Current HIV Research - Volume 3, Issue 1, 2005

Current HIV Research begins its third volume providing our readers with stimulating, timely, and in-depth articles on current HIV and AIDS research. As the Editor-in-Chief, I take this opportunity to thank the authors who contributed their ideas and insights into each article. The manuscripts published in volumes 1 and 2 highlight a wide array of innovative scientific and medical research on HIV / AIDS. Beginning with the January, 2005 issue (Volume 3, Number 1), Current HIV Research will begin publishing original scientific articles on all areas of HIV and AIDS research. The journal will continue providing in-depth review articles, however, the journal is expanding to include primary scientific research at the request of authors and readers. The journal welcomes the submission of novel and pioneering work in the basic and clinical fields of virus replication and gene expression, HIV assembly, virus-cell interaction, viral pathogenesis, epidemiology and transmission, anti-retroviral therapy and adherence, drug discovery, the latest developments in HIV / AIDS vaccines and animal models, and prevention of viral infection. Current HIV Research aims to be the international journal for both comprehensive review articles and cutting-edge scientific findings on HIV research. The Editorial Advisory Board reflects the international representation of scientists and clinicians located in 14 different nations 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 fills a special void in the existing biomedical literature in publishing manuscripts focused on all areas of HIV / AIDS research including molecular biology, biochemistry, immunology, pharmacology, epidemiology, prevention of transmission, antiviral agents and vaccine development, as well as clinical research, which should be of interest to both basic and clinical investigators. We will continue to be responsive to our readers in order to build one of the leading research journal on HIV and AIDS research and we welcome your comments.

Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) are the causative agents of Acquired Immunodeficiency Syndrome (AIDS). Without therapeutic intervention, HIV-1 or HIV-2 infections in humans are characterized by a gradual and irreversible immunologic failure that ultimately leads to the onset of a severe immunodeficiency that constitutes the hallmark of AIDS. In the last two decades AIDS has evolved into a global epidemic affecting millions of persons worldwide. Although sharing several identical properties, HIV-1 and HIV-2 have shown some important differences in vivo. In fact, a significant amount of epidemiologic, clinical and virologic data suggest that HIV-2 is in general less virulent than HIV-1. This reduced virulence is revealed by the longer asymptomatic period and the smaller transmission rate that characteristically are observed in HIV-2 infection. In this context, studies using HIV-2 as a model of a naturally less pathogenic infection could bring important new insights to HIV pathogenesis opening to new strategies to vaccines or therapeutic design. The reasons underlying the reduced pathogenicity of HIV-2 are still essentially unknown and surely are the outcome of a combination of distinct factors. In this review we will discuss the importance and the possible implications in HIV-2 pathogenesis, particularly during the asymptomatic period, of a less fitted interaction between viral envelope glycoproteins and cellular receptors that have been described in the way HIV-2 and HIV-1 use these receptors.

The HIV epidemic has resulted in medical, social and economic consequences. There is general agreement that a safe, effective and affordable preventive HIV vaccine is urgently needed to control the epidemic. To date, over 60 phase I / II trials of about 30 candidate vaccines have been conducted worldwide. In 1991, Thailand was selected by WHO, UNAIDS as one of the countries for potential HIV vaccine evaluation sites, and 10 projects with HIV phase I, II and III trials have been conducted since 1994. Strong national commitment, collaboration both at national and international levels together with infrastructure strengthening and capacity building, are very important for success. The vaccine designs pursued included synthetic peptides, recombinant protein and recombinant viral vectors followed by or with boosting doses of recombinant proteins. All phase I / II trials indicated that the candidate vaccines were safe and produced binding and a certain level of neutralizing antibodies. The recombinant vector vaccines produced both humoral and cell-mediated responses. The AIDSVAX phase III trial conducted in 1999 was the first efficacy trial of HIV vaccine in Thailand that brought valuable information for further HIV vaccine development. Recently, a phase III trial of ALVAC-HIV priming with AIDSVAX® B / E boosting was launched in 2003, and the findings of this trial will be shared with the international community. With committed parties in medical science, government, industry and the community, we hope that we can achieve success in developing a safe and effective HIV vaccine in the near future.

Globally, HIV-1 is most often transmitted heterosexually so that nearly half of all infected adults are women of child-bearing age. Infants may acquire infection from vertical transmission. Without treatment most HIV-1 infected children in Africa die before their third birthday; as a result child mortality has increased overall by 35-50%, and by greater than 100% in areas of high seroprevalence. HIV-1 infection has a heterogeneous spectrum of clinical course. Compared to HIV-1-infected adults, survival times are considerably shorter for children who acquire the virus perinatally or during infancy. Factors contributing to accelerated disease progression in infants and children are poorly understood but may include relative immunological immaturity, thymic HIV-1-mediated destruction at a time of active thymopoiesis, and HLA class I sharing between mother and infant. This review will initially discuss clinical and biological determinants of mother-to-child transmission and disease progression in HIV-infected infants and children. Our current knowledge of the mechanisms of T cell depletion is summarised and the host immune response to HIV-1 (innate and adaptive) described in the context of Pediatric HIV-1 infection.

The HIV-1 vpr gene is conserved among the human (HIV-1, HIV-2) and simian immunodeficiency viruses (SIV). HIV-1 vpr encodes a 96-amino acid, 14 kDa protein (Vpr). Research from a number of laboratories in the last decade has shown that Vpr performs multiple functions, including the induction of cell cycle arrest in the G2 phase, transactivation of the viral promoter, nuclear import of preintegration complexes, and induction of apoptosis in the infected cell. More recent studies have attempted to elucidate the cellular targets that Vpr utilizes in order to perform the above functions. This review presents the latest findings about the pathogenic events triggered by Vpr, the cellular pathways involved, and the molecular and cellular consequences of the action of Vpr in the context of HIV-1 infection.

