Ronald B. Moss

We compared the effect of priming with a synthetic oligodeoxynucleotide (ODN) immunostimulatory DNA sequence followed by vaccination with human immunodeficiency virus type 1 (HIV-1) in incomplete Freund's adjuvant (IFA) or HIV-1 antigen alone to the simultaneous administration of immunostimulatory sequences (ISS) with HIV-1 in IFA. We examined immune function involving interferon-gamma (IFN-gamma) production, RANTES (regulated upon activation, normal T cell expressed and secreted) production, and lymphocyte proliferation, all of which appear to be augmented in HIV-1-exposed, but uninfected, individuals. We demonstrate that similar levels of antigen-specific IFN-gamma were produced from lymph node cells of the animals immunized with HIV-1 antigen in IFA containing the CpG ODN 1826 (ISS; mean +/- SE = 450.8 +/- 224.3 pg/mL) and the group of animals primed with the ODN before injection with the HIV-1 in IFA (mean +/- SE = 377.7 +/- 294.8 pg/mL) or HIV-1 antigen alone (IFN-gamma = 0 pg/mL). However, the group that received the HIV-1 in IFA plus ISS mounted a stronger lymphocyte proliferation (mean net +/- SE = 29,180 +/- 1,932 cpm) compared to the group primed with the ODN before injection with HIV-1 in IFA (mean net +/- SE = 8,575 +/- 2,978 cpm). Furthermore, the group that received the HIV-1 in IFA plus ISS also mounted stronger beta-chemokine production measured as RANTES (mean +/- SE = 1,217 +/- 267.4 pg/mL) compared to the group that received the ODN before injection with HIV-1 in IFA (mean +/- SE = 129.1 +/- 48.5 pg/mL). Antibody responses from the group that received the HIV-1 in IFA plus ISS also showed a higher p24-specific response that was predominantly of the immunoglobulin G IgG2b isotype. These results suggest that the simultaneous administration of the ISS in the HIV-1 in IFA emulsion may be a condidate for testing in non-human primates and in human studies as a therapeutic and preventative vaccine.

We examined the adjuvant effects of a synthetic CpG oligodeoxynucleotide immunostimulatory sequence (ISS) using a whole-killed, gp120-depleted HIV antigen (HIV-1 antigen) in a Lewis rat model. We hypothesized that HIV-1-specific CD4⁺ T helper (Th) immune responses could be enhanced when an ISS was combined with an HIV-1 antigen in incomplete Freund's adjuvant (IFA). We also reasoned that if such Th responses were sufficient, such a combination might also induce HIV-specific CD8⁺ T cell immune responses. Here we demonstrate that the HIV-1 antigen in IFA combined with ISS stimulates both CD4⁺ and CD8⁺ HIV-specific immune responses as measured by interferon-γ (IFN-γ) in the ELISPOT assay. A strong correlation between these CD4⁺ and CD8⁺ responses was demonstrated. Furthermore, we found that the HIV-1 antigen in IFA with ISS as an adjuvant stimulated strong antibody responses to core antigen (p24). These studies suggest that the combination of the whole-killed, gp120-depleted HIV-1 antigen in IFA with ISS may be an ideal candidate to test in nonhuman primates and in human studies as a preventive HIV-1 vaccine.

The discovery of multiple subtypes of human immunodeficiency virus type 1 (HIV-1) worldwide has created new challenges for the development of both therapeutic and preventive AIDS vaccines. We examined T-helper proliferative responses to HIV-1 clade A, B, C, G, and E whole-killed virus and to HIV-1 clade G and B core (p24) antigens in HIV-1-infected subjects taking potent antiviral drugs who received HIV immunogen (Remune) therapeutic vaccination. Subjects who were immunized mounted strong proliferative responses to both whole virus and core antigens of the different clades. These results suggest that a whole-killed immunogen may have broad applications as a therapeutic as well as a preventive vaccine in the current multiclade HIV-1 pandemic.

