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Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell lymphoma/leukemia (ATL). The HTLV-1 envelope gene exhibits limited variability when examined from infected individuals, but has not been tested using infectious clones of the virus in animal models. In vitro assays indicate that HTLV-1 envelope (Env) Ser75Ile, Asn95Asp, and Asn195Asp surface unit (SU) mutants are able to replicate in and immortalize lymphocytes. Herein, we examined the effects of these Env mutants in rabbits inoculated with HTLV-1 immortalized ACH.75, ACH.95, or ACH.195 cell lines (expressing full-length molecular clones with the SU mutations) or the ACH.1 cell line (expressing wild-type SU). All rabbits became infected, and the fidelity of the mutations was maintained throughout the 8-week study. However , SU point mutations resulted in decreased antibody responses to viral group-associated antigen (Gag) and Env antigens. ACH.195 rabbits had a selective decreased antibody response to SU, and one ACH.195 rabbit had an antibody response to both HTLV-1 and HTLV-2 SUs. Some mutant inoculation groups had altered proviral loads. However, peripheral-blood mononuclear cell (PBMC) proviral loads did not correlate with antibody responses. Our data are the first to demonstrate that mutations in critical determinants of HTLV-1 Env SU altered antibody responses and proviral loads, but do not prevent viral replication in vivo. (Blood. 2005;106:3602-3608) Introduction Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus etiologically linked with adult T-cell leukemia/lym-phoma (ATL), HTLV-1-associated myelopathy/tropical spastic paresis (HAM/TSP), and a variety of other immune-mediated disorders. 1 ATL is an aggressive T-cell leukemia that typically manifests in middle-aged to elderly patients who were originally infected with the virus neonatally during breastfeeding. 2 There are 4 clinically overlapping subsets of ATL. In order of decreasing prognostic survival time, these include smoldering, chronic, lym-phoma, and acute. 3 The most severe form is the acute form, which manifests as an aggressive T-cell leukemia with concomitant hypercalcemia, bone marrow involvement, generalized lymphad-enopathy, skin lesions, and spleen and liver involvement. 4 Circulating leukemic cells in patients with ATL have a characteristic lobulated nuclear morphology and are most often CD2 , CD3 , CD4 , and CD8 T cells. 1 HTLV-1 envelope protein (Env) is unique among retroviral envelope proteins in that when isolates from ATL or HAM/TSP patients are compared, there is a high degree of sequence conservation in the env region, with variability ranging from 1% to at most 8%. 5-10 HTLV-1 Env is a 488-amino-acid protein. It is synthesized as a polyprotein precursor (gp62), which is subsequently glycosy-lated and cleaved into 2 proteins, surface unit gp46 (SU) and transmembrane gp21 (TM). 11,12 SU is required for entry into the target cell by mediating specific attachment to a cellular receptor, which was recently reported to be the glucose...