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2004-2005 Publications

Top 10 Publications (2004-2005) -- CFAR's Best!!

Please click on the links below to review current publications of research conducted by CFAR investigators.

Dr. Forshey


Dr. David Haas


Dr. Todd Hulgan


Dr. Lundquist

http:/ /


Oswald-Richter Oswald_Richter.pdf

Dr. Stephen Raffanti


Dr. Sundrud


Dr. Peter Wright


Dr. Wyma


Dr. Zhou




Abstracts for 2004-2005

Please click on the link below to view publication abstracts for 2004-2005. The research was funded by CFAR developmental awards presented in August 2004. For further information regarding eligibility and application for developmental awards, please contact CFAR at (615) 321-2260. for 2004 -2005.pdf

June-July 04


HIV Infection of Naturally Occurring and Genetically Reprogrammed Human Regulatory T-cells.

Oswald-Richter K, Grill SM, Shariat N, Leelawong M, Sundrud MS, Haas DW, Unutmaz D.

Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, Tennessee, United States of America.

PLoS Biol. 2004 Jul;2(7):E198. Epub 2004 Jul 13.

A T-cell subset, defined as CD4(+)CD25(hi) (regulatory T-cells [Treg cells]), was recently shown to suppress T-cell activation. We demonstrate that human Treg cells isolated from healthy donors express the HIV-coreceptor CCR5 and are highly susceptible to HIV infection and replication. Because Treg cells are present in very few numbers and are difficult to expand in vitro, we genetically modified conventional human T-cells to generate Treg cells in vitro by ectopic expression of FoxP3, a transcription factor associated with reprogramming T-cells into a Treg subset. Overexpression of FoxP3 in naive human CD4(+) T-cells recapitulated the hyporesponsiveness and suppressive function of naturally occurring Treg cells. However, FoxP3 was less efficient in reprogramming memory T-cell subset into regulatory cells. In addition, FoxP3-transduced T-cells also became more susceptible to HIV infection. Remarkably, a portion of HIV-positive individuals with a low percentage of CD4(+) and higher levels of activated T-cells have greatly reduced levels of FoxP3(+)CD4(+)CD25(hi) T-cells, suggesting disruption of the Treg cells during HIV infection. Targeting and disruption of the T-cell regulatory system by HIV may contribute to hyperactivation of conventional T-cells, a characteristic of HIV disease progression. Moreover, the ability to reprogram human T-cells into Treg cells in vitro will greatly aid in decoding their mechanism of suppression, their enhanced susceptibility to HIV infection, and the unique markers expressed by this subset.

PMID: 15252446 [PubMed - in process]


 The sequence of the CA-SP1 junction accounts for the differential sensitivity of HIV-1 and SIV to the small molecule maturation inhibitor 3-O-{3',3'-dimethylsuccinyl}-betulinic acid.

Zhou J, Chen CH, Aiken C.

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.


Retrovirology. 2004 Jun 29;1(1):15

BACKGROUND: Despite the effectiveness of currently available antiretroviral therapies in the treatment of HIV-1 infection, a continuing need exists for novel compounds that can be used in combination with existing drugs to slow the emergence of drug-resistant viruses. We previously reported that the small molecule 3-O-{3',3'-dimethylsuccinyl}-betulinic acid (DSB) specifically inhibits HIV-1 replication by delaying the processing of the CA-SP1 junction in Pr55Gag. By contrast, SIVmac239 replicates efficiently in the presence of high concentrations of DSB. To determine whether sequence differences in the CA-SP1 junction can fully account for the differential sensitivity of HIV-1 and SIV to DSB, we engineered mutations in this region of two viruses and tested their sensitivity to DSB in replication assays using activated human primary CD4+ T cells. RESULTS: Substitution of the P2 and P1 residues of HIV-1 by the corresponding amino acids of SIV resulted in strong resistance to DSB, but the mutant virus replicated with reduced efficiency. Conversely, replication of an SIV mutant containing three amino acid substitutions in the CA-SP1 cleavage site was highly sensitive to DSB, and the mutations resulted in delayed cleavage of the CA-SP1 junction in the presence of the drug. CONCLUSIONS: These results demonstrate that the CA-SP1 junction in Pr55Gag represents the primary viral target of DSB. They further suggest that the therapeutic application of DSB will be accompanied by emergence of mutant viruses that are highly resistant to the drug but which exhibit reduced fitness relative to wild type HIV-1.

PMID: 15225375 [PubMed - as supplied by publisher]



Perturbation of natural killer cell function and receptors during HIV infection.

Eger KA, Unutmaz D.

Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.


Trends Microbiol. 2004 Jul;12(7):301-3.

Natural killer (NK) cells play an important role in innate host defenses against a variety of pathogens. A recent report described striking perturbations in the expression of NK cell inhibitory and activating receptors in viremic human immunodeficiency virus (HIV)-infected patients, leading to functional abnormalities in these cells. This finding provides a mechanistic insight into NK cell dysfunction and its possible contribution to the impairment of innate host defenses in HIV-infected individuals.

PMID: 15223055 [PubMed - in process]



Challenges to Conducting HIV Preventative Vaccine Trials With Adolescents.

McClure CA, Gray G, Rybczyk GK, Wright PF.

*Vanderbilt University Department of Pediatrics, Nashville, TN, and daggerPerinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.

J Acquir Immune Defic Syndr. 2004 Jun 1;36(2):726-733.

