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* Department of Pediatrics, University of California San Diego, La Jolla, California;
New England Research Institutes, Watertown, Massachusetts;
Department of Pathology, University of Florida, Gainsville, Florida;
Department of Internal Medicine, University of Texas, Medical Branch, Galveston, Texas;
|| Department of Pathology, University of Southern California, Los Angeles, California;
¶ Department of Otorhinolaryngology and Communicative Sciences, Baylor College of Medicine, Houston, Texas;
** Department of Immunology/Microbiology, Rush Medical College, Chicago, Illinois;
Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania; and
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
Correspondence: Janet L. Lathey, Ph.D., Pediatric Infectious Diseases, University of California, San Diego, 9500 Gilman Dr. #0672, La Jolla, CA 92093-0672. E-mail: jlathey{at}uesd.edu
A monocyte-derived macrophage (MDM) culture assay was used to define the replication kinetics of HIV isolates. Ten-day-old MDMs were infected with HIV. Supernatants were collected and assayed for HIV p24 on days 3, 7, 10, and 14 post-infection (PI). In this assay, SF162 (macrophage tropic, NSI) produced increasing amounts of HIV p24 antigen with increasing time in culture. BRU (nonmacrophage tropic, SI) infection resulted in low levels of HIV p24 antigen with no increase in production during the culture period. A panel of 12 clinical isolates was evaluated. All isolates produced detectable levels of HIV p24 antigen in MDMs. However, the NSI viruses had significantly higher log10 HIV p24 antigen values at all times PI (P < 0.01). Co-receptor usage was determined for all 12 isolates (8 NSI and 4 SI). All SI isolates used CXCR4 for entry; two used CXCR4 only, one used CXCR4, CCR5, and CCR3, and one was a mixture of two isolates using CXCR4 and CCR5. None of the NSI viruses used CXCR4 for entry. All used CCR5 as their predominant co-receptor. Of the eight NSI isolates, three used CCR5 only, two used CCR5 and CCR2b, one used CCR5 and CCR3, and one used CCR5, CCR3, and CCR2b. Log10 HIV p24 antigen production on day 14 PI for viruses that used CCR5+CCR3 (3.79 + 1.40) was greater than for viruses that used CCR5+CCR2b (3.22 + 1.55) or CCR5 (3.32 + 1.49), and all were greater than those that used CXCR4 only (1.69 + 0.28), regardless of SI phenotype (P < 0.05). Thus, in these primary isolates, macrophage tropism and replication kinetics were closely linked to CCR5 utilization, whereas SI capacity was closely linked to CXCR4 utilization. Furthermore, viruses, which could use CCR5 and CCR3 for entry, had a replication advantage in macrophages, regardless of SI phenotype.
Key Words: macrophage tropism • viral phenotype • HIV co-receptors • HIV replication kinetics
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