Current HIV Research - Volume 4, Issue 1, 2006

Current HIV Research begins its fourth volume providing our readers with stimulating, timely, and in-depth articles on current HIV and AIDS research. I take this opportunity to thank the authors for providing such insightful reviews and original scientific findings. Current HIV Research received its first Impact Factor (1.571) from the 2004 SCI Journal Citation Reports with each issue indexed in Chemical Abstracts, BIOSIS, Science Citation Index Expanded, ISI Alerting Services, MEDLINE/Index Medicus, EMBASE/Excerpta Medica, and the National Library of Medicine/PubMed. In 2005, four times as many articles were submitted to the journal for review than in the previous year; most likely due to the increased profile of the journal in the scientific community. I would also like to thank the Editorial Advisory Board for their assistance and advice. The Editorial Advisory Board reflects the international representation of scientists and clinicians from some of the leading institutions in the world. We are proud that a similar diversity is reflected in the published and submitted articles as well. The journal publishes both comprehensive reviews and original research articles focused on all areas of HIV/AIDS research including molecular biology, biochemistry, immunology, pharmacology, epidemiology, antiviral agents and vaccine development, as well as clinical research, which should be of interest to both basic and clinical investigators. In 2006, we expect to continue publishing the high level of quality articles in Current HIV Research.

BACKGROUND: Threats by enforced Intellectual Property (IP) rights to equitable HIV treatment access by poor populations are impending. India and China's policy directions in the field will be crucial in ultimately affecting the affordability and accessibility of antiretroviral (ARV) therapy in the under-served markets. These directions, together with the exploitation level of IP-bound flexibilities and the evolutionary modelling in partnerships and trade agreements between research-based and generic pharmaceutical industry, will also affect the outcomes of self-sufficiency efforts now at their beginning in the developing world as far as domestic manufacturing of generic ARV drugs is concerned. AIMS: This paper explores key issues, implications and interaction dynamics across these challenging scenarios while attempting to provide equitable solution glimpses into the near future. RESULTS: Access-oriented long-term drug policy strategies entitled to pass muster of governments, researchbased as well as generic industries in both developed and developing countries are needed if equitable access to affordable ARV treatments by poor people has to be achieved despite enforced IP rights. Predictable dynamics between western multinationals and transitional country generic corporations let regard IP-bound Voluntary License flexibilities as a fitting measure into just mentioned needs especially if substantial incentives to generic corporations are concurrently secured. Efforts to equitably expand ARV drug access through exploiting IP opportunities should encompass attainment of self-sufficiency in domestic drug manufacturing whenever basic requirements are in place in the developing world as a whole. A credible industrial potential would act, indeed, as a boosting factor for drawing branded drug producers into technology transfer agreements, the terms of which would let all contractors enjoy substantial advantages. These perspectives consistently bind up with the foreseeable long-term trade and drug policy directions of India and China according to frontier crossing implications of their key IP management trends as well as their multifaceted penetration strategies of both the wealthy and under-served markets worldwide. As coherent with these perspectives, more disbursement by wealthy country governments and donors to basic infrastructure development in sub-Saharan African nations with stable governments in place is urged both as a priority for improving Africa's economy and a prerequisite for allowing domestic industrial plants to take off. Aiming at the targets just underscored, WHO's brokering role in negotiated agreements between wealthy and developing country-based firms as well as its technical guidance in setting international standards have always to be sought if equitable and appropriate end results are to be attained. CONCLUSION: Overall insights in this paper would mean that, while research-based corporations are to be praised whenever waiving, on humanitarian purposes, part of their profits, the trade and profit rules cannot basically be given up if long-term sustainable results are the goal to look for. Only negotiated agreements securing all contracting parties lasting advantages may ensure shifting of such a goal from mere vision to a really sustainable attainment.

In recent years, there has been an alarming increase in the number of cases of coinfection with the human immunodeficiency virus type 1 (HIV-1) and the hepatitis C virus (HCV). It is now known that coinfection of HIV-1 patients by HCV can complicate the treatment of these patients with highly active antiretroviral therapy and the interactions between anti-HIV-1 and anti-HCV medications can also affect treatment efficacy and efficiency. Equally concerning, the bidirectional interferences between the two viruses are complex and can modify the natural history of both infections. This review aims to summarize the findings of numerous scientific investigations in the area of HIV/HCV coinfection. These investigations can be broadly classified into 3 groups; (a) immune evasion mechanisms (b) viral evolution and quasispecies diversity and (c) functions of viral proteins and their interactions with host factors. Our cumulative knowledge in this area and future research on the interplay between these two viruses will be important to the development of better antiviral therapeutics.