It is estimated that 10.3 million people aged 15-24 are living with HIV infection/AIDS worldwide, with 7000 new infections occurring each day. Many of these infections occur during the adolescent years. These rates of infection make adolescents an important target for research in primary prevention. Currently, preparations are under way by the National Institutes of Health-supported HIV networks-the Adolescent Trials Network, the Pediatric AIDS Clinical Trials Group, and the HIV Vaccines Trials Network-for phase 1/2 HIV vaccine trials involving adolescents in the United States. Identifying the challenges to conducting HIV vaccine trials with this population is a crucial component of these preparations. Challenges to HIV vaccine trials with adolescents were identified by reviewing previous vaccine research for adolescents and HIV infection in adolescents and speaking with experts in HIV/AIDS and adolescent medicine. Adolescents (typically those younger than 18 years of age) are minors and fall under ethical and regulatory safeguards for their participation in clinical research including parental permission. Adolescents may not appropriately perceive personal risk, posing challenges for informed consent as well as prevention counseling during a trial. Safety and immunogenicity studies of adolescents are likely to be required by the US Food and Drug Administration before vaccine approval for this population. Early identification and subsequent follow-up of high-risk adolescents are problematic. Vaccine-induced seropositivity may present potential barriers to military service, employment, marriage, and acquiring health insurance. The age at optimal immunization, particularly for girls in some countries, may be during preadolescence. The successful completion of HIV vaccine trials with adolescents must address these challenges both in the United States and internationally. This report addresses relevant background information, identifies the issues surrounding HIV vaccine trials with adolescents, discusses what progress has been made, and addresses plans and implications for the implementation of these trials.

PMID: 15167292 [PubMed - as supplied by publisher]



Nef stimulates human immunodeficiency virus type 1 replication in primary T cells by enhancing virion-associated gp120 levels: coreceptor-dependent requirement for Nef in viral replication.

Lundquist CA, Zhou J, Aiken C.

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, A-5301 Medical Center North, Nashville, TN 37232-2363, USA.

J Virol. 2004 Jun;78(12):6287-96.

The Nef protein enhances human immunodeficiency virus type 1 (HIV-1) replication through an unknown mechanism. We and others have previously reported that efficient HIV-1 replication in activated primary CD4(+) T cells depends on the ability of Nef to downregulate CD4 from the cell surface. Here we demonstrate that Nef greatly enhances the infectivity of HIV-1 particles produced in primary T cells. Nef-defective HIV-1 particles contained significantly reduced quantities of gp120 on their surface; however, Nef did not affect the levels of virion-associated gp41, indicating that Nef indirectly stabilizes the association of gp120 with gp41. Surprisingly, Nef was not required for efficient replication of viruses that use CCR5 for entry, nor did Nef influence the infectivity or gp120 content of these virions. Nef also inhibited the incorporation of CD4 into HIV-1 particles released from primary T cells. We propose that Nef, by downregulating cell surface CD4, enhances HIV-1 replication by inhibiting CD4-induced dissociation of gp120 from gp41. The preferential requirement for Nef in the replication of X4-tropic HIV-1 suggests that the ability of Nef to downregulate CD4 may be most important at later stages of disease when X4-tropic viruses emerge.

PMID: 15163722 [PubMed - indexed for MEDLINE]



HIV infection of primary human T cells is determined by tunable thresholds of T cell activation.

Oswald-Richter K, Grill SM, Leelawong M, Unutmaz D.

Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232, USA.

Eur J Immunol. 2004 Jun;34(6):1705-14.

HIV infection of primary human T cells requires T cell activation signals. However, how strength, duration, and quality of TCR signals affect susceptibility of resting human T cells to HIV infection remains poorly understood. We found that the same threshold and duration of antigen signals that lead to optimal T cell activation are required for HIV to progress beyond the level of reverse transcription within resting T cells. Remarkably, sustained cytokine signaling from the IL-2 receptor following TCR triggering was critical in establishing productive infection. While blockade of TCR signaling pathways with inhibitors of the phosphatidylinositol 3-kinase pathway caused a partial pre-integration block, another inhibitor, rapamycin, completely suppressed the infection. In contrast, cyclosporin A or FK506, inhibitors of NFAT, failed to block infection if the T cells were pre-activated. Collectively, these results bring to light significant parallels between successful HIV infection and optimal thresholds of T cell activation. Furthermore, our results underscore the critical role of IL-2 signaling in establishing productive HIV infection. These findings have important implications for our understanding of the complex interplay of HIV with host factors induced upon T cell activation.

PMID: 15162441 [PubMed - in process]



The Role of Baseline HIV-1 Resistance Testing in Patients with Established Infection.

Chan SY, Hulgan T, D'Aquila RT.

Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, A-4102 Medical Center North, Nashville, TN 37232, USA.


Curr Infect Dis Rep. 2004 Jun;6(3):243-249.

Effective long-term treatment of HIV-1 infection is challenging because of several factors, including antiretroviral drug resistance. Antiretroviral resistance testing has short-term benefit for optimizing the choice of a rescue regimen after treatment failure. Resistance testing also is recommended before therapy in pregnancy and acute infection or recent seroconversion. The benefit of routine resistance testing before starting treatment for established infection is less clear. This report summarizes the accumulating evidence of persistence of resistant mutants after initial infection, detectability of resistant virus with standard assays before treatment of established infection, the potential adverse impact of this baseline resistance on effectiveness of therapy, and the increasing prevalence of resistance in treatment-naive patients. Taken together, these data suggest that pretreatment genotypic resistance testing also may be useful in patients with established infection. Although further study is needed, clinicians are now encouraged to routinely obtain pretreatment resistance testing.

PMID: 15142489 [PubMed - as supplied by publisher]


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