Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire.

Abstract

SummaryHuman immunodeficiency virus 1 (HW-1) infection is associated with a vigorous cellular immune response that allows detection of cytotoxic T lymphocyte (CTL) activity using fleshly isolated peripheral blood mononudear cells (PBMC). Although restricting class I antigens and epitopes recognized by HIV-l-specific CTL have been defined, the effector cells mediating this vigorous response have been characterized less well. Specifically, no studies have addressed the breadth and duration of response to a defined epitope. In the present study, a longitudinal analysis of T cell receptor (TCK) gene usage by CTL clones was performed in a seropositive person using TCR gene sequences as a means of tracking responses to a well-defined epitope in the glycoprotein 41 transmembrane protein. 10 CTL clones specific for this human histocompatibility leukocyte antigen-B14-restricted epitope were isolated at multiple time points over a 31-mo period. All clones were derived from a single asymptomatic HIV-l-infected individual with a vigorous response to this epitope that was detectable using unstimulated PBMC. Polymerase chain reaction amplification using Vol and Vfl family-specific primers was performed on each done, followed by DNA sequencing of the V-D-J regions. All 10 clones utilized Vo114 and VB4 genes. Sequence analysis of the TCK revealed the first nine clones isolated to also be identical at the nudeotide level. The TCK-o~junctional region sequence of the tenth done was identical to the junctional region sequences of the other nine, but this clone utilized distinct DB and JB gene segments. This study provides evidence that the observed high degree of HIV-l-specific CTL activity may be due to monodonal or oligoclonal expansion of specific effector cells, and that progeny of a particular CTL clone may persist for prolonged periods in vivo in the presence of a chronic productive viral infection. The observed limited TCR diversity against an immunodominant epitope may limit recognition of virus variants with mutations in regions interacting with the TCR, thereby facilitating immune escape.

Characterization of antigen‐specific repertoire diversity following in vitro restimulation by a recombinant adenovirus expressing human cytomegalovirus pp65

“…This is the case of the IE-1 protein; polymorphic regions in the coding sequence of this viral protein have been described [24][25][26], and the TCR repertoire of IE-1-specific T cell clones has been found to be highly heterogeneous [27]. Overall, persistent infections associated with a low antigen load leading to a narrowing of the virus-specific memory T cell repertoire have been described in humans infected with CMV, EBV or HIV [19,[28][29][30]. This restricted repertoire may well be due to continued selection and amplification of high affinity T cell clones, but the possibility that other clones undergo clonal exhaustion cannot be ruled out by this study [18].…”

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

“…73 Nonetheless, strong, narrowly focused CTL responses do occur occasionally in these patients, 20 and in this setting viral escape mutations can occur. 74 Vigorous oligoclonal expansions of T cells have been described in other persistent viral infections, especially HIV 75 and Epstein-Barr virus. 76 Even in these infections, however, viral mutations that affect recognition of an epitope by some CTL clones do not automatically affect all CTL clones specific for the same epitope, because different T cell clones can bind different residues in the same epitope.…”

“…75,76 The incredibly high rate of HIV production and the exceptionally high mutation rate of this virus may cause so many different viruses to be generated each day that they exceed the capacity of the immune system to respond effectively simply on a numerical basis. 78 In this regard, the ostensibly vigorous immune response HIV appears to be unable to compete with the capacity of the virus to generate mutants.…”

T cell receptor (TCR) BV gene repertoires and clonal expansions of CD4 cells in patients with HIV infections

“…Kalams et al [6] reported that single-donor cytotoxic T lymphocyte (CTL) clones recognizing a well defined epitope (pp 584-592) in the glycoprotein 41 membrane protein (gp41) exhibited restricted, and temporally stable, usage of TCR (AV14 and BV4 genes). Moreover, a limited heterogeneity among TCRBV of SIV gagspecific CTL has been reported [39] and expansions of specific TCRBVs (TCRBV7 and TCRBV14) were observed in acutely infected monkeys [40].…”

“…Depending on the complexity and stability of epitopes, which may oscillate from a single immunodominant to multiple subdominant determinants [1], restricted or diverse sets of T cell clones might be engaged, respectively. Immunodominance associated with biased T cell receptor b-chain gene (TCRBV) repertoires has been identified for several conventional antigens [2,3], and more recently reported among blood and tissue lymphocytes of AIDS patients [4,5] and with in vitro exposure to HIV components [6].…”