Fifty small breakthroughs in HIV science already in 2007 published

[bimazek]

1000 new articles already pub 2007 on HIV   i just read thru all 1000 of these articles on hiv published in 2007
so i scanned them all, by the 3rd week in january 2007 there were only 87 articles with word hiv in them... these were the most intereting ones...here is what i found... 

fifty small breakthroughs in HIV science....  i try to give a summary in non scientific words of each article    i have theory that no one is reading these articles... i mean the dr. and scientists there are just too many and a breakthrough might be missed by the right person   if you want to find the article just copy 3 or 4 unique words in article to google...


basically the lack of perforin... the molecule that distroys invades was to blame for immune system not killing hiv at start     of infection or during infection... another article shows that CD8 perforin is not functioning 
2007 Mar 12;21(5):565-74.  Early immune activation in gut-associated and peripheral lymphoid tissue during acute HIV infection.    Center for Infectious Medicine and Division of Infectious Diseases, Karolinska University Hospital, Karolinska Institutet, Huddinge, Stockholm, Sweden.     OBJECTIVE: To study innate and adaptive immune responses in gut-associated lymphoid tissue (GALT) as well as peripheral lymphoid tissue (pLT) obtained from individuals with acute HIV-1 infection syndrome. DESIGN: The expression of chemokines [regulated upon activation: normal T cell expressed/secreted (RANTES), macrophage-inflammatory protein (MIP) 1alpha/beta], cytokines (IL-1beta, TNF-alpha, IL-12, IL-4, IL-10, IL-2, IFN-gamma) and cytotoxic effector molecules (granzyme A, perforin) and cell marker (CD8) were analysed at the single cell level in GALT and pLT of patients experiencing acute HIV-1 infection (day -3 to 48 days from onset of acute symptoms). RESULTS: Substantial pro-inflammatory immune responses (TNF-alpha, IL-1beta, IL-12) and expansion in the CD8 T-cell population were noted in both compartments compared with uninfected controls. This was associated with an early increased expression of beta-chemokines (RANTES, MIP-1alpha/beta) and granzyme, but not with an increase in the expression of perforin. The upregulation of IL-2, IL-12 and IL-4 was noted in both pLT and GALT, whereas IL-10 expression was mainly increased in GALT. CONCLUSION: Taken together, these findings demonstrate that there was a broad and early immune activation in GALT and pLT during acute HIV-1 infection. The relative lack of perforin expression in both GALT and pLT, however, questions the functional efficacy of the observed immune activation in generating cytotoxic T cells that were able to eliminate HIV-infected cells.
   
   
   
Rats to the rescue!!!!! transexual or transgender or transgenic rats help cure hiv... germans love trans-ies
 Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):1015-20. Epub 2007 Jan 5.Click here to read  Links
HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription.          Department of Virology, University of Heidelberg, 69120 Heidelberg, Germany.
The current testing of anti-HIV drugs is hampered by the lack of a small animal that is readily available and easy to handle; can be infected systemically with HIV type 1 (HIV-1); harbors the major HIV-1 target cells in a physiological frequency, organ distribution, and activation state; and is established as a pharmacological model. Here, we explored the potential of outbred Sprague-Dawley rats that transgenically express the HIV-1 receptor complex on CD4 T cells and macrophages as a model for the preclinical evaluation of inhibitors targeting virus entry or reverse transcription. The concentrations of the peptidic fusion inhibitor enfuvirtide or the nonnucleoside reverse transcriptase inhibitor efavirenz required to inhibit HIV-1 infection of cultured primary CD4 T cells and macrophages from human CD4 and CCR5-transgenic rats differed by no more than 3-fold from those required for human reference cultures. Prophylactic treatment of double-transgenic rats with a weight-adapted pediatric dosing regimen for either enfuvirtide (s.c., twice-daily) or efavirenz (oral, once-daily) achieved a 92.5% or 98.8% reduction, respectively, of the HIV-1 cDNA load in the spleen 4 days after i.v. HIV-1 challenge. Notably, a once-daily dosing regimen for enfuvirtide resulted in a approximately 5-fold weaker inhibition of infection, unmasking the unfavorable pharmacokinetic characteristics of the synthetic peptide in the context of an efficacy trial. This work provides proof of principle that HIV-susceptible transgenic rats can allow a rapid and predictive preclinical evaluation of the inhibitory potency and of the pharmacokinetic properties of antiviral compounds targeting early steps in the HIV replication cycle.
           