Uracil in DNA is a deleterious event that may arise either by cytosine deamination or misincorporation of dUTP. Consequently, cells from all free-living organisms have developed strategies to protect their genome against the presence of uracils, by using uracil DNA glycosylase (UNG) and deoxyuridine triphosphatase (dUTPase) enzymatic activities. In the viral kingdom, some (namely poxviruses and herpesviruses) but not all of the DNA viruses encode their own UNG and dUTPase to control uracilation of their genome. Some retroviruses, which are RNA viruses using DNA as an intermediate of replication, also encode dUTPase. Surprisingly, though most of nonprimate lentiviruses encode dUTPase, primate lentiviruses such as HIV-1, HIV-2 or SIV do not. Because these latter viruses also replicate in nondividing cells where the dUTP/dTTP ratio is high, it is probable that they have found other ways to fight against the emergence of uracilated-viral transcripts. Indeed, recent studies showed that HIV-1 efficiently controls both the cytosine deamination and the dUTP misincorporation. The viral Vif protein acts in preventing the packaging into viral particles of the host-derived cytosine deaminase APOBEC3G enzyme, while the viral integrase domain of the Gag-Pol precursor mediates the packaging of the host-derived uracil DNA glycosylase UNG2 enzyme. In the absence of Vif or UNG2, HIV-1 viral transcripts are heavily charged in uracil bases leading to inactivation of the virus.

In HIV-1 infected cells, over 40 different mRNA species are produced by alternative splicing of the single HIV-1 primary RNA transcript. In addition, approximately half of the HIV-1 primary RNA transcripts are not spliced and are exported to the cytoplasm where they serve as mRNA and as genomic RNA. In this article, we will review current knowledge of the mechanisms by which the HIV-1 alternative splicing is regulated. Several negatively and positivelyacting cis-acting elements have been detected within the viral genome that repress or facilitate viral RNA splicing by binding to cellular proteins. These include exonic splicing silencers (ESS) and an intronic splicing silencer (ISS) that are selectively bound either by members of the hnRNP A/B family (hnRNPs A1, A1Β, A2, and B1) or by hnRNP H. Exonic splicing enhancers (ESE) are also present within the HIV-1 genome and are selectively bound by members of the SR protein family. ESS and ISS repression mediated by hnRNP A/B proteins occurs at early steps of splicing, prior to formation of pre-spliceosome complexes. Current models propose that ESS elements promote cooperative binding of hnRNP A/B proteins to the exon and prevent efficient binding of essential cellular splicing factors to the 3' splice site. SR proteins bound to ESE elements that are juxtaposed or overlapping ESS elements may counteract this inhibition. We will review data indicating the importance of the HIV-1 splicing elements and their cognate binding proteins for efficient virus replication. Differences in cis-acting splicing elements between the group M (major) and group O (outlier) HIV-1 strains will also be discussed. Finally we will review evidence suggesting the possibility that there may be changes in regulation of HIV-1 alternative splicing in infected human T cells, human macrophages and rodent cells.

The nef gene is conserved among primate lentiviruses and is one of the first viral genes that is transcribed following infection. This suggests a critical role for Nef in the virus life cycle and in the pathogenesis of lentiviral infections. In vitro, several functions have been described, including down regulation of CD4 and MHC class I surface expression, altered T-cell signaling and activation, and enhanced viral infectivity. However, the impact of these individual functions on viral pathogenicity in general, and thymic T cell production in particular, remains elusive. Here, we review the observations from experimental models that have been used to study the pathogenic effect of HIV-1 Nef on the thymus. These in vitro and in vivo studies have led to a better understanding of Nef's mechanism of action, although there still exists discord as to the contribution of Nef-mediated disturbance of thymopoiesis in the pathogenesis of AIDS.

Within the initial weeks following transmission, HIV-1 becomes well established in the lymphatic tissue reservoir. Replication of the virus occurs throughout the course of infection despite the induction of a vigorous adaptive immune response by the host. The emergence of variants with particular characteristics correlates with increased viral burden and disease progression, indicating that the fitness of the infecting virus and selected variants plays a significant role in persistent viral replication and disease progression. This article reviews studies of HIV-1 variants and pathogenicity. It focuses mainly on experimental SIV infection of macaques as a model system to decipher the significance of viral variants for infection, persistence, and disease because it is difficult to systematically examine transmission and pathogenesis of HIV-1 in humans.