Background:Although African Americans are disproportionately affected by the AIDS epidemic, they are underrepresented in AIDS research, particularly in AIDS clinical trials. This study examines a multidimensional construct of distrust and other factors that may affect willingness to participate in AIDS research. Methods:A total of 301 African Americans (aged ≥18 years) in Durham, North Carolina participated in a cross-sectional survey. In-person interviews, 20 to 25 minutes in length, were conducted with participants. Structural equation modeling was used to develop models exploring distrust and other factors affecting willingness to participate in AIDS research among African Americans. Results:Distrust was the strongest inverse predictor of willingness to participate in AIDS clinical trials. Distrust was not significantly associated with willingness to participate in AIDS surveys and educational interventions. Altruism, facilitators/ barriers, religiosity, and economic group membership were also significantly associated with willingness to participate in AIDS clinical trials. Only altruism was significantly associated with willingness to participate in AIDS surveys and educational interventions. Conclusions:Distrust about research institutions is a significant barrier to recruiting African Americans in AIDS clinical trials. Issues of distrust need to be acknowledged by researchers to develop better recruitment and retention strategies when conducting AIDS clinical trials in African-American communities. Address correspondence and reprint requests to Sohini Sengupta at Center for AIDS Prevention Studies, University of California, San Francisco, 74 New Montgomery, Suite 600, San Francisco, CA 94105, U.S.A.; email: [email protected] This study was part of a doctoral dissertation completed within the Department of Health Behavior and Health Education, School of Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Manuscript received January 10, 2000; accepted April 26, 2000. © 2000 Lippincott Williams & Wilkins, Inc.

Objective:We hypothesized that treatment of HIV-1-seropositive study subjects receiving potent antiviral therapy with an HIV-specific immune-based therapy would increase HIV-1-specific T-helper immune function. Design:10 HIV-1-seropositive study subjects receiving antiretroviral therapy were treated with an inactivated, gp120-depleted immunogen in IFA (HIV-1 immunogen, Remune) at baseline, week 12, and week 24. Methods:The frequency of HIV-1 antigen-stimulated interferon-γ (IFN-γ)producing cells was determined by the ELISPOT assay. Results:Study subjects significantly increased their frequency of HIV-1-stimulated (p < .001) or p24 antigen-stimulated (p < .01) IFN-γ-producing cells after one, two, and three treatments of HIV-1 immunogen. Depletion of CD4 cells resulted in the strongest abrogation of the IFN-γ response. The frequency of HIV-1 (r = 0.64; p = .0002) and p24 (r = 0.72; p < .001) antigen-stimulated IFN-γ-producing cells in the CD8-depleted population before and after treatment was associated with the lymphocyte-proliferative response. Conclusions:Treatment with HIV-1 immunogen significantly enhanced the frequency of HIV-1-specific IFN-γ-producing cells. Studies are ongoing to determine the relationship between this reversal of HIV-specific anergy and virologic outcomes. Address correspondence and reprint requests to Ronald B. Moss, The Immune Response Corporation, 5935 Darwin Court, Carlsbad, CA 92008, U.S.A.; email: [email protected] The views expressed in this article are those of the authors and do not reflect the official policy or position of the U.S. Department of the Navy, U.S. Department of Defense, or U.S. Government. Manuscript received December 10, 2000; accepted April 26, 2000. © 2000 Lippincott Williams & Wilkins, Inc.

The chemokine receptors CXCR4 and CCR5 have been identified as the major coreceptors for HIV-1 on CD4+ cells and macrophages. The natural ligands for these receptors are SDF-1 and the beta-chemokines (MIP-1alpha, MIP-1beta, RANTES), respectively, and are the products of a variety of immune cells, including CD8+ T lymphocytes. We hypothesized that the ability to stimulate the natural ligands for these receptors using an immune based therapy might influence in vivo chemokine receptor expression. In vivo CXCR4 expression remained stable after treatment with an HIV-1 Immunogen (REMUNE), whereas CCR5 expression on CD4+ T cells decreased (p < .05). Furthermore, HIV-1 antigen-specific production of beta-chemokines in vitro was also augmented (P < .05). These preliminary results suggest that this HIV-1-specific immune-based therapy can stimulate antigen-specific beta-chemokine production in vitro and downregulate CCR5 receptor expression on CD4 cells in vivo.

It was hypothesized that immune recognition could be stimulated with combined immune-based and potent antiviral drug therapies. This study examined h

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