding and developing new laboratories, there are clear diagnostic needs where conventional laboratory support is insufficient. Regarding HIV, rapid point-of-care (POC) testing for initial HIV diagnosis has been successful, but several needs remain. For tuberculosis, several new diagnostic tests have recently been endorsed by the World Health Organization, but a POC test remains elusive. Human immunodeficiency virus and tuberculosis are coendemic in many high prevalence locations, making parallel diagnosis of these conditions an important consideration. Despite its clear advantages, POC testing has important limitations, and laboratory-based testing will continue to be an important component of future diagnostic networks. Ideally, a strategic deployment plan should be used to define where and how POC technologies can be most efficiently and cost effectively integrated into diagnostic algorithms and existing test networks prior to widespread scale-up. In this fashion, the global community can best harness the tremendous capacity of novel diagnostics in fighting these 2 scourges.
doi:10.1093/infdis/jis044
PMCID: PMC3334507  PMID: 22457286
5.  Perspectives on Introduction and Implementation of New Point-of-Care Diagnostic Tests 
The Journal of Infectious Diseases  2012;205(Suppl 2):S181-S190.
In recent years, there has been significant investment from both the private and public sectors in the development of diagnostic technologies to meet the need for human immunodeficiency virus (HIV) and tuberculosis testing in low-resource settings. Future investments should ensure that the most appropriate technologies are adopted in settings where they will have a sustainable impact. Achieving these aims requires the involvement of many stakeholders, as their needs, operational constraints, and priorities are often distinct. Here, we discuss these considerations from different perspectives representing those of various stakeholders involved in the development, introduction, and implementation of diagnostic tests. We also discuss some opportunities to address these considerations.
doi:10.1093/infdis/jis203
PMCID: PMC3334510  PMID: 22402038
6.  Delay of SHIV infection and control of viral replication in vaccinated macaques challenged in the presence of a topical microbicide 
AIDS (London, England)  2011;25(15):1833-1841.
Objective
Development of an effective vaccine or topical compound to prevent HIV transmission remains a major goal for control of the AIDS pandemic. Using a nonhuman primate model of heterosexual HIV-1 transmission, we tested whether a topical microbicide that reduces viral infectivity can potentiate the efficacy of a T-cell-based HIV vaccine.
Design
A DNA prime and rAd5 virus boost vaccination strategy was employed, and a topical microbicide against the HIV nucleocapsid protein was used. To rigorously test the combination hypothesis, the vaccine constructs contained only two transgenes and the topical microbicide inhibitor was used at a sub-optimal dose. Vaccinees were exposed in the absence and presence of the topical microbicide to repeated vaginal R5 SHIVSF162P3 challenge at an escalating dose to more closely mimic high-risk exposure of women to HIV.
Methods
Infection status was determined by PCR. Antiviral immune responses were evaluated by gp120 ELISA and intracellular cytokine staining.
Results
A significant delay in SHIV acquisition (Log-rank test; p=0.0416) was seen only in vaccinated macaques that were repeatedly challenged in the presence of the topical microbicide. Peak acute viremia was lower (Mann-Whitney test; p=0.0387) and viral burden was also reduced (Mann-Whitney test; p=0.0252) in the combination-treated animals.
Conclusions
The combined use of a topical microbicide to lower the initial viral seeding/spread and a T-cell-based vaccine to immunologically contain the early virological events of mucosal transmission holds promise as a preventive approach to control the spread of the AIDS epidemic.
doi:10.1097/QAD.0b013e32834a1d94
PMCID: PMC3508694  PMID: 21750420
HIV; vaccine; topical microbicide; nucleocapsid inhibitor; prevention
7.  Workshop Summary: Novel Biomarkers for HIV Incidence Assay Development 
Abstract
Reliable methods for measuring human immunodeficiency virus (HIV) incidence are a high priority for HIV prevention. They are particularly important to assess the population-level effectiveness of new prevention strategies, to evaluate the community-wide impact of ongoing prevention programs, and to assess whether a proposed prevention trial can be performed in a timely and cost-efficient manner in a particular population and setting. New incidence assays and algorithms that are accurate, rapid, cost-efficient, and can be performed on easily-obtained specimens are urgently needed. On May 4, 2011, the Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), sponsored a 1-day workshop to examine strategies for developing new assays to distinguish recent from chronic HIV infections. Participants included leading investigators, clinicians, public health experts, industry, regulatory specialists, and other stakeholders. Immune-based parameters, markers of viral sequence diversity, and other biomarkers such as telomere length were evaluated. Emerging nanotechnology and chip-based diagnostics, including algorithms for performing diverse assays on a single platform, were also reviewed. This report summarizes the presentations, panel discussions, and the consensus reached for pursuing the development of a new generation of HIV incidence assays.
doi:10.1089/aid.2011.0332
PMCID: PMC3358102  PMID: 22206265
8.  Small molecule inactivation of HIV-1 NCp7 by repetitive intracellular acyl transfer 
Nature chemical biology  2010;6(12):887-889.
