Anti-human immunodefi ciency virus-1 (HIV-1) polyamide (peptide) nucleic acids (PNAs) conjugated with cellpenetrating peptides (CPPs) targeted to the viral genome are potent virucidal and antiviral agents. Earlier, we have shown that the anti-HIV-1 PNATAR-penetratin conjugate is rapidly taken up by cells and is nontoxic to mice when administered at repeat doses of as high as 100 mg/kg body weight. In the present studies we demonstrate that naked PNATAR is immunologically inert as judged by the proliferation responses of splenocytes and lymph node cells from PNATAR-immunized mice challenged with the immunizing antigen. In contrast, PNATARpenetratin conjugate is moderately immunogenic mainly due to its penetratin peptide component. Cytokine secretion profi les of the lymph node cells from the conjugate-immunized mice showed marginally elevated levels of proinfl ammatory cytokines, which are known to promote proliferation of T lymphocytes. Since the candidate compound, PNATAR-penetratin conjugate displays potent virucidal and antiviral activities against HIV-1, the favorable immunological response together with negligible toxicity suggest a strong therapeutic potential for this class of compounds.