title: A dual infection/competition assay shows a correlation between ex vivo human immunodeficiency virus type 1 fitness and disease progression.
abstract: This study was designed to examine the impact of human immunodeficiency virus type 1 (HIV-1) fitness on disease progression through the use of a dual competition/heteroduplex tracking assay (HTA). Despite numerous studies on the impact of HIV-1 diversity and HIV-specific immune response on disease progression, we still do not have a firm understanding of the long-term pathogenesis of this virus. Strong and early CD8-positive cytotoxic T-cell and CD4-positive T-helper cell responses directed toward HIV-infected cells appear to curb HIV pathogenesis. However, the rate at which the virus infects the CD4(+) T-cell population and possibly destroys the HIV-specific immune response may also alter the rate of disease progression. For HIV-1 fitness studies, we established conditions for dual HIV-1 infections of peripheral blood mononuclear cells (PBMC) and a sensitive HTA to measure relative virus production. A pairwise comparison was then 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 ex vivo fitness were then selected as controls and competed against primary HIV-1 isolates from an HIV-infected Belgian cohort. HIV-1 isolates from long-term survivors (LTS) were outcompeted by control strains and were significantly less fit than HIV-1 isolates from patients 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 efficiently than all NSI/R5 isolates. Finally, there were strong, independent correlations between viral load and the total relative fitness values 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 suggest that HIV-1 fitness together with viral load may be a strong predictor for the rate of disease progression.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Quiñones-Mateu
authors.forename: S C
authors.initials: SC
authors.lastname: Ball
authors.forename: A J
authors.initials: AJ
authors.lastname: Marozsan
authors.forename: V S
authors.initials: VS
authors.lastname: Torre
authors.forename: J L
authors.initials: JL
authors.lastname: Albright
authors.forename: G
authors.initials: G
authors.lastname: Vanham
authors.forename: G
authors.initials: G
authors.lastname: van Der Groen
authors.forename: R L
authors.initials: RL
authors.lastname: Colebunders
authors.forename: E J
authors.initials: EJ
authors.lastname: Arts
mesh_terms: D001681:Biological Assay; D015658:HIV Infections / Q000503:physiopathology* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D011237:Predictive Value of Tests; D011379:Prognosis