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Baseline HIV Type 1 Coreceptor Tropism Predicts Disease Progression

  1. Eric S. Daar1,
  2. Karen L. Kesler4,
  3. Christos J. Petropoulos2,
  4. Wei Huang2,
  5. Michael Bates2,
  6. Alice E. Lail4,
  7. Eoin P. Coakley2,
  8. Edward D. Gomperts3,
  9. Sharyne M. Donfield4, and
  10. Hemophilia Growth and Development Studya
  1. 1Los Angeles Biomedical Research Institute at Harbor-University of California-Los Angeles (UCLA) Medical Center and the David Geffen School of Medicine at UCLA, Torrance
  2. 2Monogram Biosciences, South San Francisco
  3. 3Childrens Hospital Los Angeles, Los Angeles, California
  4. 4Rho, Chapel Hill, North Carolina
  1. Reprints or correspondence: Dr. Eric S. Daar, 1124 W. Carson St., N-24, Torrance, CA 90502 (EDaar{at}LABioMed.org).

  1. Presented in part: 43rd Interscience Conference on Antimicrobial Agents and Chemotherapeutics, Chicago, Illinois, September 2003 (abstract H1722c).

 
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Abstract

Background. Human immunodeficiency virus type 1 (HIV-1) coreceptor tropism, the ability of the virus to enter cells via CCR5 or CXCR4, is a viral characteristic mediated by the envelope gene. The impact of coreceptor tropism on the natural history of HIV-1 infection has not been fully explored.

Methods. Coreceptor tropism was measured using a recombinant virus single-cycle assay on plasma specimens obtained at baseline from 126 children and adolescents in the Hemophilia Growth and Development Study cohort who were enrolled from 1989 through 1990 and underwent follow-up through 1997.

Results. Detectable CXCR4-using virus at baseline was associated with a lower baseline CD4+ T cell count and a higher plasma HIV-1 RNA level. In addition, it independently predicted a greater decrease in CD4+ T cell count over time (P < .001) and was associated with a 3.8-fold increased risk of progression to clinical AIDS.

Conclusions. This study demonstrates that coreceptor tropism, as assessed by this single-cycle assay, independently influences the natural history of HIV-1 disease.

HIV-1 clinical progression is predicted by CD4+ T cell count, plasma HIV-1 RNA level [1], and a variety of host factors [2,3–4]. In addition, the ability of HIV-1 to induce syncytia in MT-2 cells in vitro has been associated with a decrease in CD4+ T cell count and with disease progression, even though many individuals progress to AIDS without having detectable syncytium-inducing virus [5,6–7]. We now recognize that syncytia formation in MT-2 cells is generally induced by HIV-1 strains that use the CXCR4 chemokine receptor. Despite the well-established association between syncytium-inducing HIV-1 and disease progression, there are fewer data showing that CXCR4 coreceptor tropism or syncytium-inducing phenotype predict disease progression when controlling for both CD4+ T cell count and plasma HIV-1 RNA level—the latter parameter not being available at the time when many of the earlier studies were performed. There is also increasing interest in understanding the implications of coreceptor tropism in light of the development of drugs that interact with the chemokine receptors in such a way as to block HIV-1 infection. In this study, we use a recombinant envelope assay that is being widely used in other studies of pathogenesis and for screening of individuals for inclusion in CCR5 antagonist clinical trials to describe the prevalence of coreceptor tropism and its association with HIV-1 disease progression.

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Methods

Patient Population

The Hemophilia Growth and Development Study is a multicenter US study that enrolled a population-based cohort of 207 HIV-1–infected patients aged 6–19 years during 1989–1990, with a mean duration of follow-up of 7 years [8]. Every 6 months, blood samples were obtained for lymphocyte subset counts and cryopreservation of plasma samples. From this cohort, 126 patients had coreceptor tropism data available from stored plasma samples obtained around the time of entry into the study. Antiretroviral therapy (ART) was administered to study participants during the course of their follow-up at the discretion of the primary providers, with only 4 patients included in the analysis of coreceptor tropism ever being exposed to 3-drug therapy.

The human subjects committees of collaborating institutions approved the Hemophilia Growth and Development Study. Informed consent was obtained from parents or legal guardians, and informed consent or assent was obtained from all participants, in compliance with the human experimentation guidelines of the US Department of Health and Human Services.

