>A number of therapeutic vaccines also aim to boost HIV-specific T-cell immune responses, including cellular immunity (primarily "type-1" antiviral helper T-cells, and cytotoxic T-lymphocyte, or CTL, responses). Furthest along in clinical trials is Dr. Jonas Salk's immunogen, known as Remune. At the University of Alabama at Birmingham, Dr. Mike Saag has an intriguing Remune study in the works. Participants whose viral loads have been undetectable for at least six months on HAART will get three shots of Remune over the course of several months. Then HAART will be stopped for at least six weeks, to see how well Remune-induced immune responses can control HIV. from "Partial Eclipse of the HAART; New treatment strategies to overcome roadblocks." Richard Jefferys. HIVPlus - 9/1999 No. 5. aegis.com
Much attention (too much, imo) has been given to efforts to purge virus from hidden reservoirs by activating the virus with IL-2, and then killing it with HAART. Very recently Dr. Fauci found that the levels of HIV virus rebounded quickly when HAART was stopped, even in patients who had received HAART plus IL-2 and who had no detectable virus even in lymph nodes using the most sensitive measures. In addition, Fauci found that the virus that reappeared was different from the virus in reservoirs. Fauci's hopes for total eradication through the use of IL-2 are changing.
Many realize now that there are great difficulties in finding a vaccine (preventative and/or therapeutic) against HIV infection, and some are saying that a vaccine will not have to be perfect. Gallo and Montagnier, co-founders of the HIV virus, signed a statement at a recent conference, 'highlighting the urgent need to develop an AIDS vaccine “such that even a partially effective vaccine would still be valuable in significantly reducing the rate at which HIV is spreading.' ww2.aegis.com
Little attention has been paid to the details of the preliminary study of Remune in children with HIV-1, reported recently in the Journal of Infectious Disease. Surprising, because the results were very impressive. Here are some details from: "Preliminary Evaluation of Human Immunodeficiency Virus Type 1 (HIV-1) Immunogen in Children with HIV-1 Infection." In:Journal of Infectious Diseases. September 1999. 180, 3 626-640
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This Phase I double blind dose ranging clinical trial is the first clinical trial to use a therapeutic vaccine in children with HIV-1 infection.
Although the number of patients was smaller than anticipated, the results were significant and very impressive.
Ten children, all HIV positive; ranging in age from 4 to 11, with a median age of six years, were followed for 18 months.
Nine of the ten children had acquired HIV through vertical transmission; that is, from the mother during birth. One child was infected through a blood transfusion.
When HIV is acquired through vertical transmission, the disease is usually more aggressive and progression occurs more quickly; the median time to AIDS ranges from two to five years (before HAART). The average time to progression to AIDS or to the development of opportunistic infections in adults is around 10 years.
All 10 children had baseline provirus levels in PBMC ranging from 5 to 250 copies/DNA: which are low levels.
Plasma HIV-1 RNA ranged from 260 to 32,672; median 4903; mean 9479.
Baseline CD4 counts: range 421-1675. Median 929, mean: 868;
These children were all CDC class A1 or A2 at entry. They were relatively stable and symptom free at entry.
Children received antiretroviral therapy (AR) if they had any CDC defined disease other than N1 or A1. The study began in early 1996, so only nucleosides were used: DDI and/or 3TC.
-One child did not receive antiretroviral therapy - Arm A.
-Nine children received antiretroviral therapy -Arm B
-The groups were then randomized to receive either the pediatric dose of Remune, 2.5 units, or the lowest adult dose of Remune; 10 units.
They received the shots every three months, for a total of five inoculations.
RESULTS:
Eight of ten children completed the study to 18 months. One child was withdrawn at six months for noncompliance and one child showed progressive disease and was withdrawn after 15 months (#7). This is within the expected incidence of disease progression.
Both dose levels, 2.5U and 10 U, of HIV-1 immunogen were well tolerated, with more local reaction at the higher dose.
Nine of the ten children showed normal patterns of weight and height gain, according to age-appropriate growth charts. The one child whose weight gain slowed also showed increasing viral load and decreasing CD4 counts.
The interim analysis in October 1998 showed much better results using the higher dose of Remune, and all children are now receiving 10 Units of Remune. An additional 21 children have been added to the study (18 + 3).
-Four out of four children receiving the higher dose of Remune plus antiretroviral therapy showed significantly increased levels of RANTES, a beta chemokine.
-These same four children also showed significant increases in HIV-1 antibodies to GAG epitopes.
-These four children were able to maintain undetectable levels of virus for 18 months.
-At the lower dose of Remune, only one out of 4 children on AR showed significantly increased production of Rantes. This child also showed significantly increased levels of anti-HIV Gag peptides.
-In these five responders, the levels of Rantes began to increase after 6 months, corresponding to the development of anti-HIV-1 antibodies.
