Adaptation of a CXCR4-using human immunodeficiency type 1 NDK virus in intestinal cells is associated with CD4-independent replication.

Infection of epithelial colon carcinoma cell line HT29 with human immunodeficiency virus type 1 (HIV-1) NDK, a subtype D virus highly cytopathic for CD4-positive lymphocytes, results in the selection of HIV-1 variants, 1000 times more infectious for CD4(-) intestinal cells than the parental virus. Here, we demonstrate that the envelope gene of intestinal cell-adapted virus conferred to recombinant clone HIV-1 iNDK the ability to utilize CXCR4 without CD4 while retaining its tropism for CD4 lymphocytes. Among the major genetic changes required for infection of intestinal cells and CD4 independence, two potential N-glycosylation sites appeared as a result of the extension of five amino acids in the V1/V2 region and three amino acid changes ((296)KYT --> (296)NNI) were identified in the V3 loop of HIV-1 iNDK gp120. Our studies suggest that CD4-independent use of CXCR4 can be mediated by different adaptive changes related to the microenvironment of CD4(-) cell.