Measurements of HIV-1 RNA Level and Coreceptor Tropism

HIV-1 RNA level was measured at a central laboratory using the branched-DNA assay (Versant HIV-1 RNA, version 2.0, Bayer Healthcare and Diagnostics). Samples that had an undetectable HIV-1 RNA level (defined as <500 copies/mL) were retested using version 3.0 (lower limit of detection at the time of analysis, 50 copies/mL) [9]. Plasma samples with an HIV-1 RNA level ⩾500 copies/mL were sent to Monogram Biosciences (South San Francisco, CA) for analysis of tropism. Coreceptor tropism was assessed using a single-cycle recombinant virus assay [10]. Pseudotyped HIV-1 viruses were generated by cotransfection of a genomic vector carrying a luciferase reporter gene together with expression vectors containing patient virus envelope genes amplified by RT-PCR from plasma HIV-1 RNA. Unlike previous assays for tropism, such as those using MT-2 cells, the amplification from plasma assesses coreceptor tropism on uncultured and nonpassaged circulating HIV-1 envelope genes that are present in the sample. The assay detects both CXCR4- and CCR5-using virus, with coreceptor tropism defined by the ability of the recombinant viruses to infect U87 cells that have been engineered to express CD4 and either CCR5 or CXCR4. CCR5-tropic (R5), CXCR4-tropic, and dual or mixed tropic (DM) designations are verified by blocking coreceptor-mediated infection using specific antagonists. No distinction is made by this assay between dual and mixed tropism when testing virus populations. Infection of these distinct target cells is defined by luminescence, which is quantified as the number of relative light units produced in each type of target cell.

Coreceptor tropism testing was performed for 126 of the 207 patients in the Hemophilia Growth and Development Study. Data were not available for patients with HIV-1 RNA levels <500 copies/mL (n = 23), for patients who did not have adequate stored specimens (n = 18), or for cases for which we were unable to amplify the envelope gene for undefined technical reasons (n = 40). The rate of assay failure was somewhat higher than that reported in current studies using this assay. The most likely explanations for this are that the samples had been frozen for ∼15 years, and only 1 mL of plasma was sent for testing, whereas in current practice, 2 mL of plasma is sent for retesting in the event of assay failure. Assays were performed on samples as close to the baseline enrollment date as availability allowed, with 80% of coreceptor tropism data acquired from specimens collected during the first 12 months after enrollment.

Study Variables

CD4+ T cell counts were measured every 6 months, and plasma HIV-1 RNA levels were measured annually. Baseline values for each of these parameters represent the values at the time that the coreceptor tropism assay was performed. Participants were categorized as having progressed to AIDS if they met the 1987 Centers for Disease Control and Prevention definition [11]. Of the 126 patients with baseline coreceptor tropism data available, 10 met AIDS criteria prior to the time of enrollment and were not included in the survival analyses, and an additional 42 patients progressed to AIDS during the course of follow-up.

Statistical Analysis

Relationship between coreceptor tropism, HIV-1 RNA level, and CD4+ T cell count. The relationship between baseline CD4+ T cell count strata and coreceptor tropism was assessed by a Cochran-Mantel-Haenzel χ2 test. Univariate linear models were constructed to determine the ability of coreceptor tropism to predict CD4+ T cell counts (square root transformed) and plasma HIV-1 RNA levels (log10 transformed) measured at the same time. The relationship between coreceptor tropism and longitudinal CD4+ T cell count measurements were modeled. The analysis used a random effect, mixed model, with random effects for each patient and a variety of fixed effects, including coreceptor tropism, study visit number, use of ART, baseline CD4+ T cell count, and plasma HIV-1 RNA level, as well as first-order interactions with study visit number. We also tested the linearity of CD4+ T cell counts and plasma HIV-1 RNA levels for each visit and found it to be a good fit.

Relationship between coreceptor tropism and clinical progression. Cox proportional hazards models were fit to the time to model the progression to clinical AIDS [11], controlling for CD4+ T cell count and plasma HIV-1 RNA level. Kaplan-Meier analyses were plotted for time to progression to AIDS, stratified by presence or absence of detectable CXCR-using virus.

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Results

Participant characteristics. The baseline characteristics of patients with coreceptor tropism measurements were similar to those of the overall cohort, except the patients with coreceptor tropism measurements had a higher mean (±SD) plasma HIV-1 RNA level (3.7 ± 0.56 log10 copies/mL vs. 3.4 ± 0.77 log10 copies/mL) and a lower mean (±SD) CD4+ T cell count (349 ± 287 cells/µL vs. 422 ± 321 cells/µL). Sixty-two individuals with coreceptor tropism data were receiving ART at the time that the samples were collected, including monotherapy with either zidovudine, didanosine, zalcitabine, or lamivudine (n = 60) or zidovudine plus didanosine (n = 2).