Highly active antiretroviral therapy (HAART) regimens, especially those including protease inhibitors have been shown to cause, in a high proportion of HIV-infected patients, a metabolic syndrome (lipodystrophy/lipoatrophy, dyslipidemia, type 2 diabetes mellitus, insulin resistance) that may be associated with an increased risk of cardiovascular disease. A careful stratification of the cardiovascular risk of HIVinfected patients under HAART is needed according to the most recent clinical guidelines.

One of the major health problems among HIV - infected patients is the intestinal parasite infestations. It can be seen that intestinal helminth infestation in HIV - infected patients is common. However, the reported prevalence is usually similar to those of non HIV-infected patients in the same setting. The infestations are ordinary not opportunistic, hence, thus usually show no correlation to immune status of the patients. The suppression of immunity due to HIV infection shows no significant role in increasing the intestinal helminth infestations. On the other hand, having occult intestinal helminth infestations does also not worsen the outcome of HIV infection. Concerning the clinical manifestation, most of the helminth infestations are asymptomatic and the diagnosis is usually based on the stool examination. Treatments of the infestations as well as the outcomes are usually similar to immunocompetent host. Intestinal protozoa infestations are also important problems for HIV-infected patients. Some infections are ordinary, while the others are opportunistic infection. The important opportunistic intestinal parasites including C. parvum, I. belli, Cyclospora and the Microsporidia are found at high prevalence among the HIV-infected patients, especially in low immune cases with persistent diarrhea. Concerning the clinical manifestation, most of the infestations bring diarrhea and the diagnosis is usually based on the stool examination with special stains. The treatment of the opportunistic infection can usually get control of the present illness but not prevent the re-infection. Luckily, with the present wide distribution of HAART, the prevalence of the opportunistic intestinal protozoa infections is significantly decreased.

Objective: New onset diabetes mellitus type 2 is increasing among HIV-infected patients in the era of potent antiretroviral therapy. Accurately identifying HIV-infected patients with a diagnosis of diabetes in electronic medical record systems will facilitate the study of patients with this disease. Study Design And Setting: We examined electronic medical record data for all patients who initiated care at an HIV clinic between 1/1/1997 and 12/31/2001 to identify potential cases of diabetes. Case identification methods included clinician-coded diagnoses, medications, and HbA1c and glucose levels. Diabetes diagnoses were verified by clinician documentation in an electronic medical record progress note. Test characteristics of each case identification method were calculated. Results: 53 cases of diabetes were identified among the cohort of 1441 patients. Use of clinician-coded diagnoses alone or combined with other methods was the most sensitive method for identifying diabetes cases. Clinician-coded diagnoses were also the best method as assessed by standard receiver operator characteristic plots. A significant attenuation of odds ratios for associations with diabetes were found for case identification methods with imperfect specificity such as serum glucose levels. Conclusions: This study demonstrates that electronic medical record data can be used to accurately identify HIV-infected patients with diabetes. The optimal method applied will depend on the goals of a particular study.

Thrombocytopenia is a common hematologic disorder in patients infected with the human immunodeficiency virus (HIV) and represents a risk for bleeding which is further deleterious during surgery. The major causes of the thrombocytopenia include accelerated peripheral platelet destruction by antiplatelet antibodies and insufficient production of platelets from the infected megakaryocytes. Additionally, at an earlier stage of platelet development, HIV may inhibit megakaryopoiesis at multiple stages of pluripotent CD34+ progenitor stem cell differentiation possibly contributing to decreased levels of platelets in circulation. In HIV infected patients, both the serum thrombopoietin (TPO) levels and theTPO-c-Mpl complexes on the platelet surface were significantly elevated. Therapeutic infusion of HIV infected patients with pegylated recombinant human megakaryocyte growth development factor (PEG-rHu-MGDF) restores platelet counts to normal levels and reduces the c-Mpl expression per platelet. In vitro aggregation of platelets treated with TPO and agonist, adenosine diphosphate (ADP), decrease the dose of ADP that is required for half-maximum aggregation. In vivo dosing does not effect platelet aggregation showing that the metabolism of TPO following its internalization through TPO-c-Mpl complex is rapid and that dosing within the therapeutic range does not constitute increased risk of thrombotic disease.