AIDSWEEKLY Plus, Monday, December 1, 1997 issue.
Daniel J. DeNoon, Senior Editor

Drugs and monoclonal antibodies in both the late and early stages of preclinical development could deny HIV access to the cellular co- receptors it needs to enter cells.

Such agents would effectively mimic the genetic resistance to HIV seen in some infected patients with long-term nonprogression.

"Clearly, if you can stop HIV from getting into new cells, you can prevent AIDS pathogenesis," said John P. Moore of the Aaron Diamond AIDS Research Center (ADARC), New York.

Moore spoke in a plenary address to the American Society for Microbiology's 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 28 to October 1, 1997, in Toronto, Ontario, Canada.

Fusion of HIV with the membrane of CD4(+) T cells or macrophages requires interactions between the virus and cellular surface molecules. Although initial binding usually requires attachment to the CD4 molecule, fusion cannot be completed until the virus envelope also binds to one of the recently identified co-receptor molecules.

These members of the 7-transmembrane receptor family include the CC and CXC chemokine receptors CCR5 and CXCR4, which respectively mediate fusion for macrophage (M)-tropic and T-cell (T)-tropic HIV strains. Additional co-receptors have also been identified, including STRL33 (dubbed bonzo), GPR15 (dubbed bob, or brother of bonzo), and GPR1.

Early in the course of infection, the HIV strains seen in most patients are exclusively M-tropic strains with the non-syncytium inducing (NSI) phenotype. Later, as disease progression occurs, HIV strains with the syncytium-inducing (SI) phenotype become prevalent; most of these strains are dual tropic (that is, they have both M- and T-tropism).

Moore noted that exclusively T-tropic HIV strains capable of using only the CXCR4 receptor are rare outside of laboratory cultures and are seen only in patients with late-stage HIV disease.

"The phenotypic switch permits infection of naive T cells," he said. "What's interesting about this phenotypic switch is not why it occurs, but why it does not occur for so long."

During the process of fusion, factors on the HIV gp120 envelope glycoprotein interact directly with the co-receptors in a CD4- dependent manner. Antibodies are only sometimes able to interfere with this process. Moore suggested that gp120 has two faces: a neutralizing face, where neutralizing antibodies bind; and a non- neutralizing face, where antibodies bind but do not neutralize because the gp120 fusion determinants remain hidden.

"Antibody neutralization depends on inhibition of co-receptor attachment," he stated.

However, the sensitivity of primary HIV strains to antibody neutralization is not linked to their co-receptor specificity.

"It's the structure of gp120 that determines whether antibody neutralizes when it binds," Moore said. "Therefore, antibodies are not the reason for the phenotypic switch."

Some people resist HIV infection - or, once infected, maintain very low viral loads - due to mutations in their CCR5 receptors. The best described of these mutations is the delta32 mutation, which results in a shortened CCR5 molecule that cannot reach the surface of cells. This mutation, most prevalent in Caucasians of Scandinavian descent, is homozygous in 1 to 3 percent of the Caucasian population and heterozygous in about 15 percent of this population.

Moore warned that the CCR5 mutation is not totally protective against HIV, as some 5 percent of HIV transmission involves T-tropic virus. However, even people heterozygous for the mutation receive some protection: according to Moore, about a two-year delay in disease progression and death.

These findings led Moore to suggest that co-receptor expression is a crucial factor in determining whether and how quickly an HIV infected individual will develop AIDS.

"The levels of co-receptor expression may be one of the most important determinants of disease progression," he said. "Genetic or environmental factors could influence the cytokines that induce expression. The less co-receptor expression you have, the less likely it will be that infection will spiral out of control."

Moore noted that drugs capable of inhibiting HIV interactions with specific co-receptors are already under development. One such drug, the bicyclam compound AMD3100, inhibits HIV entry via the CXCR4 co- receptor at sub-nanomolar concentrations and hence could be useful in preventing the phenotypic switch that signals disease progression.

According to Moore, the drug acts quickly and is capable of blocking monoclonal antibodies against CXCR4. It does not induce signal transduction in the receptor, nor does it block signal transduction mediated by the receptors normal chemokine ligand. Moore said that Progenics Pharmaceuticals Inc., Tarrytown, New York, is currently conducting animal studies. Progenics is also developing the anti-HIV fusion protein CD4-IgG2.

In a poster presentation to ICAAC, Jose Este of University Hospital, Badalona, Spain, and colleagues (including bicyclam co- discoverer Eric de Clercq) reported that AMD3100 is both potent and selective.

"The prototype compound AMD3100 has an EC[50] of 0.005 mg/ml and a selectivity index of 100,000, making it one of the most potent anti- HIV compounds discovered to date," they wrote in their presentation abstract. "We have found that AMD3100 specifically interacts with CXCR4, the receptor for the SDF-1 chemokine, and also the co-receptor used by T-tropic strains of HIV. AMD3100 inhibited the binding of a monoclonal antibody (12G5) specific for the CXCR4 receptor, which has anti-HIV activity against T-tropic strains."

AMD3100 is not effective against HIV strains that use the CCR5 co- receptor, but Moore said that CCR5 inhibitors are being studied.

Copyright (c) 1997 - Charles Henderson, Publisher. Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588 All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.

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