Relationship of coreceptor tropism with CD4+ T cell count and plasma HIV-1 RNA level. Seventy-five of the 126 samples for which there were coreceptor tropism measurements had only detectable R5 virus, whereas the remaining 51 had viruses exhibiting tropism for both CXCR4 and CCR5 (i.e., DM virus); none had virus using CXCR4 alone. A comparison of characteristics of patients who had and did not have detectable CXCR4-tropic virus are summarized in table 1. At the time of the tropism assessment, patients who did not have detectable CXCR4-tropic virus had higher baseline CD4+ T cell counts than did individuals with DM virus (mean baseline CD4+ T cell count ± SD, 449 ± 262 cells/µL vs. 200 ± 259 cells/µL; P < .001). Consistent with this, there was a relationship between baseline CD4+ T cell count strata and the presence or absence of detectable CXCR4-using virus (P < .001) (figure 1). The baseline plasma HIV-1 RNA level was lower in patients with R5 virus than in patients with DM virus (mean baseline plasma HIV-1 RNA level ± SD, 3.5 ± 0.46 log10 copies/mL vs. 3.95 ± 0.60 log10 copies/mL; P < .001) (table 1). In contrast, there was no statistically significant difference between the groups with regard to age or estimated duration of infection.

Figure 1
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Figure 1

Distribution of coreceptor tropism, by CD4+ T cell count stratum (P < .001).

Figure 2
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Figure 2

Modeled CD4+ T cell count over time on the basis of coreceptor tropism. CCR5-tropic virus only is denoted by the solid line, and dual or mixed tropic virus (i.e., CCR5-tropic and CXCR4-tropic) is denoted by the dashed line (P < .001).

Figure 3
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Figure 3

Kaplan Meier curves for clinical progression to AIDS (P < .001). CCR5-tropic virus only is denoted by the solid line, and dual or mixed tropic virus (i.e., CCR5-tropic and CXCR4-tropic) is denoted by the dashed line.

Table 1
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Table 1

Characteristics of patients at the time of tropism assessment.

A longitudinal analysis was performed that assessed the relationship between baseline coreceptor tropism and CD4+ T cell count over time (Figure 2). In a model that included visit number, ART use, coreceptor tropism, baseline plasma HIV-1 RNA level, and CD4+ T cell count, there was an interaction between the presence of DM virus and greater decrease in CD4+ T cell count over time (P < .001).

Coreceptor tropism and clinical progression. In the univariate Cox proportional hazards model, having detectable DM virus was associated with a hazard ratio for progression to AIDS of 6.32 (95% CI, 3.15–12.68; P < .001). The hazard ratio was 3.82 (95% CI, 1.69–8.60; P = .001) after adjusting for CD4+ T cell count and plasma HIV-1 RNA level. This relationship was maintained even when use of ART at baseline was included in this model (hazard ratio, 3.6; P = .002). This observation is reinforced by the Kaplan-Meier plot in Figure 3.

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Discussion

Virologic markers that predict clinical progression include plasma HIV-1 RNA level [1], antiretroviral resistance [12], and syncytium-inducing biologic phenotype [5, 6]. Despite substantial research showing a relationship between syncytium-inducing phenotype and CXCR4 tropism and disease progression, limited longitudinal data are available to assess the independent influence that these viral characteristics have on disease progression when controlling for plasma HIV-1 RNA level. To assess the influence that coreceptor tropism has on the natural history of HIV-1 infection, we used stored samples and data from a well-characterized cohort of HIV-1–infected individuals. Unlike previous studies of tropism, which typically used MT-2 cells, we used a recombinant virus envelope assay that is high throughput, measures tropism of uncultured and nonpassaged plasma virus, and detects both CCR5- and CXCR4-using HIV-1. In addition, this assay is routinely being used to screen patients for enrollment in current clinical trials of CCR5 antagonists. These analyses revealed a cross-sectional relationship between coreceptor tropism, CD4+ T cell count, and plasma HIV-1 RNA level, and they demonstrated that detection of CXCR4-using virus by this assay independently influences the natural history of HIV-1 disease.