           




vaccines are on the way... they are good for therapudic as well as treatment and prevention............
Endpoints and Regulatory Issues in HIV Vaccine Clinical Trials: Lessons From a Workshop.
Clinical Science    JAIDS Journal of Acquired Immune Deficiency Syndromes. 44(1):49-60, January 1, 2007.
Follmann, Dean PhD *; Duerr, Ann MD, PhD, MPH, HVTN +; Tabet, Stephen MD, MPH ++; Gilbert, Peter PhD [//]; Moodie, Zoe PhD [//]; Fast, Patricia MD [P]; Cardinali, Massimo MD *#; Self, Steve PhD [//]**
Abstract:    Summary: A successful HIV vaccine would have a substantial impact on acquisition of infection, progression of disease among the infected, or infectiousness of the infected. Current vaccine candidates are anticipated to have their major effect on viremia, however, with the expectation that this would induce or be concordant with a reduced rate of AIDS, death, or infectiousness. Although direct assessment of disease progression or infectiousness may be impractical, available potential surrogates for these endpoints may be misleading. This article summarizes the proceedings of a National Institute of Allergy and Infectious Disease-sponsored workshop to explore the use of surrogate endpoints for licensure of an HIV vaccine. Early, medium, and late endpoints were discussed, along with challenges such as surrogate validity, the confounding effect of antiretroviral therapy initiation, and potential selection bias in the vaccine and placebo recipients who become infected. Results from 5 hypothetic HIV vaccine clinical trials with ambiguously successful results were presented to an expert panel for interpretation and discussion of next steps. Key recommendations included assessing magnitude and durability of surrogate effects, generalization across populations, and directed improvement of vaccines. Use of acquisition and a postinfection surrogate as coprimary endpoints was supported, along with use of composite endpoints and exploration of heterogeneity in vaccine efficacy by characteristics of the host and virus.           
   
   
   
this study says that protease inhibitors have another new good thing about them, they block the killing of cells that all
the nasty molecules and proteins that hiv produces causes in the body.... 
Clinical Pharmacology & Therapeutics advance online publication 14 March 2007; doi: 10.1038/sj.clpt.6100140
Flying in the Face of Resistance: Antiviral-independent Benefit of HIV Protease Inhibitors on T-cell Survival
S R Vlahakis1,2, G D Bren1, A Algeciras-Schimnich1, S A Trushin1, D J Schnepple1 and A D Badley1,2
Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
 2Program in Translational Immunovirology and Biodefense, Mayo Clinic College of Medicine, Rochester, Minnesota, 
 Accepted 22 January 2007; Published online 14 March 2007.
Human immunodeficiency virus (HIV) infection results in excessive apoptosis of infected and uninfected cells, mediated by host and viral factors present in plasma. As HIV protease inhibitors (PIs) have intrinsic antiapoptotic properties, we questioned whether HIV PIs could block HIV-induced CD4+ T-cell death independent of their effects on HIV replication. We demonstrate that HIV PIs block the death of CD4+ T cells induced by HIV glycoprotein 120 (gp120), Vpr, and Tat, as well as host signals Fas ligand, tumor necrosis factor, and tumor necrosis factor-related apoptosis-inducing ligand. Using gp120/CXCR4 as a model, we show that the HIV PIs specifically block mitochondrial apoptosis signaling. Furthermore, HIV PIs inhibit CD4+ T-cell death induced by viruses with high-level resistance to PIs (P<0.01) and apoptosis induced by serum of HIV patients with known resistance to HIV PIs (P=0.01). Together, these results show that HIV PIs block CD4+ T-cell death and have a beneficial effect on CD4+ T-cell survival despite PI resistance.
   
   

   
       
       
CD8 cells.. .... this is my big calling in life... i had vision in 1987 that CD8 cells where the solution to HIV...     
A large number of experimental studies have been performed over the past decade in an attempt to develop a vaccine for human immunodeficiency virus (HIV). These studies have used a variety of approaches aimed at stimulating both antibody-mediated and cell-mediated immunity. Many of these experiments have been performed in macaque models of HIV. Analysis and modeling of the results of these studies provide the opportunity to investigate the mechanisms and limitations of viral control by humoral and cell-mediated immunity. These studies suggest that CD8+ T cells do ‘too little too late’ to prevent the establishment of viral infection and latency. By contrast, passively administered antibody acts extremely early to reduce the initial inoculum and slow viral growth. In both cases, reduction in peak viral load appears crucial to the maintenance of CD4+ T cells in acute infection and for effective long-term viral control. The insights gained from studies of simian human immunodeficiency virus infection have important implications for HIV vaccination. However, important questions remain as to whether differences in pathogenesis in HIV will lead to different ‘rules of engagement’ for immune control of virus.       
       
       
       
       
       
not a happy story...............
HIV-associated dementia: An inconvenient truth
Brew and González-Scarano Neurology.2007; 68: 324-325
   
       
Selenium appears beneficial in patients with HIV-1 infection.
Clinical study  Inpharma Weekly. (1577):18, March 3, 2007.   
   
