CXCR4-tropic Viruses Are Common among Antiretroviral Treated Patients with Detectable Viremia and Associated with Lower Treatment-mediated CD4 Gains
Peter Hunt*1, J Martin1, M Bates2, W Huang2, S Spudich1, R Price1, D Williamson3, E Sinclair3, R Hoh1, and S Deeks1
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
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
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 d32 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 d32 polymorphism (p = 0.02). Even after adjustment for
nadir CD4 count, duration of HIV infection, and CCR5 d32 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.