Research initiative, treatment action: RITA

Online ISSN: 1520-8745
Publications
Article
HIV-1 is a fundamentally difficult target for vaccines because of its high mutation rate and its repertoire of immune evasion strategies. To address these difficulties, a multivalent genetic vaccine or "live genetic vaccine" was recently developed against HIV-1 using the expression library immunization (ELI) approach. In this HIV-1 vaccine, all open reading frames of HTLV-IIIb are expressed as protein fragments to retain all viral T cell epitopes, but destroy protein toxicity, inactivate immune escape functions, and reveal subdominant epitopes. In addition, each antigen fragment is fused to the ubiquitin protein to increase antigen expression and target these antigens to the proteasome to enhance cytotoxic T lymphocyte (CTL) responses. This multivalent vaccine also has the advantage of being incapable of generating infectious HIV-1 virus because of the segregation of the HIV genome into 32 separate plasmids. In this work, we demonstrate the ability of this genetic vaccine to provoke robust HLA-A*0201-restricted T cell responses in MHC class I humanized mice against gag, pol, env, and nef after a single round of immunization. In addition, this HTLV-IIIb-derived vaccine demonstrated cross-clade, envelope-specific, HLA-restricted CD8 responses against clades A, D, and E. HLA-restricted CD8 responses were generated against all 32 open reading frames encoded by the multi-plasmid genetic vaccine demonstrating that a broad repertoire of human relevant CD8 responses are provoked by this vaccine. This work supports this approach to generate multivalent T cell responses to control the highly mutable and immuno-evasive HIV-1 virus.
 
Article
The rate of HIV replication is estimated to be about 10 billion particles a day, and the cell's structure is its primary defense against infection. Cell membranes provide a defense against infection by forming a tight bond, preventing cells from being invaded by other organisms. The complex process of how HIV enters a cell is explained, and various parts of the process are illustrated. One key step in the process is fusion, which is when a virus particle attaches to a T cell, and the virus and cell merge together, allowing the virus to enter the cell. Researchers hope to find ways to interfere with fusion, so as to prevent HIV infection. Trimeris, Inc. has developed a new drug called T-20, or pentafuside, that is capable of preventing HIV from infecting a target cell. Results from studies of T-20 are provided, and ongoing studies are described.
 
Article
Both AIDS and antiretroviral treatments have been associated with body changes. The most common term used to characterize these changes is lipodystrophy. Body changes include increased abdominal girth, fat accumulation at the base of the neck, enlarged breasts in both sexes, loss of fat in the face and extremities, and the appearance of prominent veins. Blood abnormalities associated with the condition include insulin resistance and increased levels of cholesterol, triglycerides, and glucose. There may also be an increased risk of cardiac complications. Researchers are seeking the causes of the fat redistribution and lipid and glucose abnormalities. A discussion of managing and treating these conditions is included.
 
Article
HIV-specific T cell immune responses will play an important role in any HIV vaccine paradigm. Studies in rhesus monkeys have shown that significant and persistent virus-specific T cell responses can be elicited with vaccines incorporating viral genetic sequences and that these responses are primarily mediated by CD8 T cells. Benefits such as stable CD4 levels and viral control have resulted. Two vaccine candidates developed by Merck and Co., Inc., including a non-replicating adenoviral vector, have been studied in animals and are now being studied in Phase I clinical trials in humans. Important considerations include cross-clade reactivity (effectiveness in diverse HIV-infected populations), tolerability, and durability of response. Ongoing studies are looking at responses in both uninfected and infected individuals. Optimal vaccine combinations as well as the development and testing of vaccines with multiple genetic targets are part of future plans investigating this vaccine strategy.
 
Article
The effectiveness of AIDSVAX is challenged because the vaccine's principal component is designed to induce immune responses against the envelope protein gp120, which mutates easily. The vaccine cannot cause AIDS, and trials have shown it to be safe. However, those who take the vaccine will test positive on HIV antibody tests. Other issues challenging the effectiveness of AIDSVAX are discussed.
 
Article
Interferon-alpha (IFN-alpha) generation by peripheral blood mononuclear cells (PBMC) responding in vitro to HSV was first found to be deficient in patients with severe ulcerative herpes simplex virus (HSV) infections early in the AIDS epidemic. Such deficits were soon found to be associated with all opportunistic infections (OI). Further studies during the natural history of HIV infection indicated that OI did not occur so long as IFN generation remained relatively intact. OI occurred only when both IFN-alpha generation and CD4 T cell counts were sufficiently depressed. The IFN-alpha response to HSV was innate, not adaptive. Evidence that the IFN-alpha response to HSV was derived from a rare and previously undefined cell type prompted studies eventually revealing that the IFN-producing cells were identical to the "enigmatic plasmacytoid T cells" described by Lennert in lymphoid tissues in 1958. The normal functions of these cells appear to be diverse, but one such function involves initiation of the Th-1 pathway in response to certain microbial antigens. The IFN-producing cells are now known as plasmacytoid dendritic cells (pDCs), because they differentiate following appropriate stimulation, into type-2 dendritic cells. During therapy for HIV infection, pDCs recover somewhat more rapidly than CD4 T cells to levels associated with resistance to OI, and their renewed response appears closely associated with clinically apparent immune reconstitution. Increased pDCs have been associated with nonprogressor status. In HIV infection and in certain other clinical states, PBMC IFN-alpha generation and pDCs numbers correlate closely, suggesting that numerical depletion of circulating pDCs is an important component of the immune deficiency of AIDS. Losses of pDCs during HIV progression and repletion during antiretroviral therapy could be involved in both the progressive loss and reconstitution of the Th-1 pathway.
 