Defining the influence of coreceptor tropism on the natural history of HIV-1 disease is important for understanding immunopathogenesis and the potential use of coreceptor antagonists that are currently in development. The relationship to pathogenesis is particularly important in light of how powerful a predictor of progression the syncytium-inducing biologic phenotype has been shown to be. In fact, several groups have shown that the emergence of viruses with a syncytium-inducing phenotype, typically using the MT-2 assay, is associated with a decrease in CD4+ T cell count and with disease progression [5, 6, 13, 14]. Subsequently, syncytium-inducing and non—syncytium-inducing phenotypes were correlated with CXCR4 and CCR5 coreceptor tropism, respectively [15]. Several studies have expanded the results from MT-2 assays using assays that directly measure CCR5 and CXCR4 tropism. For example, Kreisberg et al. [16] studied HIV-1 isolates from early and late points during the course of disease from 8 patients in whom the emergence of CXCR4-using viruses was temporally associated with a decrease in CD4+ T cell count. In related studies, Connor et al. [17] described 6 HIV-1–infected subjects who experienced a precipitous decrease in CD4+ T cell count, and Xiao et al. [18] studied 4 patients whose disease progressed rapidly, 6 patients whose disease progressed late, and 3 patients who had long-term nonprogression. The latter authors showed that CXCR4-using viruses emerged in the patients whose disease progressed rapidly and, during the latter one-half of the study, in the patients whose disease progressed late; none of the patients with long-term nonprogression developed CXCR4-using viruses. The current study expands upon these observations, revealing that coreceptor tropism is a strong, independent predictor of disease progression in a considerably larger cohort and using a high-throughput assay that assesses viral tropism of uncultured, nonpassaged circulating plasma virus.

Despite the association seen between the presence and emergence of syncytium-inducing and/or CXCR4-using virus and disease progression, it is still not known whether the emergence of these strains is the cause or effect of adverse outcomes. Several groups have shown that CXCR4-using viruses are more cytopathic in vitro than their R5 counterparts [19]. Others have demonstrated that the interaction between HIV-1 and CXCR4 induces CD4+ and, possibly, CD8+ T cell apoptosis [20, 21]. If the emergence of CXCR4-using virus is contributing to HIV-1 pathogenesis, it will be important to understand why this population of viruses only emerges in a subset of individuals and typically after years of infection. Several factors have been suggested to predispose subjects to the emergence of CXCR4-using virus, including the presence of the SDF-1 gene polymorphism, and, in an animal model, cellular immune responses [22, 23]. Additional research in this area may provide additional insight into factors driving this potentially important pathogenic process.

The recent development of pharmacologic antagonists of the CCR5 receptor has sparked additional interest in defining the prevalence, natural history, and relevance of the emergence of CXCR4-using virus. Because CCR5 antagonists only block infection with R5 virus, individuals who have detectable CXCR4-using virus have been systematically excluded from many clinical trials that involve these agents. Recently reported studies of CCR5 antagonists alone and as part of combination therapy have shown substantial antiviral activity in patients who did not have detectable CXCR4-using virus at baseline [24, 25]. In contrast, virologic response was minimal in those who had DM virus at the time of enrollment [26]. On the basis if these findings, it may prove to be important to define the group of patients who are most likely to respond to such therapy. As seen in this cohort and in other studies, having a lower CD4+ T cell count is a strong predictor of having detectable syncytium-inducing virus or CXCR4-using virus. Nevertheless, no strata have been shown to be devoid of individuals who have or do not have detectable CXCR4-using virus (figure 1) [27,28–29]. It is clear, however, that the likelihood of a person not having detectable CXCR4-using virus—thus being an optimal candidate for treatment with a CCR5 antagonist—is greatest among those with a higher CD4+ T cell count. Furthermore, patients who are more antiretroviral experienced tend to have a higher frequency of detectable CXCR4-using virus [28], even in the face of higher CD4+ T cell counts [29]. These observations may influence decisions regarding when CCR5 antagonists might be used during the course of therapy. The use of CCR5 antagonists also raises concerns about the potential implications of viral breakthrough occurring with CXCR4-using virus or the enrichment of a preexisting population of CXCR4-using virus that is either detectable or undetectable at baseline. Some reassurance has come from a recent clinical trial in which patients with DM virus, as measured by the assay used in the current study, were treated with a CCR5 antagonist. In this study, minimal virologic benefit was seen; however, there did not appear to be adverse consequences associated with this strategy in the form of CD4+ T cell count decrease or clinical progression after 24 weeks of therapy [26].

A limitation of our study is that it defines the implications of having detectable CXCR4-using virus as assessed by a particular single-cycle assay. Although results could vary if other phenotypic or genotypic assessments were used, the current study is consistent with others and uses an assay that is being widely used. Another limitation of this study is that it focuses on the predictive value of a single coreceptor tropism measure at baseline. It is known that there are individuals who intermittently have detectable CXCR4-using virus (a finding possibly associated with the sensitivity of the assay), and that CXCR4-using virus can emerge over time [30, 31]. Although we cannot exclude the possibility that this variation might influence outcome, the data demonstrate a highly significant impact of a single coreceptor tropism assessment. The current study must also be evaluated in the context of a study population that was minimally affected by ART, which could influence the prevalence of detectable CXCR4-using virus and its clinical relevance [29]. Finally, there are other factors that can influence outcome. We recently revealed, in the same cohort, that pol replication capacity is associated with a CD4+ T cell count decrease and disease progression [32]. Nevertheless, the relationship between tropism and CD4+ T cell count decrease and disease progression remains highly significant, even when pol replication capacity is included in the models (data not shown).

