Skip Navigation LinksHome > October 24, 2006 - Volume 20 - Issue 16 > Greater CD4 T-cell gains after one year of antiretroviral th...
doi: 10.1097/01.aids.0000247583.38943.95
Research Letters

Greater CD4 T-cell gains after one year of antiretroviral therapy are associated with lower HIV-1 pol replication capacity

Barbour, Jason Da; Hecht, Frederick Ma; Little, Susan Jc; Markowitz, Martind; Daar, Eric Se; Kelleher, Anthony Df; Routy, Jean-Pierreg; Campbell, Thomas Bh; Rosenberg, Eric Si; Segal, Mark Rb; Weidler, Jodij; Grant, Robert Ma,k

Free Access
Article Outline
Collapse Box

Author Information

aPositive Health Program, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, USA

bCenter for Bioinformatics and Molecular Biostatistics, University of California, San Francisco, California, USA

cUniversity of California, San Diego, California, USA

dAaron Diamond AIDS Research Center, New York, New York, USA

eLos Angeles Biomedical Research Institute at Harbor–UCLA and the University of California, Los Angeles, California, USA

fNational Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia

gMcGill University Health Centre, Montreal, Quebec, Canada

hUniversity of Colorado Health Sciences Center, Denver, Colorado, USA

iPartners AIDS Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA

jMonogram Biosciences, Inc., South San Francisco, California, USA

kGladstone Institute of Virology and Immunology, San Francisco, California, USA.

Received 5 October, 2005

Revised 29 June, 2006

Accepted 10 August, 2006

Collapse Box


We sought to determine whether pretreatment low pol replication capacity (polRC) is associated with CD4 T-cell count gains during antiretroviral therapy (ART). Patients were recruited at north American and Australian sites. Viral polRC was measured before starting ART in all subjects. We examined 243 individuals for a median 260 days after initiating ART. Low baseline polRC was associated with greater CD4 T-cell gains independent of virological responses.

Among recently infected individuals observed before treatment, higher CD4 T-cell counts have been observed in those bearing HIV-1 of lower viral pol replication capacity (polRC) [1,2]. In the present study, we sought to determine whether pretreatment low polRC predicted higher CD4 cell gains during combination antiretroviral therapy (ART) [3–5].

Patients were recruited during early HIV-1 infection at five north American and seven Australian sites that participate in the Acute Infection and Early Disease Research Programme (AIEDRP). An individual was determined to be eligible for this study based on previously published criteria [1]. Patients chosen for study had achieved an HIV-1-RNA level less than 500 copies/μl at least once after initiating ART. All participants provided written informed consent.

Viral polRC was assessed via a modification of the Phenosense phenotypic drug susceptibility assay (Monogram Biosciences, formerly ViroLogic, Inc., South San Francisco, California, USA) [6,7]. The current polRC assay is calibrated and standardized differently from previously reports, so the results are not directly comparable with previous reports [1]. The polRC of the reference virus (set at 100%) is comparable to the average value of a large population of wild-type viruses (n = 9621) (N. Parkin, Monogram Biosciences, personal communication).

All statistical analyses were performed using the SAS system for Windows version 9.2 (SAS Institute, Cary, North Carolina, USA). In the longitudinal analysis of patients receiving ART, patients were right censored at the time they stopped ART, initiated IL-2 or were lost to follow-up. Mixed effects modeling [8,9] was used to assess the relationship of baseline and longitudinal values on longitudinal outcome variables.

We selected 243 treatment-naive individuals who met the eligibility criteria for this analysis and had specimens available for testing. Of these, 127 were recruited in New York City, 74 were recruited in San Diego or Los Angeles, 32 individuals were recruited from seven Australian sites, six from Montreal, three from Denver, and one was recruited in Boston.

At the date a first ART regimen was started, the median CD4 T-cell count was 478 cells/μl [interquartile range (IQR) 353, 659, n = 214], the HIV-1-RNA level was 4.94 log10 copies/ml (IQR 3.89, 5.73, N = 231), and polRC was 93% of control (IQR 64, 116, N = 243). ART comprised two nucleoside reverse transcriptase inhibitors, at least one protease inhibitor or at least one non-nucleoside reverse transcriptase inhibitor.

We examined the relationship between polRC and the change in CD4 T-cell count during therapy in 243 individuals from all study sites. Individuals carrying a virus of higher polRC (greater than 93% of control) experienced slower increases in CD4 T-cell counts during therapy (−0.08 fewer cells/μl per day, P = 0.002) after adjustment for HIV-1-RNA levels (−49 cells/μl lower per each 1 log10 higher HIV-1 RNA; P < 0.0001) and baseline CD4 T-cell count (−0.6 cells/μl lower per each additional CD4 T cell at therapy baseline; P < 0.0001).

When modeled as a continuous variable, higher polRC was associated with lower CD4 T-cell gain during treatment (−0.0007 fewer cells/μl per day per polRC unit; P = 0.01). This result was independent of the virological response to therapy and pretherapy CD4 T-cell count. The association between lower polRC and greater CD4 T-cell count gains during therapy remained when data from patients with evidence of phenotypic drug resistance were excluded.

The difference in CD4 T-cell count and recovery occurred after 12 months of treatment (Fig. 1) and was not caused by differential periods of follow-up. When the analysis was limited to individuals remaining in the cohort for greater than 18 months we observed that these individuals had pretreatment baseline CD4 T-cell counts (median 455 CD4 T cells/μl), and HIV-1-RNA levels (median 5.23 log10 copies/ml) comparable to the entire cohort. The polRC scores tended to be lower (median 80% of control). When restricted to those with greater than either 12 or 18 months of follow-up, polRC remained a significant and independent predictor of CD4 T-cell gains during ART.