Despite numerous studies on the impact of viral diversity, human immunodeficiency virus type 1 (HIV-1)-specific immune responses and host factors on disease progression, we still do not have a firm understanding of the pathogenesis of HIV-1 infection. Rapid depletion of CD4+ T-lymphocytes has been associated with a switch in viral coreceptor usage from CCR5 to CXCR4 in approximately 40 to 50% of infected individuals. However, the majority of infected individuals who progress to AIDS harbor only CCR5- dependent (R5) viral strains. HIV-1 disease progression is associated with an enhanced tropism of R5 viral strains for cells of the monocyte / macrophage lineage (enhanced M-tropism). However, the underlying molecular mechanisms contributing to enhanced M-tropism by R5 HIV-1 strains, and how HIV-1 variants with enhanced M-tropism cause CD4+ T-cell depletion in vivo are unknown. This review examines the relationship between viral coreceptor usage, M-tropism, and pathogenicity of HIV-1. We highlight evidence supporting the hypothesis that enhanced M-tropism of R5 HIV-1 results from adaptive viral evolution, resulting in HIV-1 variants that have increased ability to utilize relatively low levels of CD4 and CCR5 expressed on macrophages. The evidence also suggests that these late-emerging, R5 viral strains have reduced sensitivity to entry inhibitors, and increased ability to cause CD4+ T-lymphocyte loss. These variants are likely to impact HIV-1 disease progression, particularly in patients who persistently harbor only R5 viral strains.

HIV-1 TAR RNA is the binding site of the viral protein Tat, the trans-activator of the HIV-1 LTR. It is present at the 5' end of all HIV-1 spliced and unspliced mRNAs in the nucleus as well as in the cytoplasm. It has a highly folded stem-bulge-loop structure, which also binds cellular proteins to form ribonucleoprotein complexes. The Tat-Cyclin T1-CDK9 complex is the main component in the trans-activation of HIV-1 and its affinity for TAR is regulated through Tat acetylation by histone acetyl transferases. Recent studies show that this complex is able to recruit other cellular partners to mediate efficient transcriptional elongation. TRBP, PKR and La bind directly to the TAR RNA structure and influence translation of HIV-1 in either positive or negative manners. Some mutations in TAR RNA severely impair HIV-1 trans-activation, translation and viral production, showing its functional importance. The overexpression or suppression of several TAR RNAbinding proteins has a strong impact on viral replication pointing out their major role in the viral life cycle. TAR RNA has been the target of drug development to inhibit viral replication. Recent data using small molecules or RNA-based technologies show that acting on the TAR RNA or on its viral and cellular binding factors effectively decreases virion production.

The Pol protein of human immunodeficiency virus type 1 (HIV-1) harbours the viral enzymes critical for viral replication; protease (PR), reverse transcriptase (RT), and integrase (IN). PR, RT and IN are not functional in their monomeric forms and must come together as either dimers (PR), heterodimers (RT) or tetramers (IN) to be catalytically active. Our knowledge of the tertiary structures of the functional enzymes is well advanced, and substantial progress has recently been made towards understanding the precise steps leading from Pol protein synthesis through viral assembly to the release of active viral enzymes. This review will summarise our current understanding of how the Pol proteins, which are initially expressed as a Gag-Pol fusion product, are packaged into the assembling virion and discuss the maturation process that results in the release of the viral enzymes in their active forms. Our discussion will focus on the relationship between structure and function for each of the viral enzymes. This review will also provide an overview of the current status of inhibitors against the HIV-1 Pol proteins. Effective inhibitors of PR and RT are well established and we will discuss the next generation inhibitors of these enzymes as well recent investigations that have highlighted the potential of IN and RNase H as antiretroviral targets.

The Human Immunodeficiency Virus -1 (HIV-1) Nef protein that was originally identified as a viral negative factor is a 27kDa myristoylated protein. However, this so called dispensable viral protein has emerged as one of the most important proteins for viral life cycle. Nef not only establishes the host cell environment suitable for viral replication and pathogenesis but also facilitates the progression of the infection into disease. Previous efforts have been focussed to explain how Nef down modulates host cell receptors like CD4 and MHC-1 molecules, thereby helping the virus to evade host defense and to increase viral infectivity. Nef also ably modulates specific processes like apoptosis in favour of viral life cycle other than being the stimulus for cell activation and signal transduction pathways. After much maligning over its reported positive or negative functions on the HIV-1 Long Terminal Repeat (LTR) promoter, the Nef protein is now perceived to enhance viral replication and infection through a combination of different effector functions. Recent reports emphasize a role for Nef in viral gene expression and place it in a prime position to oversee and optimize viral replication. Nef may do so by enhancing Tat mediated gene expression from the LTR by activating signalling pathways that result in a concomitant increase in the activation of general transcription factors, and also by mediating translocation of repression factors from the nucleus. Thus, Nef not only enhances infection but also plays an important role in viral replication and pathogenesis.

The rate of syphilis / HIV co-infection amongst men who have sex with men (MSM) in large urban regions ranges from 20 to 70% [7]. Concurrent HIV infection can alter the clinical presentation of syphilis, the response to treatment, and complicate the diagnosis and clinical course of neurosyphilis [18]. Therefore whether to perform a lumbar puncture (LP) on every co-infected patient in order to diagnose neurosyphilis is controversial. Current clinical guidelines specify the indications for LP, but fall short of recommending LP in certain clinical situations such as early syphilis without neurological involvement. This article reviews the current literature on the relative utility and indications for LP in syphilis / HIV co-infected patients and new research in this area.