Evidence for rapid disappearance of initially expanded HIV-specific CD8⁺T cell clones during primary HIV infection

Abstract

Down-regulation of the initial burst of viremia during primary HIV infection is thought to be mediated predominantly by HIV-specific cytotoxic T lymphocytes, and the appearance of this response is associated with major perturbations of the T cell receptor repertoire. Changes in the T cell receptor repertoire of virus-specific cytotoxic T lymphocytes were analyzed in patients with primary infection to understand the failure of the cellular immune response to control viral spread and replication. This analysis demonstrated that a significant number of HIV-specific T cell clones involved in the primary immune response rapidly disappeared. The disappearance was not the result of mutations in the virus epitopes recognized by these clones. Evidence is provided that phenomena such as high-dose tolerance or clonal exhaustion might be involved in the disappearance of these monoclonally expanded HIV-specific cytotoxic T cell clones. These findings should provide insights into how HIV, and possibly other viruses, elude the host immune response during primary infection.

Direct Visualization of Cytokine-Producing Recall Antigen-Specific CD4 Memory T Cells in Healthy Individuals and HIV Patients

“…For example, the production of T cells is reduced in untreated patients, as is the life span of the T cells (30,31), yet, with antiviral treatment, the generation of precursor cells increased again and exceeded the normal rate, while the t 1/2 of T cells remained strongly reduced (32,33). After treatment, there is an initial increase in the numbers of memory T cells, and only later do frequencies of T cells with a naive phenotype return to approximately the normal range, at which time CD8 cell numbers fall (34,35). Moreover, the frequency of recall Ag-specific memory T cells in the blood may change if they are redistributed between the extralymphoid compartments and the recirculating pool, as has been postulated; additionally, depletion/exhaustion and regeneration may contribute to the overall T cell repertoire in ways that are still debated (36,37).…”

“…Most of these studies came to the conclusion that T cell reactivity declines with the progression of HIV infection, but they left open the questions of how T cell function correlates with virus load and whether this loss of function is a result of decreased frequencies or decreased cytokine output, i.e., whether it is a function of T cell exhaustion, the dilution of these cells by virus-specific CD8 cells, or their suppressed state. Although many of these changes seem to be reversible after HAART therapy (34,35), the extent to which specific immune reactivity is restored remains unclear. All 22 patients that we studied were undergoing this therapy, so it was important for us to establish how the reactivity of individual T cells to recall Ags in these patients compares with that of healthy individuals.…”

Antigen amount dictates CD8+T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

“…During highly replicative chronic viral infections such as HIV-1, hepatitis B or hepatitis C virus infection in humans, or lymphocytic choriomeningitis virus (LCMV) in mice, virus-specific CD8 + T cells initially expand and acquire effector functions early after infection but then gradually lose these functions [1][2][3][4][5][6][7][8] in a hier-archical manner: first the ability to produce IL-2 and to proliferate, then TNF-α secretion and last IFN-γ production become impaired [9][10][11][12]. This T-cell dysfunction, also termed CD8 + T-cell exhaustion, is well studied after infection of mice with a high dose of LCMV clone 13 or LCMV-Docile [13].…”

Maintenance of Large Numbers of Virus-Specific CD8+ T Cells in HIV-Infected Progressors and Long-Term Nonprogressors

“…PBMC were cryopreserved in RPMI 1640 media with 10% FBS and 7.5% DMSO at Ϫ140°C. Standard 51 Cr release assays were performed as previously described (27 51 Cr labeled, washed, and plated at 1 ϫ 10 4 cells per well into 96-well round-bottom tissue culture plates. Fresh or cryopreserved PBMC were used as effectors.…”