   
this says they can get thru the blood brain barrier with hiv drugs with nasal spray delivery   
Leah R. Hanson1 and William H. Frey II1, 2 Contact Information
Abstract  Intranasal drug administration is a noninvasive method of bypassing the blood–brain barrier (BBB) to deliver neurotrophins and other therapeutic agents to the brain and spinal cord. This method allows drugs that do not cross the BBB to be delivered to the central nervous system (CNS) and eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways. Intranasal delivery occurs by an extracellular route and does not require that drugs bind to any receptor or undergo axonal transport. Intranasal delivery also targets the nasal associated lymphatic tissues (NALT) and deep cervical lymph nodes. In addition, intranasally administered therapeutics are observed at high levels in the blood vessel walls and perivascular spaces of the cerebrovasculature. Using this intranasal method in animal models, researchers have successfully reduced stroke damage, reversed Alzheimer’s neurodegeneration, reduced anxiety, improved memory, stimulated cerebral neurogenesis, and treated brain tumors. In humans, intranasal insulin has been shown to improve memory in normal adults and patients with Alzheimer’s disease. Intranasal delivery strategies that can be employed to treat and prevent NeuroAIDS include: (1) target antiretrovirals to reach HIV that harbors in the CNS; (2) target therapeutics to protect neurons in the CNS; (3) modulate the neuroimmune function of moncyte/macrophages by targeting the lymphatics, perivascular spaces of the cerebrovasculature, and the CNS; and (4) improve memory and cognitive function by targeting therapeutics to the CNS.    Key words  HIV - intranasal - NeuroAIDS - blood–brain barrier - CNS - lymphatics
   
   
   
this article says...to me that every politician, drug company exec, and bank exec should be in prison and the entire med community put to shame for letting 25 years pass before they find anything about about HIV in the intestinal tract since they have known that the intestine is a  lymphocyte-rich site that undergoes severe depletion of memory CD4+ T-cells within days of  HIV infection. An ensuing influx of virus-specific CD8+ T-cells, which persists throughout the chronic phase of infection, has also been documented in the gastrointestinal tract. However, little is known of the functionality of these effector cells, or their relationship to disease course.  how could this be possible... "little is known of the functionality of these effector cells, or their relationship to disease course."   the major location of where HIV lives and they are just getting around to finding info about this... unbelievable...
J Virol. 2007 Mar 7;     Multifunctional HIVgag Specific CD8+ T-cell Responses in Rectal Mucosa and PBMC During Chronic HIV-1 Infection.    Department of Medical Microbiology and Immunology, Department of Internal Medicine, Division of Infectious Diseases, and Division of Gastroenterology, School of Medicine, University of California, Davis, CA.
 The intestinal tract is a lymphocyte-rich site that undergoes severe depletion of memory CD4+ T-cells within days of SIV or HIV-1 infection. An ensuing influx of virus-specific CD8+ T-cells, which persists throughout the chronic phase of infection, has also been documented in the gastrointestinal tract. However, little is known of the functionality of these effector cells, or their relationship to disease course. In this study, we measured CD8+ T-cell responses to HIV-1 peptides in paired rectal and blood samples from chronically infected patients. In both blood and rectum there was an immunodominant CD8+ T-cell response to HIV Gag as compared to Pol and Env (P < 0.01). In contrast, CMVpp65 peptides strongly elicited IFNgamma secretion in PBMC but weakly in rectal CD8+ T-cells (P = 0.015). Upon stimulation with HIV peptides, CD8+ T-cells from both sites were capable of mounting complex responses including degranulation (CD107 expression), IFNgamma and TNFalpha production. In rectal tissue, CD107 release was frequently coupled with production of IFNgamma or TNFalpha. In patients not on antiretroviral therapy, the magnitude of Gag-specific responses, as percentage of CD8+ T-cells, was greater in rectal mucosa than PBMC (P = 0.054); however, the breakdown of responding cells into specific functional categories was similar in both sites. These findings demonstrate that rectal CD8+ T-cells are capable of robust and varied HIV-1-specific responses and therefore likely play an active role in eliminating infected cells during chronic infection.   
       
   
   
       
   
this article says... the sugar coat of hiv that was thought to be a shield may be a good target for a new vaccine now that science has new knowlegde about this sugar coat and the peptides and such... so this could be a breakthrough if it works out...          Defining Carbohydrate Antigens as HIV Vaccine Candidates
   Authors: Pashov, Anastas1; Perry, Marty1; Dyar, Michael1; Chow, Marie1; Kieber-Emmons, Thomas1
  Source: Current Pharmaceutical Design, Volume 13, Number 2, January 2007, pp. 185-201(17)
Abstract:  The induction of high affinity antibodies capable of broad neutralization and protection against infection and/or disease is a major goal in the development of a vaccine for human immunodeficiency virus (HIV). Insights into the structure and function of the envelope (Env) protein of HIV-1 suggest that the virus is under strong selection pressure by the immune response leading to constant mutations in the Env protein including the N-glycosylation sites. Initially considered a shield against the immune system, the heavily glycosylated outer surface of the HIV Env protein has drawn attention lately as a legitimate target. The dense cluster of high mannose glycans and the great variety of complex glycans present epitopes that might impact on disease progression. Indeed a number of mannose binding proteins and at least one human anti-mannose antibody - 2G12, are broadly neutralizing. Due to the low immunogenicity of carbohydrates, these targets on HIV are of limited value unless new powerful immunogens are found. One approach would be the molecular design of peptide carbohydrate mimotopes that can elicit neutralizing antibodies by recruiting optimal T cell help. Here we review existing data on carbohydrate interactions and HIV immunogenicity that serves as a basis for structural concepts and approaches used for vaccine design targeting HIV associated carbohydrate antigens. In particular, the value and the limitations of chemical (peptide libraries), structural and immunological information is illustrated.