Long-term increase of CD4+ central memory cells in HIV-1-infected individuals by therapeutic HIV-1 rgp160 immunization.

OBJECTIVE: To evaluate functional potential and phenotypic markers in HIV-1-infected patients immunized with HIV-1 rgp160. METHODS: We assessed changes in T-cell phenotype and immune function in 12 HIV-1-infected individuals that were part of a therapeutic vaccine study from 1992 to 1995 [Sandstrom E, Wahren B. Therapeutic immunisation with recombinant gp160 in HIV-1 infection: a randomised double-blind placebo-controlled trial. Nordic VAC-04 Study Group. Lancet 1999;353(9166):1735-42]. The patients received 160 microg HIV-1 rgp160 or placebo i.m. at baseline (day 0), and months 1, 2, 3, 4, 6, and thereafter every 3 months. Frozen peripheral blood mononuclear cells (PBMC) were retrieved from time points 0, 9, 12 and 24 months for phenotypic analysis utilizing flow cytometry. RESULTS: Up-regulation of immune activation markers HLA-DR and CD38 was observed at baseline and throughout the monitoring period on both CD4+ and CD8+ T cells in all patients, reflecting immune activation due to persistent high viral load. Further enhanced expression of activation markers was observed over time in the vaccine group, but not the placebo group. We also observed a consistent long-term increase of the CD4+ central memory population (CD3+CD4+CD45RA-CCR7+) in the vaccinated group. CONCLUSIONS: Administration of eight doses of rgp160 in a year appeared to partially reverse some of the defects exerted by HIV-1 on the immune system. A combination of vaccination with effective antiretroviral therapy (ART) may thus represent an immunotherapeutic intervention for treatment of chronic HIV-1 infection. The improvement of a HIV-1-specific central memory population and HIV-1 antigen-specific CD4+ lymphoproliferative responses may have contributed to the short-term improved survival reported in the vaccinated group.

Cellular immune responses in asymptomatic human immunodeficiency virus type 1 (HIV-1) infection and effects of vaccination with recombinant envelope glycoprotein of HIV-1.

Effects of human immunodeficiency virus type 1 (HIV-1) recombinant envelope glycoprotein vaccines on cell-mediated immune (CMI) responses were assessed in HIV-1-infected patients. Asymptomatic, antiretroviral-treatment-naïve, HIV-1-infected patients with CD4(+) T-cell counts greater than 400/microl received multiple intramuscular injections of HIV-1 IIIB recombinant envelope glycoprotein (rgp160) vaccine or HIV-1 MN recombinant envelope glycoprotein (rgp120) vaccine (eight patients, referred to as the HIV-1 vaccinees) or placebo or hepatitis B vaccine (three patients, referred to as the controls). Lymphocyte proliferation in response to HIV-1 envelope glycoproteins, both homologous and heterologous to the HIV-1 immunogens, was absent prior to study treatment in all patients but increased significantly during the vaccination series and after the final vaccination in HIV-1 vaccinees (P < 0.05) and remained absent in control patients. In flow cytometric analyses of intracellular cytokines, T-cell receptor stimulation with an anti-CD3 antibody induced gamma interferon (IFN-gamma) expression by activated CD4(+) and CD8(+) lymphocytes at greater frequencies than did stimulation with recombinant envelope glycoprotein and p24 of HIV-1 (P < 0.05). Mean frequencies of HIV-1 envelope glycoprotein-stimulated, activated intra-cellular IFN-gamma-producing CD4(+) and CD8(+) lymphocytes and of interleukin-2-producing CD4(+) lymphocytes did not increase after vaccination, but cytokine-producing cells were detectable in some patients. Comparing pre- to post-HIV-1 vaccination time points, changes in frequencies of activated, IFN-gamma-producing CD4(+) cells correlated inversely with changes in lymphocyte proliferation in response to recombinant envelope glycoprotein in HIV-1 vaccinees (P < 0.05). Increased CMI responses to HIV-1 envelope glycoprotein measured by lymphocyte proliferation were associated with HIV-1 recombinant envelope glycoprotein vaccines.

Effect of therapeutic immunization with HIV type 1 recombinant glycoprotein 160 ImmunoAG vaccine in HIV-infected individuals with CD4+ T cell counts of >or=500 and 200-400/mm3 (AIDS Clinical Trials Group Study 246/946).

AIDS Clinical Trials Group (ACTG) 246/946 was a double-blinded, randomized, controlled trial of HIV-1 MN rgp160 ImmunoAG vaccine in HIV-infected patients with CD4(+) T cell counts >or=500 and 200-400/mm(3). The main objectives were to study the safety and immunogenicity of this vaccine and to study the persistence of the immune responses after vaccination over a longer period of time. Fifteen patients with CD4(+) T cell counts of >or=500/mm(3) were enrolled in the ACTG 246 study. ACTG 246 patients received a monthly injection of vaccine or control for 6 months and then injections every 2 months. After completion of this study, seven new patients with CD4(+) T cell counts of 200-400/mm(3) entered into the ACTG 946 study. These study patients received highly active antiretroviral therapy (HAART) (ritonavir, didanosine, and stavudine) for 9 weeks to stabilize their viral load and then each patient received a monthly injection of vaccine or control substance for 6 months with HAART. The study of these two relatively small populations showed that the vaccine was safe without any adverse effect both in the patients with CD4(+) T cell counts of >or=500 and 200-400/mm(3). The vaccine was also immunogenic in patients with CD4(+) T cell counts of >or=500/mm(3) as measured by gp160-specific lymphocyte proliferative responses, and it persisted after they had received more than six vaccine injections, for a longer period of time.

