Strong human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte activity in Sydney Blood Bank Cohort patients infected with nef-defective HIV type 1

Abstract

Proposals for the use of live attenuated human immunodeficiency virus (HIV) type 1 (HIV-1) as a vaccine candidate in humans have been based on the protection afforded by attenuated simian immunodeficiency virus in the macaque model. Although it is not yet known if this strategy could succeed in humans, a study of the Sydney Blood Bank Cohort (SBBC), infected with an attenuated HIV-1 quasispecies with natural nef and nef/long terminal repeat deletions for up to 17 years, could provide insights into the long-term immunological consequences of living with an attenuated HIV-1 infection. In this study, HIV-specific cytoxic T-lymphocyte (CTL) responses in an SBBC donor and six recipients were examined over a 3-year period with enzyme-linked immunospot, tetrameric complex binding, direct CTL lysis, and CTL precursor level techniques. Strong HIV-specific CTL responses were detected in four of seven patients, including one patient with an undetectable viral load. Two of seven patients had weak CTL responses, and in one recipient, no HIV-specific CTLs were detected. High levels of circulating effector and memory HIV-specific CTLs can be maintained for prolonged periods in these patients despite very low viral loads.

FIG. 1

Analysis of direct CTL activity and CTLp levels, T-cell counts, and viral load measurements from the SBBC members with detectable plasma viremia: D36, C18, C54, and C98. (A to D) Responses to env, gag, pol, and nef determinants are shown. Peptide determinants in panels A and B are listed in Table 2. Direct CTL activity was measured by a peptide-induced ELISPOT assay (IFN-γ-releasing cells/10⁶ PBMC) (A), a tetramer-binding assay (percent CD8⁺ T cells) (B), and direct lysis of recombinant vaccinia virus-infected BLCL (effector/target cell ratio, 50:1) (C). CTLp levels were measured against recombinant vaccinia virus-infected BLCL (D). (E and F) CD4 and CD8 counts (cells per microliter) (E) and plasma RNA viral load measurements (PCR) (F) determined during the study period. ND, tests not done.

FIG. 2

Direct CTL and CTLp levels measured in the SBBC recipients with a plasma viral load consistently below detection (<200 copies/ml): C49, C64, and C135. See the legend to Fig. 1 for details.