This investigation extends previous work by showing that the relationship between coreceptor tropism and disease progression holds true, even when using the recombinant virus entry assay that is now widely used in the clinical trials of CCR5 antagonists, as well as after controlling for other variables that were not included in previous studies, such as plasma HIV-1 RNA level [5, 6, 33]. These results strongly support the need for further investigation of factors associated with the emergence of CXCR4-tropic virus, as well as the relationship between this occurrence and disease progression. Further defining virologic correlates of disease progression and how they can be manipulated to modify the natural history of disease will advance our understanding of HIV-1 immunopathogenesis and enhance our ability to treat infected individuals.

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Members of The Hemophilia Growth and Development Study

The following individuals are the center directors, study coordinators, or committee chairpeople of the study: Dr. E. Gomperts, Dr. W. Y. Wong, Dr. F. Kaufman, Dr. M. Nelson, and S. Pearson (Children's Hospital Los Angeles, Los Angeles, CA); Dr. M. Hilgartner, Dr. S. Cunningham-Rundles, and I. Goldberg (The New York Hospital—Cornell Medical Center, New York); Dr. W. K. Hoots, Dr. K. Loveland, and M. Cantini (University of Texas Medical School, Houston); Dr. A. Willoughby and Dr. Robert Nugent (The National Institutes of Health, National Institute of Child Health and Human Development, Bethesda, MD); Dr. S. Donfield (Rho, Chapel Hill, NC); Dr. C. Contant, Jr. (Baylor College of Medicine, Houston, TX); Dr. C. T. Kisker, Dr. J. Stehbens, S. O'Conner, and J. McKillip (University of Iowa Hospitals and Clinics, Iowa City); Dr. P. Sirois (Tulane University, New Orleans, LA); Dr. C. Sexauer, Dr. H. Huszti, and F. Kiplinger (Children's Hospital of Oklahoma, Oklahoma City); S. Hawk, Dr. S. Arkin, and Dr. A. Forster (Mount Sinai Medical Center, New York, NY); Dr. S. Swindells and S. Richard (University of Nebraska Medical Center, Omaha); Dr. J. Mangos and R. Davis (University of Texas Health Science Center, San Antonio); Dr. J. Lusher, Dr. I. Warrier, and K. Baird-Cox (Children's Hospital of Michigan, Detroit); Dr. M. E. Eyster, Dr. D. Ungar, and S. Neagley (Milton S. Hershey Medical Center, Hershey, PA); Dr. A. Shapiro and J. Morris (Indiana Hemophilia and Thrombosis Center, Indianapolis); Dr. G. Davignon and P. Mollen (University of California-San Diego Medical Center, San Diego); and Dr. B. Wicklund and A. Mehrhof (Kansas City School of Medicine, Children's Mercy Hospital, Kansas City, MO).

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Acknowledgments

We thank the children, adolescents, and parents who volunteered to participate in this study; the members of the Hemophilia Treatment Centers; Mary McNally (Science Applications International); National Cancer Institute—Frederick, for managing and shipping of all clinical samples for this study; Signe Fransen and Jonathan Toma (Monogram Biosciences), for performing coreceptor tropism assays; and Bayer Healthcare and Diagnostics, for performing HIV-1 RNA measurements.

Financial support. National Institutes of Health (NIH; HD41224, AI43638, and AI27660) and the Universitywide AIDS Research Program (CCTG- CH05-SD-607-005). Development of the envelope coreceptor tropism assay was supported in part by small business, innovative research-advanced technology grants from the NIH National Institute of Allergies and Infectious Diseases (R44 AI048990).

Potential conflicts of interest. E.S.D. has acted as an investigator, consultant, and advisor for Monogram Biosciences; C.J.P., W.H., M.B., and E.P.C. are employees of Monogram Biosciences. All other authors: no conflicts.

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Footnotes

  • ↵a Participating centers and individuals are listed at the end of the text.

  • Received February 11, 2007.
  • Accepted May 2, 2007.
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  1. Clin Infect Dis. (2007) 45 (5): 643-649. doi: 10.1086/520650
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