13th Conference on Retroviruses and Opportunistic Infections Denver, Colorado - February 5-8, 2006

Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 43

Peter Hunt ¹, J Martin¹, M Bates², W Huang², S Spudich¹, R Price¹, D Williamson³, E Sinclair³, R Hoh¹, and S Deeks^1
1Univ of California, San Francisco, US; ²Monogram Biosci, South San Francisco, CA, US; and ³Gladstone Inst of Virology and Immunology, Univ of California, San Francisco, US

BACKGROUND: Among untreated HIV-infected individuals, CXCR4 (X4)-tropic viruses are uncommon except in advanced stages of immunodeficiency. However, little is known about the prevalence and immunologic consequences of X4 tropism in treated patients with detectable viremia.

METHODS: The chemokine receptor tropism of plasma viral isolates was determined by the HIV Entry Assay and compared between untreated and ART-treated, chronically infected patients sampled from 2 San Francisco cohorts. Differences between groups were adjusted for CCR5 Δ32 genotype, nadir CD4+ T cell count, and duration of HIV infection. The association between tropism and naïve (CD45RA⁺CD62L⁺), activated (HLA-DR⁺CD38⁺), and non-activated memory CD4 counts was also assessed.

RESULTS: Both the 81 untreated patients and the 186 treated patients were similar as to median CD4 counts (258 vs 294 cells/mm³) and years since initial HIV diagnosis (13 vs 12 years), but untreated patients had lower median plasma HIV RNA levels (3.6 vs 4.0 log₁₀ copies/mL) and nadir CD4 counts (60 vs 203 cells/mm³). The treated patients had a median of 4 nucleoside reverse transcriptase inhibitor (NRTI)-associated and 2 major protease inhibitor (PI)-associated mutations. Of 186 treated patients, 75 (40%) harbored dual/mixed or X4-tropic viruses compared with only 12 of 81 (15%) untreated participants, p <0.001. Among all participants, dual/mixed or X4 tropism was more common in those with lower current and nadir CD4 counts (p <0.001 for both comparisons) and in those heterozygous for the CCR5 Δ32 polymorphism (p = 0.02). Even after adjustment for nadir CD4 count, duration of HIV infection, and CCR5 Δ32 genotype, treated patients had 4-fold greater odds of dual/mixed or X4 tropism than untreated patients, p = 0.004. Patients harboring dual/mixed or X4-tropic viruses had lower naïve (p = 0.05) and resting memory CD4 counts (p = 0.02) than those harboring R5-tropic viruses, but similar activated CD4 counts (p = 0.27). Furthermore, after adjustment for plasma HIV RNA levels, treated patients harboring dual/mixed or X4 tropic viruses were maintaining 78 fewer CD4⁺ T cells/mm³ above their pre-treatment nadir than those harboring R5-tropic viruses (p = 0.002).

CONCLUSIONS: Treated patients with partial viral suppression are more likely than untreated patients to harbor dual/mixed or X4-tropic viruses, independent of the extent of current or prior immunodeficiency. Dual/mixed or X4 tropism is also associated with fewer treatment-mediated CD4+ T cell gains, perhaps due to a greater ability to deplete resting memory and naïve CD4 cells.

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2006-02-05
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