Background: Intermittent Interleukin-2 (IL-2) administration plus Antiretroviral Therapy (ART) stably restores the numbers of circulating CD4⁺ T-lymphocytes and improves immune function in most infected individuals. However, the impact of this therapeutic regimen on the evolution of HIV chemokine co-receptor usage is unknown.

Methods: Sixty-one (61) HIV individuals with 200–500 CD4⁺ T-cell/µl were enrolled in a controlled study of three regimens of IL-2 plus ART vs ART alone (3:1 ratio). Standard HIV isolation from both plasma and PBMC was performed at study entry and at 6 and 12 months (mos) (end of the trial). Viral phenotype (SI/NSI on MT-2 cells) and chemokine co-receptor usage on U87 cells co-expressing CD4 and CCR1 or CCR2b or CCR3 or CCR5 or CXCR4 were defined.

Results: A sustained significant increase in circulating CD4⁺ T-lymphocytes was observed in patients receiving ART+IL-2 vs those receiving ART alone. The frequency of HIV isolation from PBMC was not affected by IL-2 administration (about 60% in both groups). A total of 25 (21 CCR-5 dependent, R5, and 4 SI HIVs) and 7 primary (R5) isolates were obtained from PBMC at entry in the pooled ART+IL-2 and ART alone treated individuals; very limited numbers of isolates from plasma were obtained in both treatment groups. Of interest, only 1/21 individuals receiving ART+IL-2 and harboring an R5 virus at entry showed an evolution of the HIV co-receptor usage after 6 and 12 mos to an R5X4 phenotype, whereas this pattern occurred in 3/7 isolates from individuals treated with ART alone. In addition, individuals tested negative for PBMC HIV isolation showed a superior response to IL-2+ART in terms of net increase of CD4⁺ T-cell counts, a phenomenon not observed in ART alone treated people. Negative PBMC HIV isolation, adjusted for viremia levels, was an independent predictor of CD4⁺ T-cell response to IL-2+ART.

Conclusions: Intermittent IL-2 therapy may directly or indirectly interfere with the potential evolution of HIV from NSI/R5 to more pathogenic SI/CXCR4-using viruses. The observation that individuals negative for PBMC HIV isolation better respond to IL-2+ART in terms of net gain in CD4⁺ T-cells is a potential correlate of a more robust immune-mediated control of viral replication in vivo.