-The one child in Arm A (10 U Remune) not receiving antiretroviral 10U showed varying levels of viral load, with no trend. He did not show significantly increased production of Rantes nor anti-HIV antibodies to GAG. He did develop a positive CTL to the POL epitope, at 12 months.
-Seven out of nine children showed CTL activity to vaccinia and EBV at baseline, and 9 out of 9 children showed this CTL activity at 12 months.
-At baseline, five children had positive CTL responses to at least one of the HIV-1 epitopes (Gag, Pol, or Nef).
-However, only 2 of the 5 children continued to show HIV-1 specific CTL's at 18 months.
One strong responder had negative HIV-1specific CTLs at entry, and developed moderate specific lysis against Gag protein at month 12.
-None of the 10 patients had lymphocyte proliferative responses to inactivated HIV-1 antigen or to p24 at entry (measured by lymphocyte stimulation indices or LSI.
After immunization. in the 10U Remune group +AR (Arm B): one subject had strong LPR's to inactivated HIV-1 antigen (LSI=19) and to p24 (LSI=14). Another subject had elevated LSI's to inactivated HIV-1 antigen (LSI =9) but not to p24.
In the lower Remune dose, one child had a moderate LPR to p24 (LSI 6) and another child had a mild LPR to inactivated HIV-1 antigen (LSI-3)
"Children, especially those who acquire HIV through vertical transmission, may have more profound impairment in cell-mediated immunity than asymptomatic seropositive adults, even when they maintain normal CD4+ T cell counts. These children had weak recall immunities and virtually undetectable lympho-proliferative responses to p24 and gp160 at baseline."
-It could not be determined if further doses of the immunogen continued to result in decreasing viral load, because some children had undetectable viral loads at entry and maintained them throughout.
-In those receiving the low dose of Remune and AR, the viral loads increased towards baseline levels, and in two cases, exceeded baseline levels.
-In those children receiving the highest dose of Remune and AR, viral loads decreased or remained at undetectable levels.
-Considering that these children were only receiving one or two nucleosides, and not highly active antiretroviral therapy (HAART) it is remarkable that 4 of 4 children were able to maintain low levels of virus for 18 months. In general, dual therapy with nucleosides is rarely effective in maintaining low viral loads for any length of time.
"Multiple inoculations of HIV-1 immunogen were associated with certain T lymphocyte' activation, shown by consistent increases in the amounts of RANTES released from cultured lymphocytes in some children. regardless of the presence of stimuli in culture."
RANTES = Regulated-on-Activation, normal T cell-expressed and secreted.
There was an inverse correlation between viral load and the production of Rantes, that it is, the higher the levels of Rantes, the lower the viral load.
There was a direct relationship between the level of Rantes measured and increases in antibody titer against HIV-1 Gag peptides.
The beta chemokines: Rantes, MIP-1alpha, and MIP-1beta suppress HIV-1 replication by reducing the expression of the chemokine receptors- CXCR4 or CCR5 on CD4 cells. These receptors must be present for the HIV virus to attach to the CD4 cell. Less expression of receptors should result in less infection.
"These data imply that the main sources of RANTES in the current pediatric cohort were not necessarily CD4+ T helper cells but possibly CD8+ T cells and/or NK cells and suggest that HIV-1 immunogen inoculations resulted in not only the antibody induction but also certain T cell activation, which may have helped control viral replication in vivo in these children."
"Such viral suppressive activity has been reported with CD8+ T cells mediated by non-cytolytic mechanisms, releasing high levels of -chemokines, in HIV-1infected adults and children."
"These data may show the important role of Gag-specific cell-mediated immunity in controlling viral replication in infected individuals" and suggest that HIV-1 replication may be partly contained and mediated by up-regulation of beta chemokines from the effector cells."
From: "Preliminary Evaluation of Human Immunodeficiency Virus Type 1 (HIV-1) Immunogen in Children with HIV-1 Infection "
Shizuko Sei, Susan L. Sandelli, Georgia Theofan, Silvia Ratto-Kim, Mutsuko Kumagai, Lawrence D. Loomis-Price, Josephine H. Cox7, Paul Jarosinski, Claire M. Walsek (5), Pim Brouwers (1) , David J. Venzon (3) , Jing Xu (10), Philip A. Pizzo (2) , Ronald B. Moss, Merlin L. Robb, (8)and Lauren V. Wood (1)
HIV and AIDS Malignancy Branch. 2 Pediatric Branch, and 3 Biostatistics and Data Management Section, National Cancer Institute, and Departments of
Pharmacy and 5 Nursing. 4. Clinical Center, National Institutes of Health, Bethesda; 6. HIV Clinical Interface Laboratory, SAIC-Frederick, National Cancer Institute Frederick Cancer Research and Development Center, Frederick; 7 HIV Laboratory, Henry M. Jackson Foundation, and 8:Department of Retrovirology, Walter Reed Army Institute of Research, Rockville, Maryland; The Immune Response Corporation, Carlsbad, California; 10 Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
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