The zinc fingers of the HIV-1 nucleocapsid protein, NCp7, are prime targets for antiretroviral therapeutics. Here we show that S-acyl-2-mercaptobenzamide thioester (SAMT) chemotypes inhibit HIV by modifying the NCp7 region of Gag in infected cells, thereby blocking Gag processing and reducing infectivity. The thiol produced by SAMT reaction with NCp7 is acetylated by cellular enzymes to regenerate active SAMTs via a recycling mechanism unique among small molecule inhibitors of HIV.
doi:10.1038/nchembio.456
PMCID: PMC2997617  PMID: 20953192
9.  Challenges for Rapid Molecular HIV Diagnostics 
The Journal of infectious diseases  2010;201(Suppl 1):S1-S6.
The introduction of serological point-of-care (POC) assays 10 years ago dramatically changed the way HIV infections were identified and diagnosed. Testing at the POC has lead to a dramatic increase in the number of individuals who are screened and, most importantly, receive their HIV test result. As the AIDS epidemic continues to mature and scientific advances in prevention and treatment are evaluated and implemented, there is a need to identify acute (viremic pre-seroconversion) infections and to discriminate “window phase” infections from those that are serologically positive, especially in resource limited settings (RLS), where the majority of the world’s vulnerable populations reside and where the HIV incidence is highest. Rapid testing methods are now at a crossroad. There is opportunity to implement and evaluate the incremental diagnostic utility of new test modalities that are based on sophisticated molecular diagnostic technologies and which can be performed in settings where laboratory infrastructure is minimal. The way forward requires sound scientific judgment, as well as an ability to further develop and implement these tests despite a variety of technical, social and operational hurdles to declare success.
doi:10.1086/650394
PMCID: PMC2841042  PMID: 20225941
HIV; point-of-care; resource-limited settings
10.  Human Immunodeficiency Virus Type 1 Nucleocapsid Inhibitors Impede trans Infection in Cellular and Explant Models and Protect Nonhuman Primates from Infection ▿ §  
Journal of Virology  2009;83(18):9175-9182.
Here, we report that the S-acyl-2-mercaptobenzamide thioester (SAMT) class of human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein (NCp7) inhibitors was able to prevent transmission of HIV-1 from infected cells, including primary cells. Furthermore, when SAMTs were introduced during an HIV-1 challenge of cervical explant tissue, inhibition of dissemination of infectious virus by cells emigrating from the tissue explants was observed. Preliminary studies using a rhesus macaque vaginal challenge model with mixed R5 and X4 simian-human immunodeficiency virus infection found that five of six monkeys were completely protected, with the remaining animal being partially protected, infected only by the R5 virus. These data suggest that SAMTs may be promising new drug candidates for further development in anti-HIV-1 topical microbicide applications.
doi:10.1128/JVI.00820-09
PMCID: PMC2738238  PMID: 19587055
11.  Transgenic Expression in Mouse Lung Reveals Distinct Biological Roles for the Adenovirus Type 5 E1A 243- and 289-Amino-Acid Proteins 
Journal of Virology  2002;76(17):8910-8919.
Little is known about the biological significance of human adenovirus type 5 (Ad5) E1A in vivo. However, Ad5 E1A is well defined in vitro and can be detected frequently in the lungs of patients with pulmonary disease. Transgenic expression of the Ad5 E1A gene targeted to the mouse lung reveals distinct biological effects caused by two Ad5 E1A products. Either of two Ad5 E1A proteins was preferentially expressed in vivo in the transgenic lungs. The preferential expression of the Ad5 E1A 243-amino-acid (aa) protein at a moderate level was associated with cellular hyperplasia, nodular lesions of proliferating lymphocyte-like cells, and a low level of p53-dependent apoptosis in the lungs of transgenic mice. In contrast, the preferential expression of the Ad5 E1A 289-aa protein at a moderate level resulted in a proapoptotic injury and an acute pulmonary proinflammation in the lungs of transgenic mice, mediated by multiple apoptotic pathways, as well as an enhancement of the host immune cell response. Expression of the Ad5 E1A 243-aa protein resulted in proliferation-stimulated p53 upregulation, while expression of the Ad5 E1A 289-aa protein led to DNA damage-induced p53 activation. These data suggest that the Ad5 E1A 243- and 289-aa proteins lead to distinct biological roles in vivo.
doi:10.1128/JVI.76.17.8910-8919.2002
PMCID: PMC136987  PMID: 12163610

Results 1-11 (11)