Emergence and persistence of CXCR4-tropic HIV-1 in a population of men from the multicenter AIDS cohort study

Abstract

We examined the emergence of CXCR4 (i.e., X4) tropism in 67 male human immunodeficiency virus type 1 (HIV-1) seroconverters from the Multicenter AIDS Cohort Study (MACS) who were selected to reflect the full spectrum of rates of HIV-1 disease progression. A mean of 10 serial samples per donor were evaluated by a laboratory-validated, commercially available assay to determine phenotypic coreceptor use. A total of 52% of men had dual- or mixed-tropic HIV-1 detected at 1 or more of the time points tested. Use of X4 by HIV-1 was detected more frequently among men who developed AIDS (defined as a CD4(+) T cell count of <200 cells/muL and/or an AIDS-defining illness) < or =11 years after seroconversion than among those who did not (P = .005), as well as among men who exhibited a total T cell count decline (i.e., a CD3(+) inflection point), compared with those who did not (P = .03). For men in whom both X4 virus and an inflection point were detected, emergence of X4 virus preceded the inflection point by a median of 0.83 years. The median CD4(+) T cell count at first detection of X4 viruses before the onset of AIDS was 475 cells/microL. We conclude that HIV-1 variants that used X4 frequently emerged at high CD4(+) T cell counts and may contribute to the decrease in T cell numbers during late HIV-1 infection.

Figure 1

Representative longitudinal CD4⁺ and CD3⁺ T cell counts and HIV tropism patterns, by rate of progression to AIDS, in a population of men from the Multicenter AIDS Cohort Study (MACS). Progression to AIDS was defined as a CD4⁺ cell count of >200 cells/μL on 2 consecutive study visits and/or onset of an AIDS-defining illness and was considered rapid if the time since seroconversion was ≤5 years, moderate if the time was >5 to 9 years, slow if the time was >9 to 11 years, and very slow if the time was >11 years or if no event was recorded during >11 years of follow-up. Viral tropism was determined by means of the Trofile assay (Monogram Biosciences). A value of <10^2.1 relative light units (RLU) is considered negative; fluctuations below this value do not change the interpretation of the results. D, mixed CCR5-CXCR4 tropism; N, no result; vertical lines, events relative to semiannual MACS study visits; 5, CCR5 tropism only.

Figure 2

Individual patterns of X4 virus emergence among 67 men from the Multicenter AIDS Cohort Study.

Figure 3

Prevalence of X4 viruses, by time after HIV-1 seroconversion, among specimens obtained from a population of men from the Multicenter AIDS Cohort Study.

Figure 4

Prevalence of X4 viruses, by CD4⁺ T cell count, among specimens obtained from a population of men from the Multicenter AIDS Cohort Study.

Figure 5

Time of X4 virus emergence in relation to CD3⁺ inflection point among 31 men from the Multicenter AIDS Cohort Study who exhibited both X4 emergence and a CD3⁺ inflection point. See Subjects, Materials, and Methods for a description of the inflection point.