Fig. 1
Fig. 1
Image Tools

We observed that recently infected adults with lower polRC viral infections experienced greater CD4 T-cell gains during antiretroviral treatment. The advantage in CD4 T-cell recovery was observed after 12 months of continuous treatment on ART, and was independent of virological responses to therapy. PolRC was not associated with plasma RNA levels before and during therapy, which is consistent with previous reports [1]. We employed standard clinical assays to measure the HIV-1-RNA load, which do not measure small differences in residual viral replication during therapy. Differences in very low viral replication may affect long-term CD4 T-cell recovery after 12 months of therapy [10–12].

The basis for the relationship between viral replication capacity and the late recovery of CD4 T-cell count during ART is not clear, but may relate to the level or virulence of HIV-1 infection. Stoddart and colleagues [13] used the severe combined immunodeficiency–human mouse model to assess the level of viral replication in human thymic tissue, by protease inhibitor resistant variants. A virus bearing a drug-resistant protease gene was not able to infect human thymic tissue in this model, nor was it able to deplete thymic explant cultures of thymocytes (CD4 or CD8 T-cell precursors). Therefore, individuals with low polRC infections may have had less injury to the thymus, which could allow for the greater repopulation of CD4 T cells in the peripheral blood during therapy.

Our study is subject to several limitations, notably a limited sample size and the limited length of clinical follow-up. In addition, we included only individuals with acute and recent infection, whereas the majority of patients currently considering therapy have longer-term infections. The clinical utility of the polRC assay in guiding the timing of initiation or change in the treatment regimen is not known and is currently being evaluated in other populations.

Back to Top | Article Outline


The authors would like to thank the patients who participated in individual AIEDRP network site studies. They wish to thank Kimberly Schafer, Bryna Block, Florin Vaida, and Shelly Sun of the AIEDRP Statistical and Coordinating Center, and Ken Wood of Frontier Sciences, for their assistance with preparation of the manuscript, data management and derivation of the final analysis data set. They also wish to thank Michael Bates of Monogram Biosciences for assistance with the manuscript, and Jon Kaldor of the University of New South Wales for comments on the manuscript. They acknowledge Monogram Biosciences (formerly Virologic, Inc.) for providing pol replication capacity, and Phenosense drug susceptibility assays.

Sponsorship: J.D.B. is supported by K01 AI066917 (Barbour) NIH/NIAID. This work was supported by AI41531 (Levy/Hecht), MO-RR00102, AI47033 and AI41534 (Markowitz), AI36214 (Richman), AI43638 and M01-RR00425 (Daar), AI55356 and AI54907 (Campbell), AI43271 (Routy for the Investigators of the Montreal PHI Study/FRSQ), AI52403 (Walker/Rosenberg), and the AIEDRP network (5 U01 AI043638).

Back to Top | Article Outline


1. Barbour JD, Hecht FM, Wrin T, Segal MR, Ramstead CA, Liegler TJ, et al. Higher CD4+ T cell counts associated with low viral pol replication capacity among treatment-naive adults in early HIV-1 infection. J Infect Dis 2004; 190:251–256.

2. Daar ES, Kesler KL, Wrin T, Petropoulo CJ, Bates M, Lail A, et al. HIV-1 pol replication capacity predicts disease progression. AIDS 2005; 19:871–877.

3. Barbour JD, Wrin T, Grant RM, Martin JN, Segal MR, Petropoulos CJ, Deeks SG. Evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults. J Virol 2002; 76:11104–11112.

4. Sufka SA, Ferrari G, Gryszowka VE, Wrin T, Fiscus SA, Tomaras GD, et al. Prolonged CD4+ cell/virus load discordance during treatment with protease inhibitor-based highly active antiretroviral therapy: immune response and viral control. J Infect Dis 2003; 187:1027–1037.

5. De Luca ABM, Di Giambenedetto S, Cingolani A, Coakley E, Petropoulos CJ, Cauda R, Schapiro J. HIV-1 replication capacity in HAART-failing regimens patients predicts virologic and immunologic responses when accounting for viral susceptibility to the salvage regimen: results from the Argenta Trial. In: 12th Conference on Retroviruses and Opportunistic Infections. Boston, MA, USA, 22–25 February 2005 [Abstract 692].

6. Deeks SG, Wrin T, Liegler T, Hoh R, Hayden M, Barbour JD, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001; 344:472–480.

7. Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, Huang W, et al. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 2000; 44:920–928.

8. Diggle P, Liang K, Zeger S. Analysis of longitudinal data. Oxford: Oxford University Press; 1994.

9. Littell R, Milliken G, Stroup G. SAS system for mixed models. Cary, NC, USA: SAS Institute; 1996.

10. Havlir DV, Koelsch KK, Strain MC, Margot N, Lu B, Ignacio CC, et al. Predictors of residual viremia in HIV-infected patients successfully treated with efavirenz and lamivudine plus either tenofovir or stavudine. J Infect Dis 2005; 191:1164–1168.

11. Gunthard HF, Havlir DV, Fiscus S, Zhang ZQ, Eron J, Mellors J, et al. Residual human immunodeficiency virus (HIV) type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years. J Infect Dis 2001; 183:1318–1327.

12. Hunt PW, Deeks SG, Rodriguez B, Valdez H, Shade SB, Abrams DJ, et al. Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 2003; 17:1907–1915.

13. Stoddart CA, Liegler TJ, Mammano F, Linquist-Stepps VD, Hayden MS, Deeks SG, et al. Impaired replication of protease inhibitor-resistant HIV-1 in human thymus. Nat Med 2001; 7:712–718.

© 2006 Lippincott Williams & Wilkins, Inc.