A Dual Infection/Competition Assay Shows a Correlation between Ex Vivo Human Immunodeficiency Virus Type 1 Fitness and Disease Progression

doi:10.1128/JVI.74.19.9222-9233.2000

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Journal of Virology, October 2000, p. 9222-9233, Vol. 74, No. 19
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

A Dual Infection/Competition Assay Shows a Correlation between Ex Vivo Human Immunodeficiency Virus Type 1 Fitness and Disease Progression

Miguel E. Quiñones-Mateu,¹ Sarah C. Ball,¹ Andre J. Marozsan,² Vincent S. Torre,¹ Jamie L. Albright,¹ Guido Vanham,³ Guido van der Groen,³ Robert L. Colebunders,³ and Eric J. Arts¹^,^*

Department of Medicine¹ and Department of Pharmacology,² Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio 44106, and Laboratory of Immunology, Institute of Tropical Medicine, Antwerp, Belgium³

Received 3 May 2000/Accepted 7 July 2000

This study was designed to examine the impact of human immunodeficiency virus type 1 (HIV-1) fitness on disease progressionthrough the use of a dual competition/heteroduplex tracking assay(HTA). Despite numerous studies on the impact of HIV-1 diversityand HIV-specific immune response on disease progression, we stilldo not have a firm understanding of the long-term pathogenesisof this virus. Strong and early CD8-positive cytotoxic T-celland CD4-positive T-helper cell responses directed toward HIV-infectedcells appear to curb HIV pathogenesis. However, the rate at whichthe virus infects the CD4⁺ T-cell population and possibly destroys the HIV-specific immuneresponse may also alter the rate of disease progression. For HIV-1fitness studies, we established conditions for dual HIV-1 infectionsof peripheral blood mononuclear cells (PBMC) and a sensitive HTAto measure relative virus production. A pairwise comparison wasthen performed to estimate the relative fitness of various non-syncytium-inducing/CCR5-tropic(NSI/R5) and syncytium-inducing/CXCR4-tropic (SI/X4) HIV-1 isolates.Four HIV-1 strains (two NSI/R5 and two SI/X4) with moderate exvivo fitness were then selected as controls and competed againstprimary HIV-1 isolates from an HIV-infected Belgian cohort. HIV-1isolates from long-term survivors (LTS) were outcompeted by controlstrains and were significantly less fit than HIV-1 isolates frompatients with accelerated progression to AIDS (PRO). In addition,NSI/R5 HIV-1 isolates from PRO overgrew control SI/X4 strains,suggesting that not all SI/X4 HIV-1 isolates replicate more efficientlythan all NSI/R5 isolates. Finally, there were strong, independentcorrelations between viral load and the total relative fitnessvalues of HIV-1 isolates from PRO (r = 0.84, P = 0.033) and LTS(r = 0.86, P = 0.028). Separation of the PRO and LTS plots suggestthat HIV-1 fitness together with viral load may be a strong predictorfor the rate of diseaseprogression.

^* Corresponding author. Mailing address: Division of Infectious Diseases, BRB 1029, Case Western Reserve University, 10900 EuclidAve., Cleveland, OH 44106. Phone: (216) 368-8904. Fax: (216) 368-2034.E-mail: eja3{at}po.cwru.edu.

Journal of Virology, October 2000, p. 9222-9233, Vol. 74, No. 19
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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