Our Science – Wood Website

Lauren V. Wood, M.D.

Vaccine Branch Staff Clinician National Cancer Institute Building 10, Room 10S255 10 Center Drive, MSC 1868 Bethesda, MD 20892 Phone:   301-402-0199 Fax:   301-402-0575 E-Mail:   lw51p@nih.gov

Biography

Dr. Wood received her M.D. degree from Duke University School of Medicine and completed clinical training in Internal Medicine and Pediatrics at Baylor College of Medicine Affiliated Hospitals in Houston, Texas. She received further subspecialty training in Allergy and Immunology at the NIAID and investigated HIV-specific cellular and humoral immune responses in the laboratory of Dr. Anthony Fauci before joining the NCI in 1992. As a Senior Clinical Investigator in the Pediatric HIV Working Group, her clinical research involves investigation of antiretroviral and immunomodulatory therapies in children, adolescents, and young adults with HIV infection.

Research

Immune-Based Therapies for HIV Infection

The primary goal of the pediatric HIV clinical research program is to develop and conduct clinical trials of novel antiretroviral and immune-based therapies for HIV infection. Although, highly active antiretroviral therapy (HAART) has emerged as the standard of care in the treatment of HIV infection and has resulted in dramatic declines in HIV morbidity, mortality and perinatal transmission, the clinical, immunologic and virologic benefits of treatment appear to be time-limited due to persistent immune dysfunction, failure to eradicate latent reservoirs of HIV and the emergence of HIV drug resistance. Substantial in vitro and in vivo evidence suggests that antiretroviral therapy selects for mutations in HIV-1 protease and reverse transcriptase that may impair viral 'fitness' or the inherent ability to replicate. Furthermore, these drug resistant viruses appear to be more limited in their ability to cause immune dysfunction and to escape from impaired viral fitness. Dr. Wood's research focuses on three principal areas of clinical investigation:
1) Immune-based therapies designed to improve anti-HIV immunity, HIV-induced immune dysfunction and immune reconstitution.
2) Novel antiretroviral therapies that address the problem of multi-drug resistant virus and elucidate further understanding regarding the role of altered viral fitness in clinical outcomes and immune function.
3) The clinical, infectious, psychosocial and antiretroviral treatment-related complications of chronic HIV disease

Although HAART appears to be potently effective in elevating CD4+ cell counts in most individuals, it is incapable of completely reversing persistent and pervasive disturbances in T cell immune function, activation and repertoire. Dr. Wood has completed a pilot study of recombinant IL-2, a critical mediator of both cellular and humoral immune function, in combination with antiretroviral therapy. The study determined that a rIL-2 dosage range of 1.0 to 3.0 million IU/m2/dose sc BID was safe and well tolerated for long-term outpatient administration and resulted in significant increases in CD4 cell as well as improvement in functional DTH responses to recall antigens. These quantitative and qualitative improvements in immune function were independent of baseline viral load, CD4 cell counts or type of antiretroviral therapy (HAART vs. non-HAART). Importantly, rIL-2 therapy was not associated with acute or chronic increases in viral replication.

Therapeutic vaccination is an alternative approach that we have investigated to induce the strong HIV-1 specific cytotoxic and lymphoproliferative T cell responses (LPR) that appear to be critical for long-term control of viral replication and protection from disease progression. Dr. Wood has also completed a study of therapeutic vaccination with HIV-1 Immunogen vaccine (REMUNE), a gp120-depleted inactivated HIV-1 antigen formulated in incomplete Freund's adjuvant. Substantial HIV-1 specific CD4 LPR were induced to immunogen as well as native p24 antigen in response to vaccination, although no significant CTL activity was observed. The magnitude of LPRs was inversely correlated with baseline viral load while HAART administration was associated with a shorter time to development of LPRs and maximal LPRs to both immunogen and p24 antigen. Final analysis of neutralizing antibody responses induced by vaccination is in progress.

Despite identification of conserved core HIV-1 structural epitopes, therapeutic vaccine efforts to date have failed to yield formulations that consistently generate substantial HIV-specific CD4+ T helper and CD8+ CTL responses. This lack of immunogenicity may be due to HIV-induced functional defects in antigen presenting cells (APCs). Furthermore, therapeutic vaccine efforts have focused almost exclusively on the development of immunogens designed to elicit HIV-specific responses, while ignoring the therapeutic potential of innate immune responses directed against HIV that may be equally as potent. Importantly, alloimmunization has been shown to increase the production of antiviral factors such as beta-chemokines and other viral inhibitory factors as well as HIV-specific CTL. In collaboration with the NCI Frederick AIDS Vaccine Program and the CC Department of Transfusion Medicine, Dr. Wood is planning a pilot study of autologous killed HIV-1 hemi-allogeneic dendritic cell vaccines. This hemi-allogeneic approach allows potential generation of innate and adaptive immune responses against HIV while minimizing the risks associated with alloimmunization.