Article
While nearly ten percent of diagnosed cases of AIDS occur in people 50 years old and older, there has been little attention given to this group in the areas of prevention, education, psychosocial support, or treatment because HIV/AIDS is thought to be the disease of the young and sexually active. Evidence points to many infected older people contracting the disease through homosexual contact. Also, older people are often finding themselves dating again due to divorce or being widowed, and engaging in sexual activity without protection. Elderly people presenting with confusion or altered mental status or having severe bouts of pneumonia may first be evaluated for other possibilities before HIV is considered. HIV should be considered in the initial assessment in diagnosis when older patients are having more serious opportunistic-type infections in order to begin HIV treatment as early as possible. Statistics of AIDS cases by age at diagnosis reported through June 1997 are presented.
 
Article
I have always had a distaste for writing autobio-graphically when I write for this publication. It stems from a personal belief in and conviction for the so-called "scientific method"—an early indoctri-nation that disease could and would be conquered. AIDS has been the great curve ball. Still, in my heart I have always had this deep-seated sentiment that what HIV/AIDS research and medicine lack most is the scientific authority that comes from sufficient process and analytical thinking. Having been diagnosed with HIV around 1986 and involved in some form of advocacy and information dissemination since that time (sometimes loosely, other times in a more structured setting), much of the information I have written about has been "light" on the science and "strong" on the proverbial "this worked for me; maybe it will work for you." The anecdote, or as we jokingly refer to it here at The Center for AIDS (CFA): "the N=1," has been an integral part of the AIDS battle. Anecdotal infor-mation has often been best simply because some-times it has been the only information available. This has not been helped by the epidemic's history of hurried, sloppy, and huge mood swings regard-ing treatment guidelines.
 
Article
A small animal model would be very valuable for HIV/AIDS vaccine testing, investigating HIV pathophysiology, and exploring anti-HIV therapeutics. Unfortunately, HIV does not replicate in mouse cells. Provision of mouse cells with human CD4, CCR5 and cyclin T1 (cycT1) has uncovered a block to HIV assembly or release. Since mouse-human cell fusions allow viral replication, mouse cells lack at least one critical factor that permits completion of the viral life cycle. To identify this factor(s) we are employing 2 similar genetic approaches. Each cell line of a panel of monochromosomal mouse-human somatic cell hybrids was individually transduced with an HIV vector encoding both cycT1 and blasticidin resistance (HIV-CIB). Each was then transfected with vesicular stomatitis virus (VSV) G protein and measurable virus was recovered from only the hybrid-containing chromosome 2. This was verified with an M-tropic envelope and was shown to be specific to HIV. In addition, the amount of p24 release from that hybrid was substantially greater than that from the parent. A second cell line expressing chromosome 2 had a similar phenotype. CycT1 has been introduced into one chromosome 2 line to monitor the spread of HIV. In a related but separate approach, an entire collection of approximately 500 mouse-human microcell hybrids was transduced with HIV-CIB and broken down into manageable pools. Virus was similarly recovered as above from a few of the pools. Those pools were then broken down to clones and several cell clones have been identified that allow virus release. Revertants that no longer have the human chromosome are now being tested for loss of phenotype. Clones will then be tested for ability to support both HIV replication and Gag processing. Human chromosomal content of the clones of greatest interest will be determined by STS content analysis. Results from the 2 approaches are expected to be in agreement and may provide direction for an expression cloning approach.
 
Article
David is a 29-year-old Hispanic male who presents complaining of fatigue, headache, muscle aches, a sore throat, and nausea. Physical assessment demonstrates an erythematous maculopapular rash on the trunk and symmetric adenopathy. His temperature is 37.6 degrees C; other vital signs are within normal limits. Laboratory findings include a white blood cell count of 4.5/microL and a platelet count of 98,000/mm3. Blood chemistry is unremarkable. David states that his symptoms began one week ago.
 
Top-cited authors
Frederick Paul Siegal
  • St. Vincent Hospital NYC Closed
Qizhi Yao
  • Baylor College of Medicine
Ronald Collman
  • University of Pennsylvania
Dennis Walling
  • Duke University Medical Center
Thomas Gegeny