AIDSWEEKLY Plus, Monday, December 8, 1997
Daniel J. DeNoon, Senior Editor
Anti-HIV chemokines could drive the virus to mutate to the form associated with disease progression.
The finding has implications for the use of immunotherapies based on these chemokines.
Gabriella Scarlatti of the San Raffaele Scientific Institute, Milan, Italy, and colleagues have followed a cohort of nine congenitally HIV infected children in a longitudinal study. They documented a sudden drop in CD4 counts, heralding disease progression, at the same time that predominating HIV strains switched their chemokine co-receptor tropism from CCR5 to CXCR4.
"The possibility that C-C chemokines released in vivo may favor the evolution of HIV-1 toward CXCR4 usage emphasizes the caveats related to the potential use of C-C chemokines or their analogs in the therapy of AIDS," Scarlatti et al. wrote in the journal Nature Medicine ("In Vivo Evolution of HIV-1 Co-Receptor Usage and Sensitivity to Chemokine-Mediated Suppression," Nature Med, 1997;3(11):1259-65).
The great majority of wild-type HIV strains that cause infection are macrophage tropic (M tropic) and can only infect cells bearing the CCR5 chemokine receptor. CCR5 is the natural receptor for the chemokines RANTES, MIP-1(alpha), and MIP-1(beta). These chemokines are inhibitory for HIV infection.
Disease progression is associated with a switch in HIV tropism toward the T-cell tropic (T-tropic) phenotype. T-tropic strains are capable of using the CXCR4 receptor (the natural receptor for the chemokine SDF-1) and are not sensitive to RANTES, MIP-1(alpha), or MIP-1(beta).
Viral isolates obtained from the study children while they remained asymptomatic were inhibited by these chemokines. But the majority of isolates obtained after disease progression had become able to use CXCR4 and lost sensitivity to RANTES, MIP-1(alpha), and MIP-1(beta), as well as to SDF-1.
"These results suggest an adaptive evolution of HIV-1 in vivo, leading to escape from the control of the antiviral C-C chemokines," Scarlatti et al. concluded.
They suggested that chemokine-based anti-HIV therapeutics could still be used safely early in the course of disease in combination with other effective agents.
"Because of the marked C-C chemokine sensitivity of the viral strains predominating during the long asymptomatic phase, it is likely that an early implementation of C-C chemokine-based therapeutic approaches, in combination with other antiretroviral drug regimens, will help to contain the initial replication and spread of HIV-1, thus limiting its opportunity to develop viable escape mutants, and ultimately will slow the pace of disease," Scarlatti et al. predicted.
This work was supported by the Istituto Superiore di Sanita, Rome, Italy, VIII and IX Progetto AIDS, grants no. 9306-20, 9405-02, and 9403-62; by the Swedish Medical Research Council, Stockholm, Sweden; by a fellowship of the Aaron Diamond Foundation, New York; and by grants from the National Institutes of Health, Bethesda, Maryland.
The corresponding author for this study is Paulo Lusso, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
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