Scientific advances in the treatment of HIV disease have reinforced the critical need for real-time, sensitive and specific diagnostic studies of immune function (other than DTH skin testing to evaluate responses to immune-based therapies for HIV as well as cancer. Several pediatric cohorts exist within HAMB whose functional immune responses to antiretroviral treatment and immune-based therapies have been extensively characterized. In collaboration with Dr. Rebecca Caffrey of Ciphergen (Fremont, CA), and the NCI/FDA Clinical Proteomics Program, Dr. Wood is planning a retrospective analysis of patient samples using proteomic technology to discover and evaluate biomarkers of immune function in HIV-positive patients. These biomarkers may yield valuable prognostic information on the status of the immune system in HIV-positive individuals and will provide the groundwork for the prospective inclusion of proteomic analysis of functional immune responses in studies of immune-based therapeutic interventions.

A recently completed pilot study investigated genotypic and phenotypic resistance, replication capacity (RC), virologic and immunologic responses in heavily treated children given HU/ddI/d4T/efavirenz for 48 weeks. Although the majority of patients initially achieved complete viral suppression, all exhibited viral rebound. Despite viral rebound, patients experienced a net gain in CD4 cells and a decline in activated CD8/CD38 cells at 48 weeks. Intensive studies characterizing viral resistance demonstrated that genotypic and phenotypic resistance to ddI and d4T was intermittent, did not correlate with viral rebound and was associated with a sustained decrease in viral replication capacity (RC), suggesting a possible independent treatment effect of RC on immune dysregulation. In contrast, EFV resistance remained constant once it emerged. An analysis of PBMC HIV-1 proviral DNA reservoirs is in progress.

The preliminary results of our HU study stimulated further interest in pursuing the investigation of another antimetabolite, 5 fluoruracil (5-FU), in the treatment of multi-drug resistant HIV. When given in combination with zidovudine (ZDV) or stavudine (d4T), 5-FU has been shown to potentiate their antiviral activity as well as suppress replication of multi-drug resistant HIV-1. In addition, several studies have demonstrated that HIV replication dynamics in various lymphocyte and monocyte compartments are influenced by multiple parameters including viral fitness, cellular niche and microenvironments in vivo. We hypothesize that the administration of 5-FU will potentially restore sensitivity to NRTIs, especially d4T and ZDV, in heavily treatment-experienced patients with NRTI resistance mutations, resulting in improved antiviral activity and immunologic outcomes. We also hypothesize that that 5-FU administration may affect the CD4+ T lymphocyte and macrophage compartments differentially and thereby alter the viral fitness and dynamics of replicating viral quasispecies within these compartments in vivo.

Dr. Wood, in collaboration with Dr. Chad Womack of the Vaccine Research Center, NIAID, was competitively awarded an intramural NIH Bench-to-Bedside award in 2003 to investigate the safety, toxicity and preliminary antiviral activity of 5FU administered in combination with HAART regimens containing d4T or ZDV. Patients will be monitored for clinical, immunologic and virologic outcomes in addition to assessments of T cell activation and apoptosis. The effects of this combination regimen on the evolution of HIV-1 genotypic and phenotypic resistance, RC and co-receptor tropism within plasma and different lymphocyte compartments (CD4 naive and memory subsets; monocytes/macrophages) will also be determined.

The relationship between HPV infection, invasive cervical cancer, and the increased risk of its development associated with HIV co-infection are well established. Sexual acquisition of HPV infection may potentially predispose them to neoplastic pathology. Since the majority of HPV is acquired within 2 years of sexual debut, administration of a prophylactic HPV vaccine may reduce the risk of HPV-associated complications in the sexually naive population of adolescents with vertically or transfusion acquired HIV. Dr. Wood is planning to conduct a preliminary study examining the immunogenicity of a candidate HPV vaccine to determine whether prophylactic HPV vaccination is feasible in this extremely at risk population.

Our collaborators are Josephine Cox, and Thomas VanCott, Henry M. Jackson Foundation; Rebecca Caffrey, Ciphergen; and Shizuko Sei, Gene Shearer, Thomas Walsh, Jon Wigginton, Chad Womack, and Thomas Zheng at NIH.

This page was last updated on 8/26/2008.