Long-term immunotherapy in HIV infection, combined with short-term antiretroviral treatment.

Forty asymptomatic HIV-infected individuals with CD4+ lymphocyte levels above 400x10(6)/l were immunized over 5 years with recombinant envelope glycoprotein gp160 (rgp160). After 5 years there was a trend towards more non-progressors in the immunized group as compared to the matched controls. Since immunizations could activate HIV, the first 6 immunizations were followed by 2 weeks of zidovudine or placebo, double-blind. The viral load did not change during the first 6 months and was not different from that of the matched controls after 5 years. The best effect on CD4+ lymphocyte development was seen in individuals with a high viral load randomized to rgp160+zidovudine and in individuals with a low viral load randomized to rgp160+placebo. We conclude that rgp160 is safe and results in temporarily improved CD4+ development. Concomitant antiviral treatment might be of benefit, especially in patients with a more advanced disease and can today be given with more effective combinations.

Recombinant gp160 as a therapeutic vaccine for HIV-infection: results of a large randomized, controlled trial. European Multinational IMMUNO AIDS Vaccine Study Group.

OBJECTIVES: The primary objective of this study was to expand the safety and immunogenicity database of recombinant gp160 as a therapeutic vaccine in the treatment of HIV-infection. Preliminary efficacy data was also sought. DESIGN: This trial was a randomized, double-blind, placebo-controlled study. Two-hundred and eight volunteers, 96 therapy-naive with CD4 cell count >500x10(6)/l (group A) and 112 with CD4 cell count of 200-500x10(6)/l (group B, 51 out of 112 on treatment with one or two nucleoside analogues), received monthly injections of rgp160 IIIB vaccine or placebo for the first 6 months of the study; booster immunizations with rgp160 MN or placebo were given at times 15, 18, and 21 months. METHODS: Safety and immunogenicity data were obtained and measurements of CD4 cell count, plasma viral RNA, and proviral DNA were performed. Clinical outcome was recorded for the 24 months of study. RESULTS: The vaccine was safe and well tolerated. Despite the induction of new rgp160-specific lymphoproliferative responses and the presence of positive delayed type hypersensitivity skin tests to rgp160 at the end of the 24 month study, no effect on the natural history of HIV infection was detected. Within 24 months, AIDS-defining illnesses had occurred in 19 of the vaccinated volunteers and in 18 of the placebo recipients. Persons with higher plasma viral RNA levels and higher proviral DNA had a more rapid decline in CD4 cell count when compared to persons with lower values. Vaccine did not alter viral RNA or proviral DNA levels. CONCLUSION: There was no clinical benefit to therapeutic immunizations with rgp160, despite the induction of new lymphoproliferative responses.

Major histocompatibility complex genotype is associated with disease progression and virus load levels in a cohort of human immunodeficiency virus type 1-infected Caucasians and African Americans.

To assess the influence of HLA on AIDS-free survival, human immunodeficiency virus load, and CD4 cell counts, 91 Caucasian and 48 African-American seroprevalent men were typed for HLA classes I and II and TAP alleles. HLA associations with these markers were assessed by assigning sum integer scores based on 7 class I allele-TAP variants (+1) and 13 class I-class II-TAP combinations (-1) with different AIDS-free survival times found in a prior study. Subjects in both racial groups and combined with positive sum scores were less likely to have CD4 cell decline (P=.0004), to have increased virus burden (P=.014), and to develop AIDS (P=.034) in the follow-up period than were Caucasians and African Americans with scores of 0 or -1. These results confirm the reported associations of specific major histocompatibility complex genes with AIDS-free survival time in Caucasians and specifically extend them to African Americans and to two established markers of disease progression.

Apoptosis in asymptomatic HIV-1 seropositives immunized with HIV-1 env glycoprotein (gp160): effects of administration of Zidovudine in vivo and interleukin-2 in vitro.

In this paper we report the effects of VaxSyn (Protein Sciences Corp.) immunization on spontaneous apoptosis occurring in vitro after culture of PBMC in medium alone in 30 HIV-seropositive patients enrolled in a double-blind clinical trial that included three groups: treatment with VaxSyn, AZT and VaxSyn, and AZT. Our data show no significant modifications in the levels of apoptosis observed in the three groups over the long-term follow-up (up to 720 days). This was not associated with any significant modifications in other clinical or immunological features. However, analysis of apoptosis performed shortly after the first immunization (at days 3 and 7) showed a significant reduction in the rate of apoptosis in patients receiving AZT and AZT and VaxSyn, as compared with patients receiving VaxSyn alone (30.42 +/- 2.52 SE at day 0 and 23.74 +/- 1.84 at day 3; p = 0.039). Our data also indicate that addition of IL-2 in vitro had a significant inhibitory effect on mortality in all the randomization groups, especially in those receiving AZT (alone or in combination with VaxSyn).

Update on HIV vaccines.

AIDS: Development of a safe and effective AIDS vaccine remains a critical issue, particularly in developing nations where HIV infections will account for 90 percent of all new infections by 2000. The AIDS Vaccine Evaluation Group (AVEG) is conducting phase I and II studies of several candidate HIV-1 vaccines. Technical and ethical issues, including significant problems that need to be addressed in vaccine trials, are discussed. The safety of the current candidate vaccines, their immunogenicity, and the continued spread of HIV-1 in spite of educational efforts indicate that clinical trials are warranted. An extensive bibliography of articles related to vaccine development is included.^ieng