Human immunodeficiency virus type 1 fitness is a determining factor in viral rebound and set point in chronic infection

Abstract

Human immunodeficiency virus type 1 (HIV-1) isolates from 20 chronically infected patients who participated in a structured treatment interruption (STI) trial were studied to determine whether viral fitness influences reestablishment of viremia. Viruses derived from individuals who spontaneously controlled viremia had significantly lower in vitro replication capacities than viruses derived from individuals that did not control viremia after interruption of antiretroviral therapy (ART), and replication capacities correlated with pre-ART and post-STI viral set points. Of note, no clinically relevant improvement of viral loads upon STI occurred. Virus isolates from controlling and noncontrolling patients were indistinguishable in terms of coreceptor usage, genetic subtype, and sensitivity to neutralizing antibodies. In contrast, viruses from controlling patients exhibited increased sensitivity to inhibition by chemokines. Sensitivity to inhibition by RANTES correlated strongly with slower replication kinetics of the virus isolates, suggesting a marked dependency of these virus isolates on high coreceptor densities on the target cells. In summary, our data indicate that viral fitness is a driving factor in determining the magnitude of viral rebound and viral set point in chronic HIV-1 infection, and thus fitness should be considered as a parameter influencing the outcome of therapeutic intervention in chronic infection.

FIG. 1.

In vitro replication kinetics of patient isolates. (a and b) Profile of p24 antigen production in cultures of CD8-depleted PBMCs infected with isolates derived during the fifth cycle from patients in the noncontrolling group (a) and the controlling group (b). (c) In vitro replication capacities. Slopes of viral antigen production between days 0 and 6 [slope (d0-6)] were calculated by performing linear regression analysis using the natural logarithm of p24 antigen values obtained on days 0, 4, and 6 p.i. Slopes for viruses from controlling (triangles) and noncontrolling (squares) patients were compared using the Mann-Whitney test. Data are means of results from two independent experiments. (d) The extent of viral replication of first-cycle and fifth-cycle virus pairs from eight patients of the noncontrolling group and two patients of the controlling group on CD8-depleted PBMCs is depicted as p24 antigen production on days 4, 6, 10, and 14 p.i. Antigen production levels of first-cycle (closed circles) and fifth-cycle (open circles) virus pairs were compared using the Wilcoxon signed-rank test. n.s., not significant. Bars indicate means.

FIG. 2.

In vitro replication kinetics correlate with in vivo VLs. Results of the correlation analysis of in vitro replication capacities {slopes of viral antigen production between days 0 and 6 [slope (d0-6)]} and pre-ART VLs (a), post-STI VLs (b), levels of VL improvement (c), and cumulative levels of viral replication (AUC) during cycles 1 (d), 2 (e), 3 (f), and 4 (g) are shown. n.s., not significant.

FIG. 3.

Sensitivity to inhibition by chemokines. The 50, 70, and 90% inhibitory doses of RANTES (a) and MIP-1α (b) in CD8-depleted PBMC cultures are shown. Inhibitory doses for viruses from controlling (triangles) and noncontrolling (squares) patients were compared using the Mann-Whitney test. Data are means of results from two independent experiments. Results of the correlation analysis of the 90% inhibitory doses (ID₉₀) of RANTES with in vitro replication capacities {slopes of viral antigen production between days 0 and 6 [slope (d0-6)]} (c), pre-ART VLs (d), and post-STI VLs (e) are displayed. n.s., not significant. Bars indicate means.

FIG. 4.

Sensitivity to inhibition by neutralizing antibodies and CD4-IgG₂. The 90% inhibitory doses for the neutralizing anti-gp41 MAb 2F5, the anti-gp120 MAbs 2G12 and IgG₁b12, and the tetrameric CD4 molecule, CD4-IgG₂, are shown. Inhibitory doses for viruses from controlling (triangles) and noncontrolling (squares) patients were compared using the Mann-Whitney test. Data are means of results from two to four independent experiments. n.s., not significant. Bars indicate means.