AIDSWEEKLY Plus, 10 June 1996
Daniel J. DeNoon, Senior Editor

An inactivated bacterium conjugated to HIV peptides creates a vaccine capable of eliciting HIV specific cellular immunity in mice.

Remarkably, the Brucella abortus-conjugated vaccine had the same effect in mice with no CD4(+) T cells.

Researchers Cheryl Lapham of the U.S. Food and Drug Administration (FDA), Bethesda, Maryland, and colleagues reported the findings in the Journal of Virology ("Brucella abortus Conjugated with a Peptide Derived from the V3 Loop of Human Immunodeficiency Virus (HIV) Type 1 Induces HIV-Specific Cytotoxic T-Cell Responses in Normal and in CD4(+) Cell- Depleted BALB/c Mice," J Virol, 1996;70(5):3084-3092).

"The ability of B. abortus conjugates to generate potent antiviral humoral and cytotoxic responses, even under conditions of limited CD4(+) T-cell function, makes it a very attractive candidate for a vaccine carrier to treat individuals with T-cell immunodeficiency," they wrote.

"Thus, B. abortus may be suitable as a carrier in therapeutic vaccines for patients already infected with the HIV-1 and HIV-2 viruses as well as in prophylactic vaccines."

Lapham and colleagues previously found that conjugation of HIV peptides to B. abortus induced neutralizing anti-HIV antibodies, mostly of the IgG2a isotype (Golding et al., AIDS Res H, 1991;7:471-482 and Golding et al., J Virol, 1995;69:3299-3307).

Because IgG2a is induced by interferon gamma, a T-helper type 1 (Th1) cytokine, they reasoned that the vaccine could also elicit other Th1 responses, such as cytotoxic lymphocytes (CTL). Supporting this hypothesis was the recent finding that B. abortus induces secretion of the Th1 cytokine IL-12.

The researchers conjugated heat-inactivated B. abortus to an 18-amino-acid peptide based on the V3 loop of the gp120 envelope glycoprotein of HIV-1[MN] to create the vaccine they dubbed B. abortus-MN 18-mer.

Mice received two immunization with 10(8) organisms of B. abortus-MN 18-mer. When cells from the immunized mice were stimulated in vitro with peptide, an HIV specific CTL response was seen.

In a subsequent experiment, mice were treated with anti- L3T4 antibodies prior to immunization, severely depleting their CD4(+) lymphocytes. This treatment did not reduce CTL priming. Similar experiments were performed with neonatal mice.

"We demonstrated that the induction of CD8(+) MHC class I- restricted cytotoxic cells can take place not only in animals with an intact immune system but also in animals with an immature immune system (neonates) and in animals depleted of peripheral CD4(+) T cells," Lapham et al. concluded.

"Thus B. abortus is capable of eliciting all the known required helper factors in the absence of classical CD4(+) T- helper cells. This beneficial property of B. abortus may also explain our earlier finding that B. abortus conjugated either to whole inactivated HIV-1 (IIIB) or to a short peptide derived from the V3 loop of HIV-1 generated strong IgG responses with syncytium-inhibiting activities either in normal BALB/c mice or in mice depleted of CD4(+) T cells."

The corresponding author for this study is Cheryl Lapham, Laboratory of Retrovirus Research, Division of Viral Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bldg. 29B, Rm. 3G21, HFM 454, 8800 Rockville Pike, Bethesda, Maryland 20892. Phone: (301) 827- 0703. Fax: (301) 496-1810.

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